Paul Coulerie
email: paul.coulerie@unige.ch

Cyril Poullain

NewC aledonia:AHot Spotfor Valuable Chemodiversity Part 2: Basal Angiosperms and Eudicot Rosids

published or not. The documents may come

Thef lora of New Caledonia encompasses more than 3000 plant species and almost8 0% are endemic. New Caledonia is considered as ahot spot for biodiversity.With the current global loss of biodiversityand the fact that severaldrugs and pesticides becomeobsolete,there is an urgentneed to increasesampling and research on new natural products.Inthis context,wereview the chemical knowledge available on New Caledonian native flora from economicalp erspectives.W ee xpect that ab etter knowledgeofthe economic potential of plant chemistry will encourage the plantation of native plants for the development of a sustainable economy which will participate in the conservation of biodiversity.Inthe second part of this review,wefocus on the results exposed in 60 scientific articlesa nd describe the identification of 225 original compounds from basal angiosperms and eudicotr osids.W ed iscuss the economic potential of plants and molecules from medicinal and industrial perspectives.T his review also highlights severalp lants and groups,s uch as Amborella sp., Piperaceae,o rP hyllanthaceae,t hat are unexplored in New Caledonia despite their high chemical interest. Those plants are consideredt oh ave priority in future chemical investigations.

Introduction. -T he importance of biodiversity for the discovery of new naturalp roducts with economicalv alue was recognized in 1990 duringam eetingo ft he International Society of Chemical Ecology.I nt he Gçteborg Resolution [1],n atural product diversity was recognized as a treasuryo fi mmense value to human kind. This resolution also pointed out the currenta larming rate of species extinction that is rapidly depleting this treasury, with potentially disastrous consequences.T his encouraged the research for valuable naturalp roducts for the valorization and protectiono fb iodiversity [1].F rom time immemorial, plants have provided awide variety of foods, drugs,c osmetics,f ibers, and building materials,a nd have been fundamental for the development of human societies [START_REF]Ecosystems and Human Well-Being:C urrent State and Trends[END_REF]. Morer ecently,s tudieso fp lant chemistry have led to the discovery of many bioactivep roducts,s uch as for pharmacological,a gronomical, or cosmetic applications. Thed iscovery of aspirin from Filipendula ulmaria or of artemisinin from Artemisia annua are among the most populare xamples that illustrate the importance of such research [START_REF] Clardy | [END_REF] [4].Despite the development of combinatorial chemistry and rational drug design,m any authors argue that natural products are likely to continuet op rovidet he best lead-moleculesi nt he future [5] [6].I nt his context, species-rich areas,s uch as tropical and subtropical forests, are of particular interest. New Caledonia, an archipelago locatedi nt he South-West Pacific, is considered as one of the 34 majorhot spots for marine and terrestrial biodiversity [START_REF] Mittermeier | Hotspots:Earths Biologically Richest and Most Endangered Te rrestrial Ecoregions[END_REF]. Ar eview published in 2004 by Laurent and Pietra highlighted the pharmacological potential of the Neo-Caledonian marine organisms [START_REF] Laurent | [END_REF], but no review of terrestrial phytochemical investigationsisavailable yet. Considering higher plants,it is evaluatedt hat New Caledonia contains3 270 native species,ofwhich 78% are endemictothis territory [9]. This botanical diversitya lso represents ah uge reserve of original naturalc ompounds and providesareal interest for green chemistry,pharmacology,cosmetics,and agronomy.The term hot spot also points out that the biodiversity is highly threatened by human activities and therefore, this habitat must be protected [10]. Fort his purpose,t he discovery of interesting chemicals from plantswill encourage the reforestation and thus,t he protection of biodiversity.I nvestigations of the New Caledonian chemodiversity already provided original compounds and/or interesting drugs.A sa ne xample,m ethoxyellipticine, an alkaloid found in aN ew Caledonian Apocynaceae,w as used to develop ad rug (Celiptium )u sed to treat breast and liver cancers [11].

Despite phytochemicali nterest, plant chemistry remains largely unexplored in New Caledonia. During the second part of the 20th century, research mainlyfocused on the discovery of original compounds (e.g., [12 -14]). Later, biological evaluations started to be systematically associated to phytochemical analysis (e.g., [15 -17]). This was the beginning of research for economical evaluation, in a purpose of biodiversity conservation. Following the review of isolated alkaloids from New Caledonian flora by SØvenet and Pusset [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF], we present here ab roaderr eview of the phytochemistryofNew Caledonianplants and discuss their economic potential. This review summarizesp ublications available on SciFinder from 1972, when the first formal phytochemical studies of endemic plants were published, up to early 2015.

Thek nowledge availablei ns cientific literature about the chemistry of New Caledonian native plants is reported exhaustively.T he data are organized by families of plants, according to the phylogeny proposed by the Angiosperm Phylogeny Group III (APG III;see Fig. 1) [START_REF] Apg Iii | [END_REF]. This allows ac omprehensive chemotaxonomicalo rganizationo ft his review.F loricalw as used as taxonomical reference for the New Caledonian flora [9]. This review points out the economic interest of terrestrial biodiversity of New Caledonia and highlights new groups which have been poorly studied and may contain novel compounds.T his compilation highlights that the original flora from New Caledonia also contains aw ide range of original compounds.O riginality of New Caledonian compounds was updatedu sing the Dictionary of Natural Products [START_REF] Taylor | Dictionary of Natural Products[END_REF]. We considered compounds as originals when encounteredo nly in a restricted number of endemics pecies stemming from a unique genus. 1 )W ea lso point out that al ot of work remains to be done for the development of economical applications based on this biodiversity.T his review is divided into three parts.T he first part coverst he knowledge of the chemistry of New Caledonianc onifers [START_REF] Coulerie | [END_REF], whereas the two followingp arts focus on the metabolites isolated from angiosperms.T he secondp art, which is presented here,compiles the results obtained by investigation of basal angiosperms,m onocots,b asal eudicots,a nd eudicot rosids.

