Jeremy Srouji
email: jeremy.srouji@univ-cotedazur.fr

Digital Payments, the Cashless Economy, and Financial Inclusion in the United Arab Emirates: Why Is Everyone Still Transacting in Cash?

Keywords: digital payments, cashless economy, financial inclusion, complementary currencies, inequality, non-cash transactions, Gulf Cooperation Council, oil economies, remittances

Since the oil price downturn of 2015, the United Arab Emirates and fellow Gulf Cooperation Council countries have worked hard to expand digital payments in the interest of improved tax and revenue collection, transparency, and security. Yet despite a deep transformation and diversification of their payment eco-systems and the formalization of plans to become "cashless economies" modelled on South Korea and Sweden, cash continues to dominate payments in both countries. While industry players typically attribute the prevalence of cash in the region to questions of infrastructure readiness, transaction costs, and cyber-security, this paper finds that plans to expand digital payments at the expense of cash may not be well-adapted to countries with high levels of socio-economic inequality. It proposes a link between socio-economic inequality and use of cash in emerging economies, and concludes that it may be better to not view the relationship between cash and digital payments in binary zero-sum terms, until there is a better understanding of the socio-economic, technological, and policy context in which countries like South Korea and Sweden have managed to reduce their reliance on cash in favor of a diversified digital payments eco-system.

Introduction

Following the oil price downturn of 2015 and its wide-ranging economic repercussions, the United Arab Emirates and fellow Gulf Cooperation Council (GCC) countries have worked hard to expand digital payments in the interest of improved tax and revenue collection, as well as the greater transparency and security associated with moving away from cash. Regulatory reforms have resulted in a deep transformation and diversification of the payment landscape, with a widespread consensus among monetary authorities and financial institutions about the benefits of a cashless economy for businesses and individuals in terms of efficiency gains and ease of payments. The UAE's national payments strategy seeks a gradual transition to a cashless economy, while in Saudi Arabia the central bank has set out to achieve 70 percent cashless payments by 2030. The two countries have also unveiled plans to launch a central bank digital currency called "Aber" backed by distributed ledger technologies, to be trialed initially for cross-border payments by a small pool of participating banks, and expanded for wider use. Yet despite a concerted effort by monetary authorities, banks, and the payments industry to replace cash with digital payments, cash continues to dominate payments in the GCC. The objective of this paper is to explore the reasons as to why cash is so persistent in the GCC states, and whether the adoption of a digital payments eco-system modelled on South Korea and Sweden is appropriate for these countries in light of their relatively large unbanked populations and the continued importance of cash-based remittances.

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Background Literature

Economists have long seen the reduction in the use of cash and the transition to digital payment methods as part of the natural evolution of monetary and payment systems [START_REF] Trautwein | The Uses of the Pure Credit Economy[END_REF]. Much of the literature related to the cashless or the "pure credit" economy has focused on the implications of the elimination of cash for interest rates, prices, and output. Woodford, for example, has demonstrated how in a cashless economy central banks can manage price levels through control over nominal interest rates, enabling markets to operate normally [START_REF] Walsh | Interest & Prices, Foundations of a Theory of Monetary Policy[END_REF]. More recently, [START_REF] Rogoff | The Curse of Cash[END_REF] has argued that policies aimed at reducing cash or at least eliminating large notes can contribute to reining in the shadow economy, illicit trade, and tax evasion. He notes that the shadow economy in the United States accounts for between 7 to 10 percent of GDP, resulting in a significant loss of tax revenue to the US government, and is facilitated by the anonymity associated with cash transactions, compared to more traceable digital payment methods [START_REF] Rogoff | Costs and Benefits to Phasing Out Paper Currency[END_REF].

Despite a wide consensus around the potential benefits of a cashless economy, the concept has not been without its detractors. [START_REF] Cohen | Towards a Cashless Economy: Economic and Socio-Political Implications[END_REF] demonstrate that cash plays an essential role in intermediating transactions between the formal and informal sectors, and that its elimination can disrupt the ability to trade between these sectors, leading to a misallocation of productive efforts across an economy. The authors also bring to light other potentially unexpected negative consequences, such as the greater lengths actors in the shadow economy will go to launder money into the official sector in the absence of cash. [START_REF] Lagos | On Money as a Medium of Exchange in Near-Cashless Credit Economies[END_REF], for their part, have shown the existence of a "cashless limit" in a pure credit economy, arguing that even if money is not frequently used, the fact that it is available as an alternative to credit has important implications for aggregate consumption, investment, and output.

Most studies have addressed the topic from a theoretical perspective or from the context of advanced economies. Much less work has been done on the desirability of eliminating cash in favor of digital payments in emerging economies, and on the relationship between cash and digital payments in countries with high levels of socio-economic inequality. India's, albeit dramatic, experience with demonetization in late 2016, when the government withdrew large denomination notes with the intention of enhancing tax collection and shrinking the informal economy, has served to shed some light on this issue. [START_REF] Bajaj | Consumer Payment Choice and the Heterogenous Impact of India's Demonetization[END_REF] found that in the period following demonetization, aggregate household output declined by 20 percent, and aggregate welfare by 16 percent, with the consequences unevenly distributed between urban and rural households. The authors also described how switching to digital payments involved an entry cost which was unaffordable to the lower income deciles, whose welfare was more adversely affected than their wealthier counterparts. [START_REF] Karmakar | Do Households Care about Cash? Exploring the Heterogeneous Effects of India's Demonetization[END_REF], for their part, found that households with no bank accounts experienced significant declines in both income and spending in the month following demonetization, with many resorting to informal borrowing to meet immediate needs.

The Transformation of the Payments Eco-System in the UAE

The deep transformation of the payments landscape in the UAE, and initiatives to eliminate cash and trial a digital currency, are not surprising. The region counts among the wealthiest and most advanced countries in the world, with Saudi Arabia and the UAE ranked in the Global Competitiveness Index as world leaders in terms of macro-economic stability, while the UAE ranks second in the world for ICT adoption, behind only South Korea, and 15th in terms of the quality of its institutions, ahead of Australia, Germany, Japan, and the United States, reflective of its unmatched infrastructure and the great strides it has made in e-government services. In early 2017, the UAE central bank launched new electronic payment regulations, permitting peer-to-peer and retail players to participate in the country's payments eco-system alongside banks. The following year, the central bank announced a national payments strategy, which in addition to strengthening the security and efficiency of payments, and bringing down transaction costs, set the objective of gradually transitioning to a cashless economy. The e-dirham-a reloadable prepaid card required to pay for government services-initially launched in 2001 with moderate success, is also subject to a major revamp in collaboration with 22 of the country's banks. In parallel with the UAE, the Saudi central bank announced the objective of achieving 70 percent cashless payments across the kingdom over the next decade, as part of the financial sector reform plans integrated within Saudi Vision 2030. These policies crystallized cashless economy objectives that have been under discussion since at least 2012.

In the UAE, the new regulations encouraged the entry into the country's payments eco-system of a new class of payment gateways and processors, with a somewhat baffling mix of international players setting up shop alongside home-grown initiatives, the fruit of local start-up and FinTech hubs. For e-commerce-here taken to mean payments transacted on the internet via mobile, smartphone, or tablet-there are at least 15 players. This includes major international groups like Amazon's Payfort, Telr, jointly launched in the UAE and Singapore, India's CCAvenue, as well as local entities like PayBy, Foloosi, and Bahrain's PayTabs. Some local players had moved beyond online payments and were rolling out point-of-sale devices for in-store payments, competing in an area traditionally controlled by banks. Noon, one of the region's largest online retailers, launched its own payment gateway in 2020, arming itself with a captive business. With 1.4 million Chinese tourists visiting the region in 2018, China's QFPay also entered the market through a local joint venture, enabling Chinese visitors to transact QR-code based payments with Alipay and WeChat Pay at shops and restaurants [START_REF] Visele | Chinese Visitors to GCC will Increase 54% by 2023[END_REF]). On the eWallet side, Beam, an early mover that first launched in the UAE in 2012, with an attractive points and rewards scheme, soon found itself in competition with "the Pays"-Apple, Samsung, and Google Pay. Not to be outdone, 16 UAE banks joined forces to launch the Emirates Digital Wallet KLIP, which sets out specifically to eliminate cash from the economy, while in Dubai the reloadable NOL transport card used for the metro was expanded to enable payments in taxis and at corner shops. It is in fact hard to keep up with eWallet and prepaid card schemes in the UAE-particularly stand-alone initiatives set up by telcos, retailers, or individual banks-with many failing to gain any traction despite otherwise high-profile launches.

UAE payment industry and FinTech players frequently take South Korea and Sweden as models to replicate in terms of achieving a cashless future. Yet in a world where few countries have succeeded in reducing cash in favor of digital payments, it is interesting to consider what specific attributes these countries share that have made them amenable to a cashless eco-system and whether they can serve as appropriate benchmarks for the GCC states. Notable attributes of these countries are high levels of literacy, moderate levels of income inequality, and almost universal access to smartphones and mobile data. Additionally, close to one hundred percent of the adult population in South Korea and Sweden are banked. This is very different from the situation in the GCC, where a substantial part of the population consists of migrant laborers and blue-collar workers, excluded from the formal banking system.

In the UAE, 32 percent of the working population, 1.7 million individuals, is unbanked, earning less than USD 679 per month, as set out in Table 1. The additional 19 percent of workers between the USD 680 to USD 1359 band are partially unbanked, as the minimum usually required for opening a bank account is USD 1360. This means that at reasonable estimates, 35 percent of the working population, some 1.9 million individuals, are unbanked, out of a total active labor force of 5.5 million in 2018. These are reliant on money exchanges, and formal and informal networks to receive their wages and remit home savings. Additionally, while some of the unbanked may be able to afford smartphones, it is uncertain whether this segment could easily pay for a monthly mobile data plan to transact mobile payments, once rent, food, transport, and remittances are factored in. With UAE nationals comprising 11 percent of the total population of 9.6 million and concentrated in the upper income tiers with strong social safety nets, the unbanked segment is also overwhelmingly comprised of foreign workers. These socio-economic inequalities are also captured in the Human Development Index, where the percentage of unskilled labor is 41 and 47 percent for Saudi Arabia and the UAE, respectively, placing them closer to developing and emerging economies for this indicator than the high-income group to which they belong. Despite the large unbanked population, the banking sector and payments industry has maintained a positive outlook with regards to the future of digital payments in the region. In 2018, Mastercard attributed the unprecedented growth of mobile payments in the UAE to the country's large youth demographic and a mobile penetration rate of 173 percent, described as the "highest in the world" (Mastercard 2018). In reality, the figure is misleading as while mobile ownership is certainly high, smartphone adoption probably does not exceed 73 percent [START_REF] Finastra | The Future History of Payments: How the world is moving away from cash[END_REF]), an indicator difficult to measure given the UAE's wealthy frequently own multiple smartphones. Boston Consulting Group, for its part, estimated that achieving a cashless economy in the GCC would provide "at least a 1% boost to non-oil GDP, equating to nearly $3 billion" and that it was important for monetary authorities to continue addressing barriers to cashless uptake, such as high transaction costs, and cybersecurity and infrastructure readiness (BCG 2019; [START_REF] Khan | How Cashless Payments Help Economies Grow[END_REF]. In parallel, the consensus at the Success 2020 Arabian Business Forum held in Dubai in October 2019 was that the "UAE is moving ever closer to becoming a cashless society", with Visa's representative for the UAE explaining that it was important to encourage "smaller retailers and businesses on to the cashless economy" [START_REF] Halligan | UAE very close to becoming a cashless society[END_REF]. Equally, the region's press is awash with reports of the "e-payments revolution", the "cashless society", and the "end of cash".

In practice, one cannot blame banks or the payments industry for generating hype around digital payments. The payments business, whether online or in-person at points-of-sale, is lucrative. In the UAE, and mirrored around the world, merchant service fees per transaction, hidden to the buyer, range from around one percent for in-person transactions, to up to 3.0 percent for online payments. These commissions are shared between the acquiring bank, the card association (i.e., Mastercard, Visa), and the payment gateway. It is more of a volume than a value business, which is why the industry has long been more focused on the volume than on the value of transactions, as large payments are less frequent, and are as likely to be made by bank transfer or cheque. From this perspective, the two most promising regions for the growth of digital payments are the emerging markets of East Asia, the Middle East and Africa, as set out in Figure 1. In the latter, non-cash transactions are forecasted to grow by 23.1 percent between 2017 and 2022, to reach 139 billion transactions, which explains why the payments industry is so keen on the region, particularly when compared to more mature markets in North America and Europe. In the UAE, digital payment uptake has been strong across all sectors, including retail, transport, food delivery, and subscription services (i.e., music and video). Progress in peer-to-peer payments has been slower, partly because of the continued prominence of in-person paper-based know-your-customer (KYC) protocols to sign up for financial services, but regulations in this area are also catching up. How to explain therefore, considering the phenomenal rise of digital payments in the UAE since the oil price downturn, the continued dominance of cash as a percentage of overall payments? A Mastercard report in 2013 described the UAE as one of the countries "most rapidly moving away from being a predominantly cash-based society" (Mastercard 2013). At the time, cash transactions constituted 74 percent of customer payments by value at points-of-sale, as set out in Figure 2. In 2019, this had come down to 67 percent-a modest shift, particularly given the changes in technology, payment channels, and connectivity that have taken place in between, while the figure for Saudi Arabia was 64 percent (SAMA 2019). This is compared to 10 percent in Canada, 15 percent in Sweden, and 18 percent in South Korea; economies where one can confidently speak of an evolution away from cash payments (FIS 2020). Of course, the transition in these economies took place gradually, but it is interesting to note that in 2001, both Canada and Sweden were already less cash-reliant than their GCC peers, with cash accounting for around 30 and 55 percent of payments, respectively [START_REF] Engert | A Tale of Two Countries: Cash Demand in Canada and Sweden[END_REF]. While infrastructure readiness and transaction costs, particularly for smaller businesses, certainly have something to do with the continued preference for cash, one angle that has been less explored is the relationship between cash transactions and the unbanked population. One only needs to visit UAE exchange houses on payday in any given month to witness the queues of workers How to explain therefore, considering the phenomenal rise of digital payments in the UAE since the oil price downturn, the continued dominance of cash as a percentage of overall payments? A Mastercard report in 2013 described the UAE as one of the countries "most rapidly moving away from being a predominantly cash-based society" (Mastercard 2013). At the time, cash transactions constituted 74 percent of customer payments by value at points-of-sale, as set out in Figure 2. In 2019, this had come down to 67 percent-a modest shift, particularly given the changes in technology, payment channels, and connectivity that have taken place in between, while the figure for Saudi Arabia was 64 percent (SAMA 2019). This is compared to 10 percent in Canada, 15 percent in Sweden, and 18 percent in South Korea; economies where one can confidently speak of an evolution away from cash payments (FIS 2020). Of course, the transition in these economies took place gradually, but it is interesting to note that in 2001, both Canada and Sweden were already less cash-reliant than their GCC peers, with cash accounting for around 30 and 55 percent of payments, respectively [START_REF] Engert | A Tale of Two Countries: Cash Demand in Canada and Sweden[END_REF]. How to explain therefore, considering the phenomenal rise of digital payments in the UAE since the oil price downturn, the continued dominance of cash as a percentage of overall payments? A Mastercard report in 2013 described the UAE as one of the countries "most rapidly moving away from being a predominantly cash-based society" (Mastercard 2013). At the time, cash transactions constituted 74 percent of customer payments by value at points-of-sale, as set out in Figure 2. In 2019, this had come down to 67 percent-a modest shift, particularly given the changes in technology, payment channels, and connectivity that have taken place in between, while the figure for Saudi Arabia was 64 percent (SAMA 2019). This is compared to 10 percent in Canada, 15 percent in Sweden, and 18 percent in South Korea; economies where one can confidently speak of an evolution away from cash payments (FIS 2020). Of course, the transition in these economies took place gradually, but it is interesting to note that in 2001, both Canada and Sweden were already less cash-reliant than their GCC peers, with cash accounting for around 30 and 55 percent of payments, respectively [START_REF] Engert | A Tale of Two Countries: Cash Demand in Canada and Sweden[END_REF]. While infrastructure readiness and transaction costs, particularly for smaller businesses, certainly have something to do with the continued preference for cash, one angle that has been less explored is the relationship between cash transactions and the unbanked population. One only needs to visit UAE exchange houses on payday in any given month to witness the queues of workers While infrastructure readiness and transaction costs, particularly for smaller businesses, certainly have something to do with the continued preference for cash, one angle that has been less explored is the relationship between cash transactions and the unbanked population. One only needs to visit UAE exchange houses on payday in any given month to witness the queues of workers waiting to remit money home, often in the form of cash, sometimes via payroll cards on which wages are disbursed, to understand why cash remains important in GCC economies. UAE-based foreign workers remitted USD 45 billion to their home countries, mainly in East and South Asia in 2019-the equivalent of 11 percent of the UAE's GDP (UAE Central Bank 2019). This was just through formal channels. The World Bank estimates that an additional 35 to 75 percent of the total value of global remittances are delivered through informal channels [START_REF] Freund | Remittances: Transaction Costs, Determinants, and Informal Flows[END_REF]. In the Middle East, individuals send funds via the age-old hawala system, a trust-based network where cash is handed to a local agent, either a corner shop or a designated community member, whose counterpart in the home country disburses the funds to the intended recipient, against a small commission. While hawala operates outside of formal channels, it is essential for sustaining remittance corridors to locations where recipients have no easy access to exchange houses or banks. In the absence of digital money transfer technologies accessible to both senders and recipients along these corridors, it is difficult to imagine how this segment of the population can forgo cash.

This leads to the interesting question of whether a link can be established more generally between socio-economic inequality and reliance on cash. In Figure 3, the Gini coefficient for income inequality within countries is compared to the total value of payments transacted in cash for 37 emerging and advanced economies. What is apparent is that countries like Sweden and South Korea that have implemented solid digital payment eco-systems and substantially reduced cash are also among the least unequal societies in the world. In Saudi Arabia and South Africa, the latter one of the world's most unequal societies, cash continues to dominate payments, despite otherwise advanced infrastructure, booming industrial sectors, and high levels of integration into the global economy. While no Gini coefficient was available for the UAE, Saudi Arabia's position on the chart is a good approximation of the position of GCC states. What the chart suggests is that in countries with high levels of inequality, eliminating cash may be more challenging, especially where bank accounts and digital payments solutions are out-of-reach to poorer segments of society, or represent a high switching cost, as discussed by [START_REF] Bajaj | Consumer Payment Choice and the Heterogenous Impact of India's Demonetization[END_REF].

waiting to remit money home, often in the form of cash, sometimes via payroll cards on which wages are disbursed, to understand why cash remains important in GCC economies. UAE-based foreign workers remitted USD 45 billion to their home countries, mainly in East and South Asia in 2019-the equivalent of 11 percent of the UAE's GDP (UAE Central Bank 2019). This was just through formal channels. The World Bank estimates that an additional 35 to 75 percent of the total value of global remittances are delivered through informal channels [START_REF] Freund | Remittances: Transaction Costs, Determinants, and Informal Flows[END_REF]. In the Middle East, individuals send funds via the age-old hawala system, a trust-based network where cash is handed to a local agent, either a corner shop or a designated community member, whose counterpart in the home country disburses the funds to the intended recipient, against a small commission. While hawala operates outside of formal channels, it is essential for sustaining remittance corridors to locations where recipients have no easy access to exchange houses or banks. In the absence of digital money transfer technologies accessible to both senders and recipients along these corridors, it is difficult to imagine how this segment of the population can forgo cash.