In NewCaledonia, angiosperms are particularly diverse sincethis groupencompasses 3099 species, more than 90% of all vascular plants,and is characterized by its remarkable originality,s howing 77.8% endemism [ 9].M ore in detail, several groups whicha re abundantly representedi nt he tropics are totally absent in New Caledonia, such as Balsaminaceae and Begoniaceae,a nd other groups, such as Annonaceae,A steraceae,o rB ignoniaceae,a re clearly under-represented [9]. In parallel,w ecan find several relictual taxa, Amborella trichopoda being the perfect example,and ahigh levelofspeciation in several gondwanian groups,s uch as Lauraceae (47 endemic species)o r Cunoniaceae (90endemic species,corresponding to 30% of the world diversity of this group) [ 9].M yrtaceae and Rubiaceae are the most important families,e ncompassing 257 and 211 species,respectively.Aswill be shown, many of the published phytochemicals tudies on New Caledonian angiosperms led to the isolationo fo riginal naturalc ompounds.A lso,s everalo ft hem weres hown to be highly bioactive,s howing high potential for pharmaceutical applications. On the contrary,o ther economic perspectives for New Caledonian plants, such as cosmetic or agronomic applications,a re poorly documented. As summarized in Fig. 1,w ec an also notify that we did not find any publication related to endemic speciesf rom 60% of the angiosperm families.

Protoangiosperms, Monocots, and Basal Eudicots. -Annonaceae. This family is represented by twelve species (includingelevenendemic species)that are divided into six genera. Annonaceae is ahuge tropicalbotanicalfamily that encompasses more than 2000 species including several comestible fruits (e.g., Annonas quamosa and Annona muricata)o rp lants used for perfumery (e.g., Cananga odorata and Mkilua fragrans). Annonaceae are known to contain polyphenols (includingu nusualC -benzylflavonoids), terpenes, acetogenins,a nd alkaloids (mainly from the isoquinolineg roup)a ss hown in many publications dedicatedtothese plants (e.g., [22]and [23]).They are also frequently describedi nf olk medicines [START_REF]Phytochemistry of Plants Used in Tr aditional Medicine[END_REF]a nd numerous species show strong bioactivities,s uch as insecticidal or antitumoral activities [START_REF] Rattan | [END_REF] [26].

Thec hemistry of five species has beeni nvestigated in New Caledonia: Xylopia pancheri, Xylopia vieillardii, Meiogyne tiebaghiensis (syn.: Desmos tiebaghiensis), Hubera nitidissima (syn.: Polyalthia nitidissima), and Goniothalamus dumontetii.T hirteen isoquinolinea lkaloids,i ncluding an unusual morphinanedienone (pallidine;s hown in Fig. 2)w ere identified from M. tiebaghiensis [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF].X . pancheri and H. nitidissima containagreat variety of aporphine and isoquinolinealkaloids from benzylisoquinoline and protoberberine groups, including four lindoldhamined erivatives (namely N,N-dimethyllindoldhamine*, isodaurisoline*, 7-O-methyllindoldhamine*, and 7'-Omethyllindoldhamine*) that are presented in Fig. 2 [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF] [27] [28]. Only few biological tests were associated to those studies despite that several classicald rugs,s uch as morphine,p ossess an isoquinolines keleton. Indeed, only X. pancheri demonstrated light periphericalv asodilatory activity [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF].

H. nitidissima also contains several flavonoids,s uch as mangiferin (see Fig. 3)and quercetin derivatives.Leaves of this plant contain ah igh concentration of mangiferin and are considered as an important natural source for this natural colorantand powerful antioxidant [29]. G. dumontetii was also investigatedf or protein kinase inhibition activity (DYRK1A and CDK1/cyclin B) for anticancer perspectives or neurodegenerative treatment. It contains aristolactams (namely velutinam, aristolactams AII and AIIIa)and one lignancalled(À)-medioresinol (see Fig. 3). Aristolactam AIIIa (see Fig. 2)i sastrong inhibitor of DY RK1A and CDK1/cyclin Bs howing IC 50 values of 0.08 and 0.2 mm on these enzymes [30] [31].D espite stronge videncef or the possible economicalp otential of this family,e specially for drug discovery and cosmetics, the knowledge concerning the chemistryo fNew Caledonian Annonaceae is scarcea nd should be further studied. 2 ) Atherospermaceae.N emuaron is am onospecific genus and Nemuaron vieillardii is the only memberofthe family Atherospermaceae in New Caledonia. This tree is foundin humid forests of the main island.E lsewhere in the world, this family is known to produce phenolic compounds,such as chalcones or flavanones,a nd to biosynthesize alkaloids, mainly belonging to the isoquinoline group.B isbenzylisoquinolines are evenconsidered as chemical markers of this family [START_REF] Taylor | Dictionary of Natural Products[END_REF]. Barks and leaves of N. vieillardii were investigated for their alkaloidal content. Consistent with the chemotaxonomic knowledge presented above,t his study revealed the presenceo fn umerousi soquinoline alkaloids, suchaslaurotetanine, norisocorydine,atheroline, and nemuarine*, an originalb isbenzylisoquinoline [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Thes tructureso ft hese alkaloidsa re presented in Fig. 4. N. vieillardii also produces anise smelling aromatic com- pounds.Thus,the plantisapotential sourceofessential oils and could be of interestfor the perfume industry. However, according to our knowledge,noanalysis of the essential oil contento ft his plant has been reported yet.

Hernandiaceae. This family is representedi nN ew Caledonia by two genera and three species,i ncludingt he endemic plant Hernandia cordigera. Species from this family,including Gyrocarpus americanus which is native to New Caledonia, are described to contain lignans and alkaloids [32] [33]. H. cordigera also produces several characteristic lignans,s uch as 5'-methoxyyatein*, 5'-methoxypodorhizol, and cubebininolide, that are presented in Fig. 5,a nd aporphine alkaloids( e.g.,c assythicine, nandigerine,n antenine, hernagine,a nd ogiverinew hich are presented in Fig. 6) [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF].