This leads to the interesting question of whether a link can be established more generally between socio-economic inequality and reliance on cash. In Figure 3, the Gini coefficient for income inequality within countries is compared to the total value of payments transacted in cash for 37 emerging and advanced economies. What is apparent is that countries like Sweden and South Korea that have implemented solid digital payment eco-systems and substantially reduced cash are also among the least unequal societies in the world. In Saudi Arabia and South Africa, the latter one of the world's most unequal societies, cash continues to dominate payments, despite otherwise advanced infrastructure, booming industrial sectors, and high levels of integration into the global economy. While no Gini coefficient was available for the UAE, Saudi Arabia's position on the chart is a good approximation of the position of GCC states. What the chart suggests is that in countries with high levels of inequality, eliminating cash may be more challenging, especially where bank accounts and digital payments solutions are out-of-reach to poorer segments of society, or represent a high switching cost, as discussed by [START_REF] Bajaj | Consumer Payment Choice and the Heterogenous Impact of India's Demonetization[END_REF]. There is no doubt that in the UAE and the GCC more needs to be done to promote financial inclusion. A recent IMF report on the region found significant gaps in access to finance, particularly for women, youth, and small-and-medium enterprises (SMEs). The latter only received 4.5 percent of There is no doubt that in the UAE and the GCC more needs to be done to promote financial inclusion. A recent IMF report on the region found significant gaps in access to finance, particularly for women, youth, and small-and-medium enterprises (SMEs). The latter only received 4.5 percent of total bank loans, lower than the regional average for the Middle East and North Africa. The report also highlighted the continued importance of informal finance, echoing the findings related to remittances and the use of cash above, but this time in relation to loans, stating that "26 percent of adults in GCC reported having borrowed informally", compared to 13 percent in advanced economies, and that "GCC households rely on informal financing channels, where peer financing . . . remains the dominant source of financing, with bank loans being the residual" (Ben [START_REF] Ltaifa | Gulf Cooperation Council: How Developed and Inclusive are Financial Systems in the GCC? Washington: IMF[END_REF]. The situation for SMEs, which in the UAE account for an estimated 60 percent of non-oil GDP, has been particularly challenging since the oil-price downtown of 2015. This set off a wave of SME loan defaults equivalent to USD 1.4 billion, hitting the banking sector and drying up new loans, particularly trade finance, the main lubricant in oil economies where the retail sector is entirely reliant on imports [START_REF] Everington | UAE Economy Minister Unworried by 'Natural' Level of SME Loan Defaults[END_REF]. This as the region registered its largest ever current account deficit of USD 127 billion, equivalent to 9.1 percent of combined GDP, putting immense pressure on the maintenance of the US dollar anchor [START_REF] Iradian | GCC: Dollar Pegs Will Be Maintained[END_REF]. In fact, much of the drive by monetary authorities to expand digital payments can be traced to the oil-price downturn of 2015 and the subsequent implementation of a value-added tax regime in all six GCC states, as governments cut spending and scrambled to make up for lost revenue. This from the perspective that digital payments leave a clearer accounting trail and result in better tax collection.

Another reason for the prevalence of cash payments is that in countries with high socio-economic inequality, financial literacy tends to be low. In both Saudi Arabia and the UAE, efforts are nonetheless being made to increase participation in the formal banking system. Saudi Arabia's Financial Sector Development Program has sought to enhance financial planning skills for youth and women and increase access to digital financial services for the unbanked. These efforts seem to have yielded positive results, with 69 percent of adults having bank accounts in 2017, compared to 51 percent in 2011. In the UAE, financial literacy initiatives seem to be more focused on middle-and upper-income earners to improve individual financial planning, while one FinTech, NOW Money, has launched a mobile banking and remittance solution for low-income workers [START_REF] Buller | NOW Money Offers Banking Alternatives for MENA's Unbanked[END_REF]). On the SME front, the Emirates Development Bank in 2019 launched a USD 27 million credit guarantee to improve access to finance for small businesses.

The Relationship between Cash and Digital Payments in Emerging Economies

The broader point related to the cashless economy, both in the economics literature as well as in payment industry circles, is that the choice between cash and digital payments is often presented as a binary one. This supposes a linear evolution from cash to digital payments, where a rise in digital payments should result in a decline in the use of cash. It is a view that intuitively makes sense and is often repeated in GCC banking and payment industry circles. Reality, however, appears to be more nuanced, with empirical data showing that for most emerging and advanced economies, both digital payments and cash-in-circulation are on the rise. Figure 4 looks at currency-in-circulation as a percentage of GDP for nine major developed and emerging economies, showing declines only in Russia and Sweden since 2007. In the seven other markets, including Saudi Arabia and the UAE, currency-in-circulation-that is, cash outside of banks and deposit-taking institutions-has increased. Some interesting work has been done to explain this counter-intuitive phenomenon, even if it is not yet fully understood. Ashworth and Goodhart (2020), analyzing the Eurozone, Japan, the United Kingdom, and the United States, demonstrate remarkably that cash-in-circulation has been consistently on the increase in these markets since the 1990s. Recent increases could be correlated to the low interest rates that have prevailed since the global financial crisis, as well as the rise of the shadow economy and informal work. A BIS study focused on 20 emerging and advanced economies for the period 2000 to 2016 found that cash-in-circulation had increased from 7 to 9 percent of GDP during the period [START_REF] Bech | Payments are a-Changin' but Cash Still Rules[END_REF]. The report reached similar conclusions with regard to low interest rates, as individuals had less incentive to hold money in savings accounts. The authors also found that currency holdings related particularly to higher denomination notes, leading them to speculate that money was likely being held more with a store-of-value purpose in mind than as a means of payment.

Less is known about the reasons underlying the increase in cash-in-circulation in emerging economies or those with large unbanked populations. Anecdotal evidence suggests that the adoption of mobile money and e-wallets as alternatives to bank accounts has resulted in an expansion of the cash-based economy. More than 60 percent of mobile money transactions globally are based on the cash-in-cash-out model, where individuals utilize licensed agents to either top-up or receive cash held in mobile wallets, enabling them to disburse salaries or transact peer-to-peer payments across large distances [START_REF] Naghavi | State of the Industry Report on Mobile Money[END_REF]. Additionally, this is not just for within-country transfers. A significant proportion of remittances between France and major west African economies like Côte d'Ivoire, Mali, and Senegal are transacted via Orange Money, one of the most widely used mobile money applications in French-speaking Africa.

Similarly, in South Africa, the country's leading economics advisory firm, Genesis Analytics, found in 2018 that a rise in non-performing micro-loans had resulted in a return to mobile money, prepaid cards and cash, and an avoidance of bank accounts, where positive balances can automatically be debited to settle outstanding debts. To match the services offered by mobile money, South African banks also enabled their customers to make instant cash transfers to anyone in the country with access to an ATM terminal, with no need for the recipient to hold an account at the bank (Ketley 2018); another example of digital technologies expanding cash-in-circulation. What these trends reveal is that for many emerging markets, the relationship between cash and digital payments may not be a zero-sum game. Rather, the cash-based and the digital economy appear to reinforce each other, with digital technologies boosting cash-in-circulation, and cash-in-circulation in turn sustaining the digital payments eco-system. While further study is required to better understand these trends in emerging markets, what they suggest is that policies seeking to eliminate cash prematurely may result in more harm than good. Ashworth and Goodhart (2020), analyzing the Eurozone, Japan, the United Kingdom, and the United States, demonstrate remarkably that cash-in-circulation has been consistently on the increase in these markets since the 1990s. Recent increases could be correlated to the low interest rates that have prevailed since the global financial crisis, as well as the rise of the shadow economy and informal work. A BIS study focused on 20 emerging and advanced economies for the period 2000 to 2016 found that cash-in-circulation had increased from 7 to 9 percent of GDP during the period [START_REF] Bech | Payments are a-Changin' but Cash Still Rules[END_REF]). The report reached similar conclusions with regard to low interest rates, as individuals had less incentive to hold money in savings accounts. The authors also found that currency holdings related particularly to higher denomination notes, leading them to speculate that money was likely being held more with a store-of-value purpose in mind than as a means of payment.

Less is known about the reasons underlying the increase in cash-in-circulation in emerging economies or those with large unbanked populations. Anecdotal evidence suggests that the adoption of mobile money and e-wallets as alternatives to bank accounts has resulted in an expansion of the cash-based economy. More than 60 percent of mobile money transactions globally are based on the cash-in-cash-out model, where individuals utilize licensed agents to either top-up or receive cash held in mobile wallets, enabling them to disburse salaries or transact peer-to-peer payments across large distances [START_REF] Naghavi | State of the Industry Report on Mobile Money[END_REF]. Additionally, this is not just for within-country transfers. A significant proportion of remittances between France and major west African economies like Côte d'Ivoire, Mali, and Senegal are transacted via Orange Money, one of the most widely used mobile money applications in French-speaking Africa.

Similarly, in South Africa, the country's leading economics advisory firm, Genesis Analytics, found in 2018 that a rise in non-performing micro-loans had resulted in a return to mobile money, prepaid cards and cash, and an avoidance of bank accounts, where positive balances can automatically be debited to settle outstanding debts. To match the services offered by mobile money, South African banks also enabled their customers to make instant cash transfers to anyone in the country with access to an ATM terminal, with no need for the recipient to hold an account at the bank (Ketley 2018); another example of digital technologies expanding cash-in-circulation. What these trends reveal is that for many emerging markets, the relationship between cash and digital payments may not be a zero-sum game. Rather, the cash-based and the digital economy appear to reinforce each other, with digital technologies boosting cash-in-circulation, and cash-in-circulation in turn sustaining the digital payments eco-system. While further study is required to better understand these trends in emerging markets, what they suggest is that policies seeking to eliminate cash prematurely may result in more harm than good.

Conclusions

The drive towards a cashless economy in Saudi Arabia and the UAE seems to have hit a wall, despite the best efforts of monetary authorities, banks, and the payments industry to establish a world-class digital payments eco-system modelled on South Korea and Sweden. Both economies remain heavily cash-reliant, with cash accounting for 67 percent of the total value of payments in the UAE in 2019, and 64 percent in Saudi Arabia. Explanations for this trend tend to point to infrastructure readiness, cybersecurity concerns, and high transaction costs, particularly merchant service fees for small businesses. Much less work, however, has been done to understand the socio-economic context in which countries like South Korea and Sweden, among the world's most egalitarian societies, have reduced their reliance on cash and diversified their payment eco-systems, and whether this is comparable to the UAE, where an estimated 35 percent of the working population is unbanked, where cash-based remittance corridors continue to be important, and where informal lending is still prevalent among businesses and households. In discussing the cases of Saudi Arabia and the UAE, this paper has also sought to reflect on a tendency in economics, as well as in industry circles, to see cash and digital payments in binary terms, with a linear evolution expected from one to the other. In reality, across the world cash-in-circulation is increasing in parallel with digital payments, in a dynamic that is still not fully understood. For emerging economies, it may well be that cash and digital payments play complementary and not alternative roles. This does not mean that such countries should renounce plans to become cashless economies, but that these plans would need to be backed by financial inclusion initiatives that promote equitable access to digital financial services, connectivity, and infrastructure. The alternative could mean adding digital exclusion to long-standing socio-economic exclusion.

Figure 1 .

 1 Figure 1. Current and forecasted non-cash transactions by region for 2017-2022, in billon transactions, (A) actuals and (F) forecasted. Non-cash transactions here are defined as all electronic payments, debit and credit cards transactions, bank transfers, and cheques (Capgemini 2019).

Figure 2 .

 2 Figure 2. Cash versus non-cash payments in the UAE, 2013 and 2019. In percent value of total pointof-sale payments (Mastercard 2013; FIS 2020).

Figure 1 .

 1 Figure 1. Current and forecasted non-cash transactions by region for 2017-2022, in billon transactions, (A) actuals and (F) forecasted. Non-cash transactions here are defined as all electronic payments, debit and credit cards transactions, bank transfers, and cheques (Capgemini 2019).

Figure 1 .

 1 Figure 1. Current and forecasted non-cash transactions by region for 2017-2022, in billon transactions, (A) actuals and (F) forecasted. Non-cash transactions here are defined as all electronic payments, debit and credit cards transactions, bank transfers, and cheques (Capgemini 2019).

Figure 2 .

 2 Figure 2. Cash versus non-cash payments in the UAE, 2013 and 2019. In percent value of total pointof-sale payments (Mastercard 2013; FIS 2020).

Figure 2 .

 2 Figure 2. Cash versus non-cash payments in the UAE, 2013 and 2019. In percent value of total point-of-sale payments (Mastercard 2013; FIS 2020).

Figure 3 .

 3 Figure 3. Value of total payments transacted in cash versus income inequality for 37 emerging and advanced economies, 2019. The Gini coefficient for Saudi Arabia relates to 2014 and was obtained from the World Bank's World Development Indicators. The countries included in the sample are listed in Appendix A (UNDP 2019; FIS 2020).

Figure 3 .

 3 Figure 3. Value of total payments transacted in cash versus income inequality for 37 emerging and advanced economies, 2019. The Gini coefficient for Saudi Arabia relates to 2014 and was obtained from the World Bank's World Development Indicators. The countries included in the sample are listed in Appendix A (UNDP 2019; FIS 2020).

Figure 4 .

 4 Figure 4. Currency-in-circulation as a percentage of GDP in nine emerging and advanced economies, 2007 and 2019. M0 is defined as currency-in-circulation outside banks, though the US Federal Reserve includes in its definition vault money, held by banks to meet the immediate cash needs of clients. All data are drawn from the respective central bank of each country. The first data point for the UAE relates to 2010 in the absence of older data.

Figure 4 .

 4 Figure 4. Currency-in-circulation as a percentage of GDP in nine emerging and advanced economies, 2007 and 2019. M0 is defined as currency-in-circulation outside banks, though the US Federal Reserve includes in its definition vault money, held by banks to meet the immediate cash needs of clients. All data are drawn from the respective central bank of each country. The first data point for the UAE relates to 2010 in the absence of older data.

Table 1 .

 1 Monthly income segmentation in the United Arab Emirates, in US dollars 1 , 2018.

	Income Range (USD)	Percent Employed	Working Population	Total Estimated Unbanked vs. Banked Population
	1 to 269	17%	936,485	32 percent of working population
	270 to 679	15%	803,239	unbanked, ~1.7 M individuals
	680 to 1359	19%	1,061,177	19 percent partially unbanked, ~1 M individuals
	1360 to 5399	27%	1,486,040
	5400 to 13,599	11%	589,109	40 percent of working population
	13,600 to 20,399	1.4%	78,409	banked, ~2.2 M individuals
	Above 20,300	0.6%	33,722
	Unclassified	9%	484,974
	Total	100%	5,463,155

1 Income segments converted to USD and rounded for presentation purposes. Source: (UAE Federal Competitiveness and Statistics Authority 2018), Labor Force.

J. Risk Financial Manag. 2020, 13, 260; doi:10.3390/jrfm13110260 www.mdpi.com/journal/jrfm

J. Risk Financial Manag. 2020, 13, x FOR PEER REVIEW 6 of 11

Funding: This research received no external funding.

Acknowledgments: Publication of this paper was financially supported by Monneta (monneta.org), a German non-for-profit organization, and the Development Economics Research Group at the International Institute of Social Studies (ISS) of Erasmus University Rotterdam (www.iss.nl). The author wishes to thank Georgina Gomez at the ISS for her virtual seminar on money plurality held in May 2020, which led to the idea for this paper.

Conflicts of Interest:

The author declares no conflict of interest.

Appendix A

The countries included in the sample in Figure 3 are Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Colombia, Denmark, Finland, France, Germany, Hong Kong, India, Indonesia, Ireland, Italy, Japan, Malaysia, Mexico, Netherlands, Nigeria, Norway, Peru, Philippines, Poland, Russia, Saudi Arabia, South Africa, South Korea, Spain, Sweden, Thailand, Turkey, UK, USA, Vietnam.


Isabelle Toubia

Christophe Nguyen

Stéphane Diring

Lamiaa M A Ali

Ludivine Larue

Rabab Aoun

Céline Frochot
email: celine.frochot@univ-lorraine.fr

Magali Gary-Bobo
email: magali.gary-bobo@inserm.fr

Marwan Kobeissi
email: mkobeissi@ul.edu.

Fabrice Odobel
email: fabrice.odobel@univ-nantes.fr

Synthesis and Anticancer Activity of Gold Porphyrin Linked to Malonate Diamine Platinum Complexes

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Cancer still remains one the major cause of mortality in the world in spite of the many progresses made in medical treatments for several decades. Conventional cancer treatment includes surgery, chemotherapy and radiotherapy. Platinum based compounds, such as Cisplatin, are widely used as anticancer therapeutic agents, but they have dose-limiting side effects and some cancer lines have become resistant to these drugs. 1 Photodynamic therapy (PDT) is an approved clinical treatment in oncology. It has many advantages such as low-cost, less invasiveness and minimal side-effects than conventional chemotherapy. [START_REF] Fan | Overcoming the Achilles' heel of photodynamic therapy[END_REF] PDT requires a photosensitizer, such as a porphyrin derivatives, which are known to better concentrate within the tumor tissue. [START_REF] El-Far | The interaction of tumour-localizing porphyrins with collagen, elastin, gelatin, fibrin and fibrinogen[END_REF] Currently, many porphyrin based photosensitizers are developed used in the clinic. 2c, 34 The Photofrin was the first photosensitiser approved by the Food and Drug Administration (FDA) in 1993 for bladder cancer therapy. Now, it is used for several cancers. Then, a second generation of photoactive compounds was produced and developed for clinical use such as Foscan, Metvix, Laserphyrin, Redaporphin. In addition, several compounds such as Tookad, Radachlorin are under clinical trials for cancer treatment. Light excitation of photosensitizers produces reactive oxygen species (ROS) in tumor and ultimately leads to cancer cell death, a method that confers higher selectivity to cancer cells than Cisplatin-based chemotherapy treatments.

The combination of a porphyrin or a phthalocyanine with an appended platinum, [START_REF] Lau | A Zinc(II) Phthalocyanine Conjugated with an Oxaliplatin Derivative for Dual Chemo-and Photodynamic Therapy[END_REF] gold, [START_REF] Longevial | Porphyrins Conjugated with Peripheral Thiolato Gold(I) Complexes for Enhanced Photodynamic Therapy[END_REF] or ruthenium, [START_REF] Schmitt | Ruthenium Porphyrin Compounds for Photodynamic Therapy of Cancer[END_REF] complex has been attempted to design innovative anticancer drugs. Interesting synergetic anticancer properties are obtained thanks to the dark chemostatic effect of the metal complex amplified by the PDT effect generated upon light excitation of the porphyrin or the phthalocyanine. 5a, b Recently, Che and co-workers reported the great pverotential of cationic gold(III) porphyrins as cytotoxic agent towards various cancer cell lines. [START_REF] Sun | Stable Anticancer Gold(III)-Porphyrin Complexes: Effects of Porphyrin Structure[END_REF] This discovery has stimulated many studies with gold porphyrins to develop anticancer drugs. [START_REF] He | A Cancer-Targeted Nanosystem for Delivery of Gold(III) Complexes: Enhanced Selectivity and Apoptosis-Inducing Efficacy of a Gold(III) Porphyrin Complex[END_REF] Interestingly, while Cisplatin anticancer drugs bind to DNA and induce cell death by binding to purine nucleic bases such as guanine and adenine, 1a gold porphyrins target mitochondria and particularly the heat shock protein. [START_REF] Hu | Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60[END_REF] As a consequence, the combination of Cisplatin derivative with gold porphyrin could lead to synergistic effect owing to different modes of action.

The most general mechanism of action of PDT is the generation of singlet oxygen by energy transfer from the photosensitizer excited triplet state to the triplet ground state of oxygen (classified as type II mechanism in PDT). It is well-accepted that photosensitizers with triplet excited states are more favorable than singlet ones to sensitize oxygen, because oxygen has a triplet ground state therefore energy transfer process from excited states of similar multiplicity are more efficient. [START_REF] Wilkinson | Quantum Yields for the Photosensitized Formation of the Lowest Electronically Excited Singlet State of Molecular Oxygen in Solution[END_REF] Gold porphyrins are known to undergo intersystem crossing with unity quantum yield owing to the heavy atom effect induced by the presence of gold. [START_REF] Brun | Charge transfer across oblique bisporphyrins: two-center photoactive molecules[END_REF] As a result, itis reasonable to anticipate that gold porphyrins could be promising candidates for PDT, such as it was shown for palladium porphyrins. 11d, e However, to the best of our knowledge, there is so far no single study of the phototoxic activity of gold porphyrin derivatives.