Hernandia nymphaeifolia (ex Hernandia peltata)a lso contains alkaloids includingaporphine derivatives,together with furanoid lignans whichs howed potent antiplatelet aggregation activities and could potentially be used as naturalanticoagulants in the future [34].Further biological evaluation should be encouraged by the fact that aporphine alkaloids and lignans, such as the antiprotozoal agent lysicamine [35] or the anticancer agent aviculin [36],c an be highly active natural compounds. Otherwise,t he heart wood of H. cordigera has been exploitedi nt he past for carpentry and is also traditionally used in New Caledonia for attractingand trapping chrysomelids(Monolepta semi-violacea), an important pest for crop fields [START_REF] Mille | Animaux nuisiblese tu tiles des jardins et vergers de Nouvelle-CalØdonie, SociØtØ Entomologique de Nouvelle-CalØdonie[END_REF].A preliminary investigation of volatiles fromt his plant did not allow us to explain this biological activity.

Lauraceae. ThefamilyLauraceae is represented in New Caledonia by six genera (including the endemic genus Adenodaphne)a nd 48 species,a ll beinge ndemic except Cassythafiliformis.Lauraceae is an important tropical and subtropicalfamily in terms of diversity,comprising 30 to 50 genera and ca. 2000 species, but also from an economical point of view,since it contains important species exploited for timber( e.g., Ocotea bullata), food (e.g., Persea americana), or fragrances(e.g., Aniba rosaeodora). Phytochemicals in Lauraceae are diverse and include alkaloids( e.g., benzylisoquinoline and aporphine derivatives), essential oils,p olyphenols,a nd terpenoids [START_REF] Taylor | Dictionary of Natural Products[END_REF] [START_REF] Custódio | [END_REF].

New CaledonianL auraceae weref irst investigated for their alkaloidal content (seeo riginal structures in Fig. 7). In 1985, Tillequin, Koch et al. described the presenceoftwo new morphinane alkaloids with as aturated C-ring (oreobeiline* and6 -epioreobeiline*)t ogetherw ithk nown alkaloids( wilsonirine, thaliporphine, isoboldine,a nd pallidine) in Beilschmiediao reophila [39].A mong the1 9e ndemic Cryptocarya speciesthata re referenced in NewC aledonia, five specieswereinvestigatedfor theirchemicalcontent.

Bioguided fractionation of aleaf extract of Cryptocarya chartacea led to the isolation of pinocembrin and six new mono-and dialkylated flavanones named chartaceones A* -F*( see Fig. 8). Chartaceones C* -F*s how strong inhibitory activitiesonthe dengue virus RNApolymerase, with IC 50 values ranging from 1.8to4.2 mm,and thus could lead to the discovery of an ew antiviral drug [40].

Cryptocarya longifolia, Cryptocarya odorata,and Cryptocarya oubatchensis containm any isoquinoline alkaloids, such as antofine,l aurotetanine, and laurolitsine,a nd original structures,s uch as longifolidine*a nd longifolonine* (see Fig. 7), which were isolated from C. longifolia [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Thus, C. oubatchensis contains two original secodibenzopyrrocoline alkaloids called cryptowolinol* and cryptaustoline* (see Fig. 7). Cryptocaryaphyllostemon also was characterized by the presenceo fc ryptowoline*, phyllostemine*, phyllosteminine*, phyllosterone,p hyllocryptine*, and phyllocryptonine* (see Fig. 7) [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Velucryptine*( see Fig. 7)w as isolated from Cryptocarya velutinosa [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Thec ytotoxic activities of some of these compounds were evaluated against KB cells andrevealeda significant anticancer potential of antofine derivatives, whichd isplayed IC 50 values ranging from 1t o6 .3 nm [18][41].O therwise,e ssentialo il obtainedf rom the wood of Cryptocarya odorata was also studied and was characterized by the presence of uncommon a-pyrone derivatives, such as 6-heptyl-5,6-dihydro-2H-pyran-2-one [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF].

Twoo ft he 14 endemic Litsea species were also investigated.A porphinoid alkaloids, tetrahydroisoquinoline,and an orphinane dienone alkaloidwere isolated from the leaves of Litseal ecardii. Corydine, glaucine,a nd Nmethylcoclaurine were isolated from the leaves of Litsea triflora and were later found in other plant families as well [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Other endemic Lauraceae have not been investigated yet. Moreover, an extended evaluationo fb ioactivities of these plants may lead to the discovery of new naturaldrugs in view of the alkaloidal content of these plants.Also,some speciesa re highly aromatic and should be studied for cosmetic perspectives.

Menispermaceae. Menispermaceae are represented in New Caledonia by seven species (five endemic)a nd are dividedinto four genera.Among the endemic species, only Pachygone loyaltiensis (ex Pachygone vieillardii)h as been investigated. This plant is describeda sp urgative in Melanesian traditionalp harmacopoeia. It is characterized by dimeric alkaloids,such as daphnoline and daphnandrine (see Fig. 9), together with other alkaloids that have not been identified yet [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Otherwise,a no riginal alkaloid called hypserpine* (see Fig. 9)w as isolated from the bark of Hypserpa neocaledonica.F inally,t he chemistry of Stephania japonica has been investigated, mostly for alkaloids of different groups (e.g.,a knadicinea nd protostephanine which are shown in Fig. 9)a nd for several bioactivities,such as antimicrobial and multidrug resistance reversing activities [42].

Monimiaceae. This family is represented in New Caledonia by ten endemic species: Kibaropsis caledonica, the only memberofthis genus,and nine Hedycarya species. Other members of this family are knownt oc ontain essentialo il and variouso riginal and/orb ioactive chemicals,s uch as alkaloids and butanolides [43]. In New Caledonia, only Hedycarya baudouinii was investigated by phytochemists.I tc ontains aw ide rangeo fa lkaloids, includingi soquinoline,p avine,a nd aporphine derivatives includingt he original compoundh edycarine* which is shown in Fig. 10 [18]. Other Monimiaceae should be investigated,a tl east for their alkaloidal content and to search for new bioactive compounds.

Monocots. Among all studies on monocots (more than 500 species and 48% endemism)w ec ould not find any publication dealing with the chemistry of an endemic species from New Caledonia. Indeed, the chemistry of Appendicula reflexa,anative Orchidaceae,h as been investigated recently due to its anticancer potential [44]. Ab ioguided fractionationo ft his plant extract was performed to find new compounds with anticancer or antineurodegenerative potential. This studyl ed to the isolation of six phenanthrene derivatives,i ncludingt wo novel derivatives,n amely 2,3,5,6-tetramethoxyphenanthrene-1,7-diol and blestrin E( see Fig. 11). Them ost activec ompounds,2 ,3,5,6-tetramethoxyphenanthrene-1,7diol and 3,4,6-trimethoxyphenanthrene-2,7-diol (see Fig. 11), exhibited IC 50 values of 0.07 and 0.2 mm on CDK1/cyclin B, respectively [44]. Orchidaceaec omprises more than 200 species and half of them are endemic to New Caledonia. All of thesep lants are strictly protected and their chemical investigation should be associated with horticulturalm ultiplication to be considered.

Proteaceae. Proteaceae is an important tropical and subtropical family.I tc ontains ca. 2000 species that are mostly concentratedi nt he southern hemisphere.I nN ew Caledonia, it is representedb y4 3e ndemic species, classifiedi nto nine genera. Only few species have been investigated for theirc hemical content or economical potential. Eleven original tropane alkaloids were isolated from leaves of Eucarpha strobilina (ex Knightia strobilina): acetylknightinol*, strobiline*, dihydrostrobiline*,k nightoline*, knightinol*, 3a-(cinnamoyloxy)tropan-6-ol*, 6b-(benzoyloxy)-3a-hydroxytropane (also found in Erythroxylum spp.),s trobamine*, chalcostrobamine*, strobolamine*, knightalbinol*, and knightolamine* [13] [45]. Tw o exampleso ftheses tructuresa re given in Fig. 12. [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Original cyclophanes from the turrianegroup were isolated from Kermadeciae lliptica: kermadecins A* -H* [ 46]. Kermadecins I* and J* and isokermadecins D* and F* were isolated from the bark of Kermadecia rotundifolia [47]. Kermadecins A* and B* (see Fig. 13)s howed significant anticancer activities againstL1210 and KB cells [46], while kermadecins D* and F* and isokermadecin D* (see Fig. 13)p ossess significant inhibitory effects on acetylcholinesterase [47].

Other members of this family,such as from the endemic genera Beaupreopsis, Garnieria, Sleumerodendron,a nd Virotia,a re still untouched. Recently, fatty acids from seeds of Grevillea exul var. rubiginosa and Alphitonia neocaledonica (Rhamnaceae)h ave been investigated. They are characterized by ahigh percentage of unsaturated fattya cids and are even considered by the authors as a promising sourceo fw-5-monoenes that are uncommoni n the plant kingdom [48]. As shown in this article,t he investigation of the nutritive potential of seeds is also an original axis for the research of economical valorization of the New Caledonian flora. It could be extended to other families.Finally, Grevillea spp., Beauprea spp., Virotia spp., and Stenocarpus milnei are under investigation by Stratoz SAS and local research centersf or theirc ontento f manganese bindersw ith industrial application in catalysis for green chemistry.T hese investigationsa re closely associated with revegetalization programsofdamaged sites after mining.

Winteraceae.Z ygogynum is the only genus of this family that is present in New Caledonia. It comprises 31 endemic species. SØvenet and Pusset revealed the uncommon alkaloidal contento fZygogynum pauciflorum [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. They isolated the original alkaloids calledbubbialine* and bubbialidine* (see Fig. 14)which are structurally related to nor-securinine,acompound that was previously isolated from Euphorbiaceae.

Other phytochemical studies led to the isolation of four original and bioactivet etralones,n amely zygolone A*, 4'-O-methylzygolone A*, 3'-deoxyzygolone A*, and isozygolone A* (see Fig. 15), from Zygogynum stipitatum, Zygogynum pancheri, Zygogynum acsmithii,a nd Zygogynum baillonii [49]. These compounds expressedp otentb inding activities on peroxisome proliferator-activated receptor-g and thus could be potentially used for treatment of diabetes.T etralones also showed cytotoxic activities against KB cancer cells with IC 50 values ranging from 1.4to6.5 mm [49].

In 17)f rom Z. pancheri and Z. acsmithii [50].T wo original drimanes,n amely isodrimanial* and 1b-{[(E)-4methoxycinnamoyl]oxy}bemadienolide*(Fig. 17)w ere also isolated from the bark of Z. baillonii [51].

Drimanese ndowedw ith ad ialdehydef unctionality, such as isodrimanial* that is shown in Fig. 17,s howed potent cytotoxic activities againstKB, HL60,and HCT116 cancer cells (IC 50 values ca. 1 mm) [51].

Eudicot Rosids. Fabiids. Calophyllaceae. This family consists of four speciesi nN ew Caledonia, half of them being endemic,a nd comprisest wo genera. Pantropical Calophyllum inophyllum (tamanou)h as been widely studied, especially for the oil obtained from its seeds which proved to be vulnerarya nd cicatrizing. Calophyllolide, inophyllum, and other complex polyphenols are considered as responsible for such effects [52].Moreover, inophyllums showed inhibition of HIV-1 reverse transcriptase in cellulo, with IC 50 values ranging from 1.4t o1 .6 mm [53].

Otherwise, Calophyllumc aledonicum contains characteristic calolongic acid and caledonic acid* together with twelve original xanthones,such as caledonixanthones A* -M* (see Fig. 18) [54 -56].The latter compounds displayed Celastraceae. This family is represented by 24 species, including 21 endemics, and comprises seven genera (includingt hree endemics). Despite the originality of New Caledonian Celastraceae,o nly two endemics pecies have been investigatedfor theiralkaloidalcontent yet. Peripterygia marginata containso riginal cinnamoylspermidine derivatives (namely periphylline*, dihydroperiphylline*, isoperiphylline*, and neoperiphylline*) and Dicarpellum pronyensis contains a-aminoalcohols togetherwith uncommon linears ympathomimetic alkaloidsc alled dicarprines A* -C* [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Examples of thesestructures are presented in Fig. 19.

Also, Celastrus paniculatus,atraditional ayurvedic medicinal plantu sed because of its various neuroactive properties (e.g.,memoryenhancing, analgesic, and sedative properties)h as been studied, especially with regard to its oil content [60]. Most of the New Caledonian members of this family remain totally unexplored. In view of the results obtains previously,C elastraceae represent an attractive groupf or the discovery of new bioactive compounds.