In this work, we have investigated the combination of Cisplatin derivatives covalently connected to a gold porphyrin in order to take advantage, on one hand, of the intrinsic cytotoxicity of the platinum complex added to that of the gold porphyrin and, on the other hand, of the potentially high phototoxicity of gold porphyrin upon light excitation (Chart 1). In addition, the affinity of porphyrin for tumor cells could also enhance selectivity and concentration of Cisplatin into tumor and thus increase the anticancer activity. However, this affinity is not sufficient legitimating that targeting strategies are currently explored to enhance the selectivity towards cancer cells. [START_REF] Singh | Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics[END_REF] Overall, the gold porphyrin platinum complex conjugates could have superior anticancer activity than individual compounds.

To test this idea, we report herein the preparation and the biological properties of three new dyads composed of gold porphyrin connected to a platinum diamine complex liganded via a malonate anchor (Chart 1). The diamine ligands around platinum(II) used in this work are ammoniac, cyclohexane diamine (CyDA) and pyridine methyl amine (Py).These three amine ligands where selected in this study, because related platinum complexes, such as Cisplatin, Picoplatin and oxaliplatin, have shown effective anticancer activities. 1a, 5f, 14 The three dyads were tested in human healthy and tumor cell lines to quantify their cytotoxicity without light excitation and their phototoxicity under light excitation.

Chart 1. Structures of the compounds investigated in this study.

It was demonstrated that gold(III)/Pt(II)conjugates are more potent by 2 to 5.6-fold than the corresponding platinum complexes. The cyclohexyldiamine (CyDA) derivative exhibited the most cytotoxic effect among the series. Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of others reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state. Overall this study indicates that the incorporation of two different cytotoxic metals in the same molecule represents a remarkable cytotoxic effect compared to traditional homometallic Pt(II) drugs and that an increased cancer cell death was obtained after light irradiation only in cancer cells.

Synthesis of the compounds

The synthesis of the reference platinum compounds (Pt-NH3, Pt-Py and PtCyDA) is illustrated in Scheme 1. First, p-cresol 1 was O-alkylated with bromoditertbutyl malonate 2 according to a Williamson substitution reaction affording 3 in 36% yield. We suspect that this lower yield stems from a second O-alkylation of compound 3, concomitant with its bromination and further nucleophilic substitution by p-cresol as already reported on a similar compound. [START_REF] Johnson | 1,3]dioxepines[END_REF] The tertbutyl esters of the malonate were subsequently hydrolyzed with trifluoroacetic acid (TFA) to give compound 4. Finally, the dicarboxylato platinum complexes were obtained in 92% yield according to Dhara's methodology, which consists in activating the carboxylic acid groups by deprotonation using sodium hydroxide before being reacted with the platinum amino precursor containing two weakly bound aqua ligands. 14a, 16 Scheme 1. Synthetic route for the preparation of the reference platinum complexes. Reagents and conditions: a) THF, NaOH, RT, 24h, 36% ; b) TFA, 70 o C, 1h, 100% ; c) EtOH, NaOH ; d) EtOH/Water (5/5), diamine(dinitro)platinum(II), RT, 48h, 92%.

The preparation of the dyads made of gold porphyrin/platinum complex required the porphyrin 8 as key intermediate (Scheme 2). Towards this goal, the ditertbutyl 4-(4-formylbenzyl)malonate 7 was first prepared by C-alkylation of the 4-(bromomethyl)-benzaldehyde6 in 64% yield. The tertbutyl ester was preferred over methyl or ethyl malonate owing its fast and quantitative hydrolysis in acidic conditions. Indeed, gold porphyrins are electron deficient molecules and in basic conditions they can undergo nucleophilic addition of hydroxide in meso position. [START_REF] Segawa | Direct hydroxylation at the meso position of gold(III) tetraphenylporphyrin by nucleophilic addition: novel hydroxyphlorin derivatives[END_REF] The key porphyrin 8 was synthesized by crosscondensation of pyrrole with benzaldehyde and ditertbutyl 4-(4-formylbenzyl)malonate 7. Using Adler conditions (reflux of the reagents in propionic acid), [START_REF] Adler | A simplified synthesis for meso-tetraphenylporphine[END_REF] the porphyrin was obtained in 12% yield, while Lindsey conditions (reaction conducted at RT in CH2Cl2) [START_REF] Lindsey | Rothemund and Adler-Longo reactions revisited: synthesis of tetraphenylporphyrins under equilibrium conditions[END_REF] with BF3-OEt2 as catalyst afforded 8 in lower yield (5%). However, Lindsey conditions with a mixture of two catalysts BF3-OEt2/TFA: 0.019/1 at 0.01 M improved the yield of 8 to 22%.

The insertion of Au(III) into the porphyrin was performed according to Sauvage methodology 20 using a Au(I) based complex surrounded with weakly binding ligand (THT=tetrahydrothiophene) and can be conducted under mild reaction conditions (Scheme 2). Classical conditions, using the salt KAuCl4 in refluxing acetic acid, were too harsh and caused hydrolysis of the ester groups and partial decarboxylation. Lastly, the introduction of the platinum complex was accomplished with Dhara's methodology similarly as for the reference complexes except that the solvent was adapted to these more hydrophilic compounds (mixture of ethanol and water). The complexes were characterized by proton NMR and IR spectroscopy, elemental analysis as well as by high resolution mass spectrometry.

The dyads AuP-PtNH3, AuP-PtPy and AuP-PtCyDA are soluble in ethanol, DMSO and acetone. Scheme 2. Synthetic route for the preparation of the dyads gold porphyrin linked to platinum complex.

Reagents and conditions: a) THF, NaH, ditertbuthyl malonate, 1h, 78% ; b) CH2Cl2, BF3.Et2O, TFA, 2h, DDQ, 2h, 22% ; c) CHCl3, Au(THT)2BF4, lutidine, reflux, 3h, 70% ; d)TFA, 70 o C, 7h, 94% ; e) ethanol/water, NaOH, diamine(dinitro)platinum(II), RT, 48h, 90%.

UV-vis electronic absorption spectra

The absorption spectra of the dyads gold porphyrin/platinum complex along with that of the reference AuTPP recorded in dichloromethane are shown in Figure 1 and the spectroscopic data are gathered in Table 1. The spectra of the dyads are essentially dominated by the transitions of the gold(III)porphyrin, since the Pt complexes does not exhibit any absorption band in the visible region. The presence of the malonate on one phenyl substituent does not modify the transition on the porphyrin, since there is no -conjugation with it. In addition, the meso aryl substituents of porphyrins are known to orient with circa 60° angle preventing electronic interaction between them. Unsurprisingly, the presence of the appended platinum complex does not alter the spectrum of the gold porphyrin owing to the deconjugation induced by the methylene spacer between the porphyrin and the Pt complex. The absorption bands of the gold(III)-porphyrin are characterized by a hypsochromic shift of both the Soret and the Q-bands relative to those in the free base porphyrin (Figure 1). These spectral features are explained by Au III -N bonding interactions, consequently leading to stabilization of the HOMO levels, and an increase in the HOMO-LUMO gap with respect to that of the free base. 22

Singlet oxygen measurements

Most of the porphyrins used in PDT operate according to a type II mechanism, that is the production of singlet oxygen by energy transfer from the photosensitizer excited state to oxygen present in the biological tissues. 2a, b The singlet oxygen quantum yield production was therefore measured to assess the potential of these gold porphyrin systems to act as sensitizers for PDT. The measurements were recorded in methanol and the production of singlet oxygen was assayed by recording the band at 1270 nm of singlet oxygen emission after gold porphyrin systems illumination. Unfortunately, none of the gold porphyrin and dyads prepared in this work produced detectable luminescence signal setting, thus a singlet oxygen quantum yield was below 1%. This unexpected result probably stems from the short lived triplet excited state of gold(III) porphyrins (≈ 1.5 ns), which decay to ground state before the energy transfer to surrounding oxygen could take place. [START_REF] Brun | Charge transfer across oblique bisporphyrins: two-center photoactive molecules[END_REF][START_REF] Eng | Triplet Photophysics of Gold(III) Porphyrins[END_REF]

Biological activity

In order to determine the therapeutic potential of these new compounds, we have first studied the cytotoxicity induced in human breast cancer cells (MCF-7) and in healthy human fibroblasts (FS-68).