Clusiaceae (ex Guttiferae). This family is represented in New Caledonia by 20 species and is divided into two genera (Garcinia and the endemic genus Montrouziera). SomeC lusiaceae are majestic trees,s uch as Montrouziera cauliflora,a nd can be used for joinery work. From a chemical point of view,f our of the 14 endemic Garcinia species were shown to contain xanthones that are related to various biological activities,s uch as antimalarial and antileishmanial activities [56][60 -64].E xamples of original and bioactive xanthones are given in Fig. 20.

Five new depsidones (garcinisidones B* -F*) were isolated from Garcinia neglecta and Garcinia puat (var. puat). These compounds expressed antiviral activities against the Epstein -Barr virus and potential for cancer chemoprevention [61]. Garcinia vieillardii also contained numerous xanthones,s uch as pancixanthones Aa nd B, isocudraniaxanthones Aa nd B, original vieillardiixan- Garcinia virgata,w hich has been studied out of cosmetic interest, containsv arious xanthones,i ncluding the novel virgataxanthones A* and B* and the cytotoxic anti-KB guttiferones Iand J* (see Fig. 20). It also produces original formylated tocotrienols* (see Fig. 21), together with b-a nd d-tocotrienol, and benzophenones,s uch as cotoin [64] [65]. Anothers tudy focused on tocotrienol derivatives from Garcinia amplexicaulis and confirmed the great interest in this genus fromcosmetic perspectives due to antiangiogenic activity [66]. Finally,anew xanthone calledmontrouxanthone* and adihydroisocoumarin, montroumarin* (see Fig. 20), along with the two known compounds 1,3,5-trihydroxy-4-(3,7-dimethylocta-2,6-dien-1-yl)-9H-xanthen-9-one and kaerophyllin, were isolated from Montrouziera sphaeroidea [67]. Other Montrouziera species have not been investigatedy et.

Cunoniaceae. Despitethe wide diversityand originality of the CunoniaceaeinNew Caledonia,only little is known about the chemistry of these plants.T his family is representedby90species,all beingendemic, and comprises four genera (including two endemicg enera: Codia and Pancheria). Euphorbiaceae. This family is highly represented in New Caledonia:1 9g enera that consist of 72 species (58 endemics). Other Euphorbiaceae are also of high economic importancethroughout the world. Indeed, their chemical investigation led to the discovery of many active compounds and several of them,s uch as prostratin and jatrophane,a re now commercializeda sd rugs [71].T o assess their important pharmacological potential, we should mention that Euphorbiaceae speciesare oftencited by traditionalh ealers in New Caledonia as in other countries [START_REF]Phytochemistry of Plants Used in Tr aditional Medicine[END_REF].

However, only few species were chemically investigated:t he genus Croton is frequently described in the literature as arich source of biologically active compounds, such as compounds showinga ntiulcer, antitumor,a nd cocarcinogenic activities. In New Caledonia,t his genus is representedb yt wo species, and one of them has been investigated. Several original diterpenes,includingthe new trachylobanes crotinsularina nd crotinsulactone,a nd the new clerodane-typet erpenoids furocrotinsulolides Aa nd B, and an ew phenolic disaccharide (3,4-dimethoxyphenyl rutinoside)w ere isolated from the non-endemic species Croton insularis [72].T he structures are shown in Fig. 22.

Also, Macaranga vedeliana has been studied by ethnopharmacologists.T his plant is used by traditional Kanak healers to relieve pain and cure tonsillitis.C hemical investigationso ft he leaves of M. vedeliana led to the discovery of macarangin, ag eranyl-substituted flavonol, and vedelianine,ahexahydroxanthene derivative,t hat have been found later in other Macaranga spp. [ 73][74]. Other pantropical speciesh ave been studied, for example Excoecaria agallocha,w hich contains numerous original terpenoids, such as seco-labdane diterpenes of the excoecarin series and phorbole sters (e.g., [ 75]a nd [76]). Otherwise,t he bioguidedf ractionation of bark extracts from Trigonostemon cherrieri led to the isolation of antiviral O-bearing daphnane diterpenoidorthoesters with an uncommonc hlorinated moiety:t rigocherrins A* -F* and trigocherriolides A* -D* [77] [78]. Examples of these compounds are presented in Fig. 22.T hese results confirm the interest in terpenoids from Euphorbiaceae,e specially for the search of antiviral compounds [71].O ther species, such as Homalanthus spp., that are described in the traditional Kanakp harmacopoeia proved to be active in preliminary biological screening and should be subjected to further investigations.

Chemical investigationso fE uphorbiaceae can also be oriented towardo ther goals. Codiaeum peltatum and Fontainea pancheri are known to be strongly refused by herbivorous animals.Ac hemicali nvestigationo fF. pancheri led to the identification of an ew guanidine-type Fig. 22. Examples of significant bioactive and original terpenoidsencountered in Euphorbiaceae alkaloid:fontaineine [79].T his indication may lead to the discovery of other interesting toxic compounds in C. peltatum.The family Euphorbiaceae also contains aromatic plants which could be investigated for potential use in perfumery (e.g.,f lowerso fBaloghia spp.). Cocconerion balansae,famousinNew Caledoniafor its bloody sap,may containf lavonoids or coumarins but no scientific publication is available concerning this plant.W ea re convinced that this group shouldb ef urther investigated due to cosmetic and pharmacological potential.

Linaceae. This family is represented in New Caledonia by six Hugonia species,all but one being endemic.Absouline*, an original alkaloid presented in Fig. 23,a nd four other pyrrolizidin alkaloidsw ere isolated from Hugonia oreogena and Hugonia penicillanthemum [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. Pyrrolizidin alkaloidsm ight be synthetized by plants to protect themselves against herbivores and were frequently reported to be responsible for planttoxicity [START_REF] Rizk | Naturally Occurring PyrrolizidineAlkaloids[END_REF].