The cells were incubated in darkness during 72 h with increasing concentrations of each compound (from 0.01 to 100 µM). The concentrations of the drugs which led to 50% cell mortality (IC50) were determined. As shown in Figure 2, obtained cytotoxicity data in both cell lines showed the classical sigmoidal dose-response curves when plotted as a logarithmic function of concentration (µM). Figure 2a,b illustrates the dose dependent cytotoxic effect of the reference platinum complexes Pt-NH3, Pt-Py and PtCyDA which are in the range of those reported with similar compounds and the ranking is consistent with previous studies 5f, [START_REF] Escribano | DNA binding studies of a series of cis-[Pt(Am)2X2] complexes (Am = inert amine, X = labile carboxylato ligand)[END_REF] : Pt-NH3<Pt-Py<PtCyDA. Overall, the Pt complex with the ligand CyDA is the most cytotoxic of the series with a lowerIC50 value than Cisplatin (IC50(Cisplatin)≈ 5 M). 25 Importantly, the cell death is very low in healthy fibroblasts, IC50 is too high to be calculate precisely (≥100 µM) (Figure 2c). This result highlights the targeting of cancer cells by these compounds. Then, the cytotoxic activity of gold porphyrins AuTPP, 9 and 10 was investigated in both human breast cancer cells (Figure 3a) and in healthy fibroblasts cells (Figure 3b). The results first show that overall, the gold porphyrins are more potent than the reference platinum complexes. Although the difference of cytotoxicity in cancer cells between Pt-CyDA and 10 is small, but on healthy fibroblasts this difference become very high; close to 100 fold (Table 3c). In addition, the introduction of the malonate substituent on the porphyrin decreases its cytotoxic activity, since the simple AuTPP has the lowest IC50. This result is consistent with the report of Che and co-workers, showing that any substituent pattern on AuTPP results in a weakening of its cytotoxicity. 8a Important features for the anticancer activity of gold(III) porphyrins are the size of the macrocycle, which must fit in the cavity of the target receptor (certainly heat shock protein) [START_REF] Hu | Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60[END_REF] and the lipophilicity of the porphyrin because its biological properties might be related to the fact it is a planar aromatic organic cation. [START_REF] Modica-Napolitano | Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells[END_REF] Thus, complex 9 with bulky hydrophobic malonate substituent displayed the least activity, which might be attributed to traffic entrance into cells. A long floppy alkyl chain might have been more favorable to tether the platinum complex and to maintain the cytotoxic activity of gold(III) porphyrin. Finally, we note that for gold porphyrins AuTPP and 10, the cytotoxicity is lower on healthy cells than cancerous ones, a significant advantage to decrease side effects during the treatment. Then, the photodynamic therapy efficiency of the gold porphyrins was studied in order to determine the possibility of a dual therapy that could increase, after light excitation, the cell death already due to the cytotoxicity of the compound (Figure 4). Cancer cells were thus incubated for 24 h with AuTPP, 9

and 10at a concentration of 0.5 µM and then irradiated or not with the mercury lamp of a fluorescent microscope (20 min, exc = 390 -420 nm, 39 J.cm -2 ). The cell death quantification performed 2 days after illumination demonstrates a decrease in living cells treated and submitted to photoexcitation. In fact, light excitation induces a supplementary cell death in addition to their intrinsic cytotoxicity and the most significant effect was obtained by the photoexcitation of AuTPP for which the illumination induced 18% of cell death to add to the 70% of cell death obtained without light. However, the additional cell mortality generated upon light excitation remains modest, indicating that gold porphyrins have weak, but not null, cytotoxic as compared for other sensitizers, such as free base porphyrins. 13a, 27 As mentioned above, the low phototoxicity of gold porphyrins is certainly explained by the very weak singlet oxygen generation quantum yield of these compounds, since porphyrins usually display higher ones. 27a, 28 Finally, the toxicity (Figure 5) and phototoxicity (Figure 6) of the three dyads were tested. On cancer and healthy cells (Figure 5a,b,c), all of them display IC50 values at the micromolar level, which are lower than those of the reference platinum complexes, but remain in the same range, let alone a bit better, as that of the reference gold porphyrin 10. Again, the most active dyad is AuP-PtCyDA, where the Pt is liganded with cyclohexane diamine. The cytotoxicity effect of the bimetal porphyrin conjugates AuP-PtNH3, AuP-PtPy and AuP-PtCyDA was increased by 5.6, 4.7 and 2 fold enhancement, respectively, compared to their corresponding Pt-complexes. These results would suggest that porphyrins granted the transport of the complex inside the cancer cell for more favorable cytotoxicity. As expected, the CyDA complex showed the highest effect. Similarly as for the reference gold porphyrins (AuTPP, 9 and 10), light excitation increases cell mortality, but to a low extent (Figure 6). Similarly as for the reference gold porphyrins (AuTPP, 9 and 10), light excitation increases cell mortality, but to a low extent (Figure 6). In addition, AuP-PtCyDA does not exhibit PDT efficiency in these conditions." shown that all these porphyrin derivatives are poor oxygen photosensitizers, therefore it is likely that the ROS production is induced by generating cytotoxic radicals via electron transfer from excited AuP + to surrounding organic molecules such as glutathione, a ubiquitous antioxidant in cells, upon reductive quenching of AuP + excited state, which is a strong oxidant. [START_REF] Brun | Charge transfer across oblique bisporphyrins: two-center photoactive molecules[END_REF] Accordingly, PDT effect can arise by a type I mechanism, which passes via the formation of oxidized species, inducing thus an oxidative stress by oxidizing GSH to glutathione disulfide. Photosensitizers operating upon a type I mechanism is particularly interesting in hypoxic environments found in many solid tumours. Finally, we decided to study the PDT effect in healthy fibroblasts in the same conditions as those used for cancer cells (Figure 8). For this, FS-68 cells were incubated 24 h with 0.5 µM of compounds and were submitted to light excitation at exc = 390 -420 nm, 39 J.cm -2 . The quantification of living cells 2 days after the PDT experiment showed a total absence of phototoxic effect. This result highlights the specific effect of PDT on cancer cells and suggests that there could be no photoxicity on healthy cells around the tumor.

Conclusion

For the first time, we report three new dyads consisting of two appended cytotoxic moieties such as a gold(III) porphyrin and a platinum complex and their biological properties towards cancer cells were investigated in the dark (chemostatic effect) and upon light excitation (PDT effect) and compared to their corresponding individual platinum(II) complexes. To evaluate the decrease in side effects that could occur with such compounds, the effect on healthy cells was also studied. The main results of this work are: i) the diamine ligand around the Pt centre has a high impact on the cytotoxicity of the resulting complex and cyclohexane diamine is the best ligand; ii) the gold porphyrins are poor singlet oxygen photosensitizers and thereby exhibit low phototoxicity with the present systems, but improvement can be obtained with modification of the porphyrin core, such as fluorination. The presence of fluorine atoms on meso phenyl substituents could enhance both the oxidizing power [START_REF] Poddutoori | Ultrafast charge separation and charge stabilization in axially linked 'tetrathiafulvalene-aluminum(III) porphyrin-gold(III) porphyrin' reaction center mimics[END_REF] and the lifetime of the triplet excited state. Indeed, it is postulated that gold porphyrins display ligand to metal charge transfer transitions, which are responsible of the fast decay of the triplet excited state. [START_REF] Eng | Triplet Photophysics of Gold(III) Porphyrins[END_REF] However, the phototoxicity is not null and most probably result by a type I mechanism; iii) the introduction of a malonate group of one phenyl substituent of AuTPPs lightly decreases cyto-and photoxicity the gold porphyrin; iv) the dyad AuP-PtCyDA displays interesting cytotoxic activity towards cancer cells, for which the mechanism of action would be interesting to be investigated.The enhanced cytotoxicity indicates that porphyrins allow the delivery of the complex into cancer cells. The complex might have dual biological functioning between Au(III) and Pt(II) arms. The former as reported would interact with mitochondria and the latter would target DNA; both mechanisms cause cancer cell death.

Importantly, all compounds present a close or clearly higher cytotoxic activity in cancer cells than healthy cells and the PDT effect, even slight, induced around 15 or 20% more cancer cell death for AuTPP, AuP-PtNH3 and AuP-PtPy in conditions totally harmless for healthy cells (0% cell death).

Further biological analysis would clarify the anticancer activity if it is based on specific metal or both.

Additional analysis of the intracellular metal contents such as ICP-analysis to monitor the uptake of the whole stable bimetal conjugate by cancer cells would clarify the delivery mechanism. On the other hand, the incorporate mode of action exhibited by the two metals may be even amplified using an alternative photosensitizer. These studies are in due course in our laboratory.

Ditertbutylmalonate p-cresol (3).

A total of 1 g (9.24 mmol) of p-cresol 1 and 2.7 g (9.24 mmol) of bromoditertbutyl malonate2were dissolved under argon in 20 ml of distilled THF. 0.36 g (9 mmol) of pulverized NaOH was added, and the mixture was stirred for 24 h at room temperature. The organic solution was diluted with water and extracted with dichloromethane. The combined organic phases were washed with water and dried over Na2SO4.The solvent was evaporated and the crude product was purified by column chromatography (SiO2; CH2Cl2/petroleum ether 5/5). Yield: (1.08 g, 36%).NMR

( 1 H, CDCl3, 300 MHz) δ (ppm): Compound (4). 206 mg (0.63 mmol) of 3 was dissolved in 1 ml TFA and heated at 70°C for one hour.

The solvent was evaporated and the product was dried under vacuum. Yield: (134 mg, 100%). IR (ATR): General procedure 1 (GP 1). Compound 4 was dissolved in water and the carboxylic acid functions were activated into sodium carboxylates, using 2 eq of NaOH. 1.2 eq of the respective diammine(dinitro)platinum(II) complex was dissolved in ethanol and added.The solution was stirred for 48 h at room temperature. The precipitated complexes Pt-Py, Pt-NH3, Pt-CyDA were filtered and dried.

Pt-NH3. According to GP1, 20 mg (0.095 mmol) of 4 was dissolved in 2 ml water, 7.6 mg (0. were added to a solution of 0.55 ml (5.38 mmol) of benzaldehyde, 600 mg (1.79 mmol) of 7, and 0.35 ml (5 mmol) of freshly distilled pyrrole in 1 l of CH2Cl2. The mixture was kept at room temperature for 2 h. 1.2 g (5.2 mmol) of DDQ was added when the aldehydes were completely reacted, and the mixture was kept at room temperature for an additional 2 h. The solvent was evaporated and the crude product was purified by column chromatography (SiO2; CH2Cl2/hexane 6/4) to remove tetraphenylporphyrin.

The monosubtituted porphyrin was then eluted with CH2Cl2 in form of a thick, purple band. Yield: (331 mg, 22%). UV-Vis (CH2Cl2, nm) λmax (nm): 418 (ε 4.2 × 10 5 mol -1 .L.cm -1 ), 522 (1.1 × 10 4 ), 557 (4.1 × 10 3 ), 655 (2.3 × 10 3 ). NMR ( 1 H, CDCl3, 300 MHZ) δ (ppm) : 8.41-8.80 (m, 8 H), 8.23-8.20 (dd, 2H, J = 7.08, 7.67 Hz), 8.14-8.11 (d, 2H, J = 8.02 Hz), 7.76-7.74(m, 9H), 7.61-7.58 (d, 2H, J = 8.15 Hz), 3.83-3.77 (t, 1H, J = 8.41 Hz), 3.49-3.46 (d, 2H, J = 7.94 Hz), 1.55 (s, 18H). HRMS (ES+) [M+] m/z 843.3908 found, 842.3910 calc.

Porphyrin (9). A total of 700 mg (0.83 mmol) of porphyrin 8 and 1.9 g (4.1 × 10 -3 mmol) [Au(THT)2]BF4

were dissolved in 5 ml chloroform. 193 µl (1.6 × 10 -3 mmol) of 2,6-lutidine was added and the reaction was heated to reflux. A gold mirror very rapidly deposited on the walls of the flask, and the reaction mixture turned reddish. After refluxing for three hours, the solution was evaporated to dryness. The residue was taken up in dichloromethane and purified through a silica column, eluting the free base porphyrin with dichloromethane and the desired red-orange band with CH2Cl2/AcOEt (9/1).Yield: (602 mg, 70%). UV-Vis (CH2Cl2, nm) λmax (nm): 408 (ε 3.1 × 10 49.16; H, 3.55; N, 5.92. calc C, 48.81; H, 3.17; N, 6.28.

Singlet oxygen detection. Singlet oxygen emission was detected through a double ruled grating SPEX monochromator (600 grooves/mm blazed at 1 μm) and a long-wave pass (780 nm). All spectra were measured in 4 faces quartz cuvettes. All the emission singlet oxygen luminescence have been displayed

with the same absorbance (less than 0.2) with the lamp and photomultiplier correction.

Biological experiments

Cell culture. Human breast adenocarcinoma cells (MCF-7) (purchased from ATCC) were cultured in Dulbecco Eagle's Minimal Essential Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (P/S). Adult Human Dermal Fibroblast cells (FS-68) were maintained in Roswell Park Memorial Institute (RPMI) medium supplemented with 10% FBS and 1% P/S. Both cell lines were allowed to grow in humidified atmosphere at 37 °C under 5 % CO2. For cytotoxic and phototoxic studies, the compounds (powder) are first diluted in DMSO at the concentration of 10 mM.

Then, they are sonicated during 30 seconds and diluted at the required concentrations in culture medium of each cell line".

Cytotoxicity study. MCF-7 and FS-68 cells were seeded into 96-well plates at a density of 10 3 cells/cm 2 .

One day after cell growth, cells were incubated with or without different concentrations of compounds (from 0.01 to 100 µM) for 3 days. After the incubation time, cells were incubated with 0.5 mg mL -1 MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide)during 4 h to determine mitochondrial enzyme activity. Then, MTT precipitates were dissolved in ethanol/DMSO (1:1) solution and absorbance was measured at 540 nm.

Phototoxicity assay. Both cell lines, MCF-7 and FS-68 cells, were seeded into 384-well plates at a density of 10 3 cells/cm 2 and allowed to grow for 24 h. Cells were incubated or not (control) with 0.5 µM concentration of compounds solution for 24 h. After incubation, cells were exposed, or not, to light using mercury lamp of a fluorescence microscope at excitation ranges between 390-420 nm for 20 min (39 J.cm -2 ). Two days after, MTT assay was performed to evaluate the phototoxic effect of compounds.

ROS production. The detection of ROS was performed during the phototoxicity experiment. Forty five minutes before irradiation, cells were incubated with 20 µM concentration of DCFH2-DA(Cellular ROS Assay Kit, Abcam, USA). Cells were exposed to light using mercury lamp of a fluorescence microscope at excitation ranges between 390-420 nm for 20 min (39 J.cm -2 ). After irradiation, cells were washed and fluorescence emission of DCF was detected at 450 nm using fluorescent microscope.

Figure 1 .

 1 Figure 1. Normalized absorption spectra of the porphyrin derivatives recorded in dichloromethane.

Figure 2 .

 2 Figure 2.Cytotoxic study of Pt-NH3, Pt-Py and PtCyDA. (a)Human breast cancer cells (MCF-7) and (b) healthy fibroblasts cells (FS-68) were incubated 72 h with increasing concentrations of Pt-NH3, Pt-Py and PtCyDA and maintained in darkness. Values are means ± standard deviation of 3 experiments. (c) IC50 values are reported for each cell line.

Figure 3 .

 3 Figure 3. Cytotoxic study of AuTPP, 9 and 10. (a)Human breast cancer cells (MCF-7) and (b) healthy fibroblasts cells (FS-68) were incubated 72 h with increasing concentrations of AuTPP, 9 and 10and maintained in darkness. Values are means ± standard deviation of 3 experiments. (c) IC50 values are reported for each cell line.

Figure 4 .

 4 Figure 4.Phototoxicity of AuTPP, 9 and 10incubated at 0.5 µM with MCF-7 cells during 24 h and irradiated 20 min at exc = 390 -420 nm (39 J.cm -2 ).Values are means ± standard deviation of 3 experiments.

Figure 5 .

 5 Figure 5. Cytotoxic study of dyads AuP-PtNH3, AuP-PtPy and AuP-PtCyDA. (a)Human breast cancer cells (MCF-7) and (b) healthy fibroblasts cells (FS-68) were incubated 72 h with increasing concentrations of dyads AuP-PtNH3, AuP-PtPy and AuP-PtCyDAand maintained in darkness. Values are means ± standard deviation of 3 experiments. (c) IC50 values are reported for each cell line.

Figure 6 .

 6 Figure 6.Phototoxicityofdyads AuP-PtNH3,AuP-PtPyandAuP-PtCyDAincubated at 0.5 µM with MCF-7 cells during 24 h and irradiated 20 min at exc = 390 -420 nm (39 J.cm -2 ). Values are means ± standard deviation of 3 experiments.

Figure 7 .

 7 Figure 7.ROS production in MCF-7 cells incubated with Pt-CyDA, AuP-PtCyDA and AuTPP at 0.5 µM during 24 h and irradiated 20 min at exc = 390 -420 nm (39 J.cm -2 ). Green luminescence shows the generation of ROS detected at  = 450 nm.

Figure 8 .

 8 Figure 8. Phototoxicity of gold porphyrins 10, 9, AuTPP and dyads AuP-PtNH3,AuP-PtPy,AuP-PtCyDAincubated at 0.5 µM with healthy fibroblasts (FS-68) during 24 h and irradiated 20 min at exc = 390 -420 nm (39 J.cm -2 ). Values are means ± standard deviation of 3 experiments.

1H and 13 C

 13 NMR spectra were recorded on an AVANCE 300 UltraShield BRUKER and AVANCE 400 BRUKER. Chemical shifts for 1 H and[START_REF] Singh | Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics[END_REF] C NMR spectra are referenced relative to residual proton in the deuterated solvent (CDCl3  = 7.26 ppm for 1 H, DMSO-d 8  = 2.50 ppm for 1 H) or to an internal reference (TMS,  = 0 ppm for both 1 H). NMR spectra were recorded at room temperature, chemical shifts are written in ppm and coupling constants in Hz. High-resolution mass (HR-MS) spectra were obtained by electrospray ionization coupled with high resolution ion trap orbitrap (LTQ-Orbitrap, ThermoFisher Scientific),working in ion-positive or ion-negative mode.Chemicals were purchased from Sigma-Aldrich or Alfa Aesar and used as received. Thin-layer chromatography (TLC) was performed on silica sheets precoated with Merck 5735 Kieselgel 60F254. Column chromatography was carried out with Merck 5735 Kieselgel 60F (0.040-0.063 mm mesh).Bromo ditertbutyl malonate 2, 4-(bromomethyl)-benzaldehyde6and platinum precursors Pt(OH2)2(NH3)2-(NO3)2, Pt(OH2)2(Py)-(NO3)2 and Pt(OH2)2(CyDA)-(NO3)2were synthesized according to literature.

  1706 cm -1 (C=O).NMR ( 1 H, CDCl3, 300 MHz) δ (ppm): 7.10-7.08 (d, 2H, J = 8.63 Hz), 6.82-6.80 (d, 2H, J = 8.61 Hz), 5.25 (s, 1H), 2.22 (s, 3H). HRMS (ES+) [M+] m/z 209.0454 found, 209.0450 calc.

  -4.13 (t, 2H, J = 5.44 Hz), 3.46-3.44 (d, 2H, J = 5.44 Hz). HRMS (ES+) [M+] m/z 1225.2269 found, 1225.2247 calc. Elem. Anal. Exp C,

  [START_REF] Silvers | The crystal and molecular structure of triclinic tetraphenylporphyrin[END_REF]

Table 1 .

 1 Maximum absorption wavelengths and molar extinction coefficients of the porphyrins recorded in dichloromethane at room temperature.Compoundsabs / nm(log / M -1 cm -1 )

	AuP-PtNH3	407 (5.49); 522 (4.18)
	AuP-PtPy	407 (5.45); 526 (4.01)
	AuP-PtCyDA	407 (5.52); 529 (4.03)
	8	417 (5.69); 507 (4.12); 542 (3.76);
		584 (3.64); 637 (3.39)

9 407 (5.60); 527 (4.23) 10 407 (5.49); 524 (4.16) AuTPP 409 (5.44); 527 (4.11)

  19 mmol) of NaOH was added, combined with 40 mg (0.11 mmol) of diamine(dinitro)platinum(II) dissolved in 2 ml EtOH, and stirred for 48 h. The precipitated complexPt-NH3was filtered, washed with water and dried. Yield (38 mg, 92%).IR (ATR): 1669 cm -1 (C=O).NMR ( 1 H, DMSO, 300 MHz) δ (ppm): 7.03 (br, 2H),