Rhizophoraceae. Rhizophoraceaei sr epresented in New Caledonia by twelve species (five endemic) and is divided into four genera. These plants comprise the mangroves and thus,a re restricted to an extreme environment. Thep articular edaphic conditions related to Rhizophoraceae could also affect their chemical composition. Among the five endemic species that are listed in New Caledonia, three of them belong to the genus Crossostylis: Crossostylis biflora, Crossostylism ultiflora,and Crossostylis sebertii.Each of them contains alkaloids, such as hygrine and tropanol derivatives,i ncluding the uncommon disulfurated brugine (see Fig. 24), an alkaloid that has been found only in Rhizophoraceae [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF]. To the best of our knowledge,n oo ther species have been investigated regarding their chemicalcontent.

Salicaceae (ex Flacourtiaceae). Salicaceae are represented in New Caledonia by 56 species,a ll but one being endemic, and are divided into four genera. Homalium encompasses 18 species and one of them, Homalium guillainii (ex Homalium pronyense), has been studied. Four alkaloids with am acrocyclic spermidines tructure were isolated from the leaves of this plant (see structures in Fig. 25): homaline,h opromine*, hopromalinol*, and hoprominol* [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF].

Other members of this family may contain original and/ or bioactive compounds.W et hink that this groups hould receive morea ttentionf rom phytochemists,e specially the endemic Lasiochlamys genus that containse leven species. Casearia silvana, Lasiochlamys peltata,a nd Xylosma vincentii were studied for their Ni content [START_REF] Kersten | [END_REF];t hese species synthetize specialb inders of Ni, such as ac itrate-complex form [82].T hese organometallic complexes are of high interest since they are used to improve the yield and stereoselectivity of chemical synthesis [83].

Violaceae. This family is representedinNew Caledonia by nine species,a ll being endemic, and is divided into two genera.O nly one species was studied: Hybanthus austrocaledonicus.Anew hopane-type triterpenoid, 3-epiwoodwardinic acid* (see Fig. 26)together with otherpreviously isolated compounds,s uch as 24-methylidene cycloartenone,2 4-methylidene cycloartenol, b-sitostanone,2 1 bhydroxycaloncobalactone,a nd daucosterol, were isolated from the leaf extract of this plant [84].

Moreover, H. austrocaledonicus is knowna sh yper Ni-accumulating species and shown to contain several metabolites synthetized especially for heavy metal chelation [85].

Malvids. Meliaceae. This family is represented in New Caledonia by 13 species,i ncluding eight endemics,a nd is divided into fourg enera. Two Dysoxylum spp.h ave been studied and both contain bioactive terpenoids. Dysoxylum macranthum contains eleven original tirucallane-type triterpenes, dymacrinsA *-K*( see examplesi nFig.27), together with two previously described tetracyclic triterpenes and two known pregnane steroids [86].D ymacrins B*,C *, H*, and J* showed moderate cytotoxic activities against KB cells (IC 50 values between 1a nd 8.3 mg ml À1 ). Myrtaceae. This family is the most represented in New Caledonia. It contains 22 genera, including six endemics, and 257 species,o nly three being non-endemic: Melaleuca quinquenervia, Sannantha virgata,a nd Syzygium malaccense.M yrtaceae are often described in the literature for containing essential oils,t erpenes,a nd flavonoids [START_REF] Bruneton | Pharmacognosy, Phytochemistry,M edicinalP lants[END_REF]. Despite the importance of this group,o nly af ew species have been investigatedyet. Forexample, we were unable to find any publication concerning the endemic Syzygium spp. although Syzygium is the third most important genus in New Caledonia (71s pecies).

Volatiles from several endemic species have been analyzed. Thus,t he essential oils obtainedf rom the leaves of all seven endemic Melaleuca species were analyzed. They were shown to contain high amountso fm ono-and sesquiterpene hydrocarbons [START_REF] Hnawia | [END_REF].E ssential oils from endemics pecies were significantly differentf rom the one obtainedf rom M. quinquenervia (niaouli)which is known to contain various sesquiterpene alcoholsa nd to exhibit antimicrobiala ctivity [90] [91].E ssential oils obtained from three Eugenia species have also recently been analyzed for chemotaxonomical reasons [92]. Thus, Eugenia gacognei, Eugenia horizontalis,a nd Eugenia noumeensis were shown to contain acetophenone derivatives together with mono-a nd sesquiterpenes [92].F inally,l eaf essential oil from Arillastrum gummiferum,t he only member of the endemic genus Arillastrum,h as been investigated:i tc ontains limonene (80%),o ther monoterpenes,such as a-and b-pinene,and caryophyllene was the major sesquiterpene [93].W eshould notice that this tree is characteristic for some of the biotopesw ec an observe on serpentines oils,f orming monospecific forests in some cases.I th as been extensively exploited in the pastf or carpentry,seeing its population highly reduced, and is now threatened by mining activities (see www.oeil.nc). This tree should be integrated into reforestation plans and ab etter knowledge of its chemistry could give supplementary reasonsf or that.

Thec hemistryo ft hree Tristaniopsis species (Tristaniopsis callobuxus, Tristaniopsis yateensis,and Tristaniopsis glauca)i sa lso described in the literature.T hey contain ellagic acid and another original tannin called 3,4,5trimethoxyphenyl( 6-O-galloyl)-b-d-glucopyranoside [94]. These plants demonstrated in vitro antiplasmodial activities.E llagic acid and glycoside A3A were identified as antimalarial active compounds(IC 50 0.5 and 3.2 mm,r esp.) and exhibited very low cytotoxic activities on human skin fibroblast cells and HepG2 [ 94] [95]. Recently,b ioguided fractionationo fl eaf extract from Carpolepis laurifolia for antiviral activity against DENV has led to the isolation of betulinic acid and five apigenin derivatives,i ncludinga n unusual C-methylapigenin [96].

Other species may containv aluablec hemicals,s uch as polyphenols with antioxidant or dying properties.A lso, fruit chemistrys eems to be interestingi nt his family since severals pecies (e.g.,f rom Eugenia and Syzygium genera) produce aromatic and tasty fruits.

Rutaceae. This family is representedinNew Caledonia by 86 species,including 77 endemics,and is dividedinto 22 genera.Rutaceae is widely known for its alkaloid-containing genera. More than 60 alkaloids were isolated from Boronella, Melicope, Sarcomelicope, Myrtopsis, Geijera, Comptonella, Dutaillyea, Zanthoxylum,o rFlindersia species [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF] [97]. Someo ft hese compounds,s uch as acronycine derivatives,showedp otent antitumor activities.S ome examples representing the diversity of the original structures found in New Caledonian species are presented in Fig. 28.

Alkaloids from Rutaceae are furoquinoline, acronydine,acronycine, acridone,orindole derivatives and therefore should be associated with many bioactivities.H owever,o nly few biological evaluations of these plants have been published. Otherwise,c oumarins were isolated from severalN ew Caledonians pecies:r amosin,m yrsellin*, and myrsellinol* (see Fig. 29)w ere isolated from leaves of Myrtopsis sellingii and Myrtopsis corymbosa [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF] [98]. Other previously described coumarins are also represented in Myrtopsis spp., such as bergapten, phellopterin, seselin, and osthol, this class of compounds is showing cosmetic potential, such as for sun-protection [START_REF] Samuelsson | Drugs of Natural Origin[END_REF].These plants also containu nusual alkaloidss uch as myrtopsinea nd 8-Fig. 27. Examples of original bioactive triterpenes isolated from Meliaceae methoxyflindersine* (see Fig. 28), triterpenes,a nd sterols (lupeol and sitosterol) [START_REF] Sevenet | The Alkaloids:C hemistry and Pharmacology[END_REF].

Despite the fact that Rutaceae express ahigh economical potential, these plants remain widely unexplored. Also, no investigation of the volatiles from any endemic species has been done yet, despite the fact that oil bodies beneath their leaves are characteristic for Rutaceae.M oreover, endemic Rutaceae are mostly representedo ns erpentine soils and should be further investigatedt of ind new economic justifications for their integration into revegetalization programs afterm ining prospection and exploitation.

Sapindaceae. This family is represented in New Caledonia by 71 species,i ncluding6 5e ndemics,a nd is divided into 14 genera.T riterpenoids aponins and acylated prosapogenins were isolated from stem barko fHarpullia austrocaledonica [17] [START_REF] Okougan | [END_REF]. Four original acylated farnesyl diglycosides called crenulatosides A* -D*( see one exam-ple in Fig. 30)were isolated from leaves of Guioa crenulata [101].

Otherwise,l inear triterpenes called cupaniopsins A* -E* were isolated from barks of Cupaniopsis azantha, Cupaniopsis phalacrocarpa,a nd Cupaniopsist rigonocarpa and were evaluated for theira ctivities against peroxisome proliferator-activated receptor-g (PPA R-g) [ 102]. The mostp otent compound,c upaniopsin A* (K i 15 nm), is presented in Fig. 30.AsGuioa gracilis extracts are usedin cosmetics and pharmaceutical preparations for treatment of skin aging [103], Guioacrenulata and Guioa villosa were subjected to bioguided fractionationf or tyrosinase inhibitory activity.T his study led to the isolation of seven farnesyl diglycosides called crenulatosidesA *-G* (see two examples in Fig. 30), flavonoids,o ne trimeric proanthocyanidin,t wo triterpenes,a nd ac erebroside called soyacerebroside I( see Fig. 30)w hich appearedt ob ea potent tyrosinase inhibitor [104]. Strasburgeriaceae. This family is only represented by the endemic species Strasburgeria robusta.T hree known saponins were isolated from the stem bark of this plant: 1-O-(24-hydroxytormentoyl)g lucopyranoside and nigaichigosides F1 and F2 [113]. No biological test was associated with this study,b ut related saponins previously showed pharmacological activities and more generally,saponins are associated with various traditional and industrial applications,s uch as for fish poisoning and production of steroid hormones for the pharmaceutical industry [START_REF] Balandrin | Saponins Used in Tr aditional and Modern Medicine[END_REF]. Also,a n improved knowledge of the chemistry of S. robusta could allow ab etter understanding of its isolated and ancestral positionint he phylogenic tree (see Fig. 1).

Thymelaeaceae. This family is represented in New Caledonia by 19 species,a ll but one beinge ndemic. New Caledonian Thymelaeaceaea re divided into four genera, including the two endemic Deltaria and Solmsia.Only one endemic species was studied in New Caledonia: Lethedon salicifolia (ex Lethedon tannensis).

Investigation of al eaf extractf rom this plant led to isolation of several 5-hydroxy-7-methoxyflavones and glycoside derivatives,i ncludingo riginal lethedosides A* -C*, lethediosides A* and B*, and lethedocin* (see structures in Fig. 32). These flavones showed cytotoxic activities againsth uman nasopharynx carcinoma KB cells [115][116]. This family remains vastly unexplored, especially regarding the endemic genera Deltaria and Solmsia that are dedicated to serpentinesoil and thus are especially threatened by mining activities and degradations.

Conclusions. -A ss hown in several recent review articles,n atural products offer new perspectives for industrial innovations,s uch as for pharmaceutical or cosmetic applications.This renew of interestinnatural compounds is both relatedt oe cological preoccupations and to the great extent of tools available for phytochemical studies [117]. As an example,c ouplingp ossibilities offered by new chromatographic instruments,s uch as 2D-LCa ssociated with HR-MS or NMR withhigh throughput screenings and moderni nformatics software,a llowed the beginningo f efficient complex mixture studies (metabolomics,s ynergies, etc.). We hope that this new economic interest in naturalc ompounds will encourage the protection of particular original biotopes called hot spots and of the New Caledonianf lora. This review compiles publishedd ata concerning the chemistryo fN ew Caledonian basal angiosperms (14 families,1 76 species including 160 endemics), monocots (29 families,5 72 species including 276 endemics), and eudicot rosids (56f amilies,1 287 species including 1093 endemics).W efocused on endemic species and present an update of original compounds that can be considered as specific to New Caledonian flora. We also highlighted economic perspectivesf or these natural compoundsa nd endemic plants. Thus,t his reviewc ompiles data provided by 60 articles dealing specifically with chemical investigations of endemic basalangiosperms and eudicot rosids and includes more than 60 previous articles also dedicated to these plantsc ited in ap revious review by SØvenet and Pusset.