	6.66 (br, 2H), 5.70 (s, 1H), 4.29 (br, 6H), 2.20 (s, 3H). HRMS (ES+) [M+] m/z 459.0412 found, 459.0427
	calc. Elem. Anal. Exp C, 27.68; H, 3.20; N, 6.19 .calc C, 27.47; H, 3.23; N, 6.41.
	Pt-CyDA. According to GP1, 40 mg (0.19 mmol) of 4 was dissolved in 3 ml water, 15 mg (0.38 mmol) of
	NaOH was added, combined with 90 mg (0.2 mmol) of diamine(dinitro)platinum(II) dissolved in 3 ml
	EtOH, and stirred for 48 h. The precipitated complex Pt-CyDA was filtered, washed with water and
	dried. Yield (90 mg, 92%).IR (ATR): cm -1 (C=O).NMR ( 1 H, DMSO, 300 MHz) δ (ppm): 7.06-7.03 (d, 2H, J
	= 8.53 Hz), 6.68-6.65 (d, 2H, J = 8.9 Hz), 6.16-6.03 (dd, 2H, J = 9.9, 30.91 Hz), 5.66 (s, 1H), 5.45-5.33
	(dt,2H, J = 37.28, 8.96 Hz), 2.21 (s, 3H), 2.09 (br, 2H), 1.84-1.80 (d, 2H, J = 12.95 Hz), 1.46-1.44 (d, 2H, J
	= 8.86 Hz), 1.22 (br, 2H), 1.04-0.97(t, 2H, J = 10.22 Hz). HRMS (ES+) [M+] m/z 539.1061 found, 539.1053
	calc.
	Yield (89 mg, 92%).IR (ATR): 1681, 1649 cm -1 (C=O).NMR ( 1 H, DMSO, 300 MHz) δ (ppm): 8.44-8.42 (d,
	1H, J = 5.97 Hz), 8.18-8.12 (td, 1H, J = 7.73, 1.58 Hz), 7.66-7.63 (d, 1H, J = 7.8 Hz), 7.54-7.50 (t, 1H, J =
	6.96 Hz),7.05-7.02 (d, 2H, J = 8.36 Hz), 6.71-6.68 (d, 2H, J = 8.9 Hz), 6.64-6.62 (d, 1H, J = 5.57 Hz), 5.70
	(s, 1H), 4.15-4.14 (br, 2H),2.21 (s, 3H). HRMS (ES+) [M+] m/z 511.0761 found, 511.0764 calc.
	Porphyrin (8). BF3.Et2O 16 µl (1.2 × 10 -2 mmol) and 0.5 ml (6.46 mmol) of trifluoroacetic acid (TFA)

Pt-Py. According to GP1, 40 mg (0.19 mmol) of 4 was dissolved in 3 ml water, 15 mg (0.38 mmol) of NaOH was added, combined with 89 mg (0.2 mmol) of diamine(dinitro)platinum(II) dissolved in 3 ml EtOH, and stirred for 48 h. The precipitated complex Pt-Py was filtered, washed with water and dried.

  PtNH3was filtered, washed with water and dried. Yield (58 mg, 90%). IR (ATR): 1619 cm -1 (C=O). UV-Vis (CH2Cl2, nm) λmax (nm): 408 (ε 2.8 × 10 5 mol -1 .L.cm -1 ), 526 (1.3 × 10 4 ). NMR ( 1 H, DMSO-d6, 300MHz) δ (ppm): 9.35-9.28 (m, 8H), 8.29-8.27 (d, 6H, J = 6.64 Hz), 8.26-8.17 (d, 2H, J = 8.01 Hz), 8.14-7.91 (m, 9H), 7.82-7.79(d, 2H, J = 7.55 Hz), 4.38-4.34 (t, 1H, J = 7.08 Hz), 4.36-4.28(br, 6H), 3.55-3.54 (d, 2H, J = 5.31 Hz). HRMS × 10 5 mol -1 .L.cm -1 ), 526 (1.3 × 10 4 ). NMR ( 1 H, DMSO-d6, 300MHz) δ (ppm): 9.33-9.30 (m, 8H), 8.52-8.50(d, 1H, J = 5.78 Hz), 8.27-8.25 (d, 6H, J = 6.39 Hz ), 8.16-8.13 (d, 2H, J = 7.92 Hz), 8.13-7.90 (m, 9H), 7.83-7.80 (d, 2H, J = 7.92 Hz), 7.67-7.64 (d, 1H, J = 7.94 Hz), 7.55-7.50 (t, 1H, J = 7.12 Hz),6.61-6.59 (br, 2H), 4.39-4.35 (t, 1H, J = 6.75 Hz), 4.17

	(ES+) [M+] m/z 1151.2090 found, 1151.2090 calc. Elem. Anal. Exp C, 48.69; H, 3.48; N, 6.35. calc C,
	48.56; H, 3.61; N, 6.5.
	AuP-PtCyDA. According to GP2, 60 mg (5.6 × 10 -2 mmol) of gold porphyrin 10 was dissolved in 16 ml
	EtOH, 4.5 mg (0.11 mmol) of NaOH was added, combined with 27.66 mg (63.8 × 10 -3 mmol) of
	diamine(dinitro)platinum(II) dissolved in 12 ml of a mixture EtOH/H2O(1/1).The mixture was stirred 5 mol -1 .L.cm -1 ), 526 (1.2 × 10 4 ). NMR ( 1 H, CDCl3, for 48h at room temperature. The solvents were evaporated. The complex was dissolved in DMF and 300 MHz) δ (ppm): 9.26-9.23 (m, 8H), 8.24-8.22 (d, 6H, J = 6.53 Hz), 8.16-8.14 (d, 2H, J = 8.09 Hz), 7.90-precipitated with a saturated solution of NaCl. The precipitated complex AuP-PtCyDA was filtered, 7.83 (m, 9H), 7.71-7.69 (d, 2H, J = 7.78 Hz), 3.83-3.78 (t, 1H, J = 7.76 Hz), 3.51-3.49 (d, 2H, J = 8.09 Hz), washed with water and dried. Yield (61 mg, 90%). IR (ATR): 1626 cm -1 (C=O).UV-Vis (CH2Cl2, nm) λmax 1.55 (s, 18H). HRMS (ES+) [M+] m/z 1037.3326 found, 1037.3341 calc. (nm): 408 (ε 2.8 × 10 5 mol -1 .L.cm -1 ), 526 (1.3 × 10 4 ). NMR ( 1 H, DMSO-d6, 300MHz) δ (ppm): 9.34-9.30
	(m, 8H), 8.29-8.26 (dd, 6H, J = 7.27, 7.63 Hz), 8.18-8.15 (d, 2H, J = 8 Hz), 7.98-7.91 (m, 9H), 7.81-7.78
	Porphyrin (10). 630 mg (0.607 mmol) of gold porphyrin 9 was dissolved in 2 ml TFA and heated at 70 o C
	for seven hours. After removal of the solvent under reduced pressure, the product was dissolved in
	methanol and purified using exclusion size chromatography. Yield: (530 mg, 94%). IR (ATR): 1634 cm -1
	(C=O). UV-Vis (CH2Cl2, nm) λmax (nm): 408 (ε 2.8 × 10 5 mol -1 .L.cm -1 ), 526 (1.3 × 10 4 ). NMR ( 1 H, DMSO-d6, Exp C, 49.61; H, 3.79; N, 6.02. calc C, 49.3; H, 3.45; N, 6.34.
	300 MHz) δ (ppm): 9.44-9.40 (m, 8H), 8.22-8.18 (m, 6H), 8.09-8.06 (d, 2H, J = 8.13 Hz), 7.94-7.86 (m,
	8H), 7.76-7.73 (d, 2H, J = 7.98 HZ), 3.92-3.88 (t, 1H, J = 6.18 Hz), 3.71-3.69 (d, 2H, J = 5.85 Hz). HRMS AuP-PtPy. According to GP2, 60 mg (5.6 × 10 -2 mmol) of gold porphyrin 10 was dissolved in 16 ml EtOH,
	(ES+) [M+] m/z 925.2075 found, 925.2089 calc. 4.5 mg (0.11 mmol) of NaOH was added, combined with 23.88 mg (56 × 10 -3 mmol) of
	diamine(dinitro)platinum(II) dissolved in a mixture of 2.5 ml EtOH and 17.5 ml H2O. The solution was
	stirred for 48h at room temperature. The solvents were evaporated. The complex was dissolved in General procedure 2 (GP 2). Compound 10 was dissolved in EtOH and the carboxylic acid functions DMF and precipitated with a saturated solution of NaCl. The precipitated complex AuP-PtPy was were activated into sodium carboxylates using 2 eq of NaOH. 1.2 eq of the respective filtered, washed with water and dried. Yield (61 mg, 90%). IR (ATR): 1631 cm -1 (C=O). UV-Vis (CH2Cl2, diammine(dinitro)platinum(II) complex was dissolved in Ethanol/Water (1/1) and added. The solution was stirred for 48 h at room temperature. The solvents were evaporated. The complexes were nm) λmax (nm): 408 (ε 2.8
	dissolved in DMF and precipitated with a saturated solution of NaCl. The precipitated complexes AuP-
	PtNH3 ,AuP-PtPy, AuP-PtCyDA were filtered, washed with water and dried.
	AuP-PtNH3.According to GP2, 60 mg (5.6 × 10 -2 mmol) of gold porphyrin 10 was dissolved in 16 ml
	EtOH, 4.5 mg (0.11 mmol) of NaOH was added, combined with 23.74 mg (67.2 × 10 -3 mmol) of

diamine(dinitro)platinum(II) dissolved in 12 ml of a mixture EtOH/H2O(1/1).The mixture was stirred for 48h at room temperature. The solvents were evaporated. The complex was dissolved in DMF and precipitated with a saturated solution of NaCl. The precipitated complexAuP-(d, 2H, J = 8.36 Hz), 6.13-5.99 (m, 2H), 5.45-5.32 (m, 2H), 4.35-4.30 (t, 1H, J = 6.56 Hz ),

3.44-3.42 (d, 2H

, J = 6.82 Hz), 2.15-2.12 (m, 2H), 1.86-1.82 (t, 2H, J = 8.76 Hz), 1.48-1.46

(d, 2H, J = 9.28 Hz)

, 1.23-1.21 (m, 2H), 1.06-1.01 (m, 2H). HRMS (ES+) [M+] m/z 1231.2739 found, 1231.2716 calc. Elem. Anal.

Acknowledgments

We thank Campus France (Eiffel grant), Pays de la Loire (LUMOMAT project), CNRS-L and the Lebanese University for the financial support of this project.

Experimental part

Synthesis of the compounds

Generalities