According to the bibliographywesummarized here,we identified225 original compoundsthat are specific to New Caledoniane ndemic species.U ntil now,p hytochemical research mainlyf ocused on alkaloids and terpenoids, leading to the discovery of 83 and 47 original structures, respectively 3 ). This is clearly linked to the research of bioactivecompounds for pharmaceutical applications.This reviewhighlighted the economic potential of several plants, such as from Annonaceae, Clusiaceae,a nd Rutaceae families.I nm ost cases,alot of work remains to be done before industrial application. However,for some plants that contain heavy metal binders,the chemical synthesis of thesec ompounds is studied, and they should be soon exploitedf or industrial utilization. This project is closely associated with revegetalizationofserpentine soils and is a perfect example of the economic potential of the New Caledonianp lant diversity.I ti llustrates the necessity to protect the New Caledonian flora and to pursue its chemical investigation.

Severalfamiliesthat provedtocontain interesting and/ or original compounds are still largely unexplored,f or example Euphorbiaceae,M yrtaceae,a nd Celastraceae. Manygroups have remained completely untouched despite the fact that several of them seem to be particularly attractive for phytochemical investigations.T hough A. trichopoda is considered as the mostb asal floweringp lant in the world, no chemical investigation of this plant has been performed yet. However, such an investigationcould lead to interesting resultsf or chemotaxonomy and plant evolution. Also,n one of the endemic monocots has been investigatedy et. Finally,C hloranthaceae (three endemic species),Piperaceae (15 species including eight endemics), Elaeocarpaceae (47 species including 44 endemics), Picrodendraceae (18 species including1 7e ndemics), and Phyllanthaceae(120 species including113 endemics)which have not been investigated either, are,a ccording to our opinion, prime targets for the searcho fo riginala nd bioactive compounds.

Theauthors are thankfultoall researchers working for increasing the knowledge of New Caledonian plants and promoting their protection, to those we had the chancetowork with and to the others that have inspired us.W ee xpress our special thankst ob otanists and ecologists T. JaffrØ, J. Munzinger, P. Birnbaum, V. Hequet, T. Ibanez, and L. BarrabØ who helped us during this work.W eare also grateful to A. Fourney and the reviewers who accepted to read and comment this manuscript.

Fig. 1 .

 1 Fig. 1. Phylogenetic tree of New Caledonian basala ngiosperms and eudicot rosids realized with TreeGrapha nd data from APGIII (see the Supporting Information 2 )f or the entire phylogenetic tree of New Caledonianp lant families).C hemical families encoutered in endemic species are mentioned on the right. EO,e ssential oil. 0C orrespondst oc omplete absence of chemical knowledge for any endemics pecies of af amily (nothing is mentionedfor families containing no endemic species).

Fig. 2 .

 2 Fig. 2. Structureso foriginal and bioactivecompounds isolated from Annonaceae

Fig. 3 .

 3 Fig. 3. Remarkable polyphenols isolated from Annonaceae

Fig. 4 .

 4 Fig. 4. Examples of alkaloids isolated from Atherospermathaceae

Fig. 6 .

 6 Fig. 6. Examples of alkaloidsisolated from Hernandiaceae

Fig. 5 .

 5 Fig. 5. Lignans isolated from H. cordigera

Fig. 7 .Fig. 8 .

 78 Fig. 7. Original alkaloids isolatedfrom Lauraceae

Fig. 9 .

 9 Fig. 9. Typical alkaloids encountered in Menispermaceae

Fig. 12 .Fig. 11 .Fig. 13 .

 121113 Fig. 12. Typical original tropane alkaloids encountered in endemic Proteaceae

  as econd study, Allouche et al. isolated three additional original butanolides,(3 S,4R,5S)-3-[(7Z)-hexadec-7en-1-yl]dihydro-4-hydroxy-5-methylfuran-2(3H)-one (1), methyl( 2 S,9Z)-2-[(1R)-1-hydroxy-2-oxopropyl]octadec-9-enoate (2), 3-[(7Z)-hexadec-7-en-1-yl]-4-hydroxy-5-methoxy-5-methylfuran-2(5H)-one (3), which are shown in Fig. 16,t ogether with twelve drimane sesquiterpenes (six new structures including the two examples shown in Fig.

Fig. 14 .Fig. 15 .Fig. 16 .

 141516 Fig. 14. Original alkaloids isolatedfrom Winteraceae

Fig. 17 .Fig. 18 .Fig. 19 .

 171819 Fig. 17. Originalb ioactive drimane sesquiterpenes isolated from Winteraceae

  Fogliani and co-workers studied various biological activities of 50 Cunoniaceae crude extracts,such as antimicrobial, anti-inflammatory,o ra ntidiabeticala ctivities,s earching for inhibitors of xanthine oxidase and scavengers of superoxide anions.T hey demonstrated the presence of ellagitannins (ellagic acid 4-O-b-d-xylopyranoside,mallorepanin,and mallotinic acid along with corilagin, chebulagic acid, ellagic acid, and gallic acid)w ith anti-

Fig. 20 .

 20 Fig. 20. Examples of original xanthones isolated from Garcinia spp.

Fig. 21 .

 21 Fig. 21. Original and bioactivet ocotrienold erivatives isolatedf rom Clusiaceae

Fig. 24 .

 24 Fig. 24. Originalsulfurated tropane alkaloid found in Rhizophoraceae

Fig. 23 .

 23 Fig. 23. Original alkaloid found in Hugonia spp.

Fig. 25 .Fig. 26 .

 2526 Fig. 25. Alkaloids isolated from Salicaceae

Fig. 28 .Fig. 29 .

 2829 Fig. 28. Examples for significative diversity of original alkaloidsisolated from Rutaceae

Fig. 30 .Fig. 31 .

 3031 Fig. 30. Examples of original and bioactive sesquiterpene and triterpene derivativesi solated from Sapindaceae

Fig. 32 .

 32 Fig. 32. Original flavone derivativesi solated from L. salicifolia

)O riginal compounds are tagged by an asterisk in the text and figures.

)C ompounds are considered as originals when encountered only in ar estricted numbero fe ndemic species stemming from au nique genus.