Bou Nour

Cindy Karroum

Adrien Patinote

Georges Chouchou

Mona Moarbess

Pierre Diab-Assaf

Carine Cuq

Issam Deleuze-Masquéfa

Pierre-Antoine Kassab

Bonnet

2-a]pyrazine, imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline and pyrazolo[1,5-a]quinoxaline derivatives

Keywords:

est destinée au dépôt

Synthesis of pyrazolo[1,5-a]quinoxalines Synthesis of imidazo[1,5-a]quinoxalines

The aim of this study is to obtain new IKK inhibitors, analogues of BMS-345541.

Synthesis of imidazo[1,2-a]pyrazines

5a 6a 7a

IKKα inhibition activities are less than 20 % at 10 μM for all compounds.

Compound 6a in the ATP binding pocket of IKKβ.

Four series of imidazopyrazines, imidazoquinoxalines and pyrazoloquinoxalines were efficiently synthesized with short reaction times by using microwave assistance. The compounds were evaluated for their IKKα and IKKβ inhibition. We found a good correlation between the biological activity as selective inhibitors on the IKKβ and the docking study performed. Compound 6a bearing a methyl group at the position 8 and a bromine group at position 1 showed remarkable activity.

Introduction

Targeting the activation of NF-κB-dependent pathway by IKK inhibitors is becoming an increasingly popular avenue for the development of novel therapeutic interventions for inflammation and cancer. Many pharmaceutical companies are developing inhibitors that target IKK.

  Synthesis of imidazo[1,2-a]quinoxalines IKK inhibitory activities of imidazo[1,2-a]pyrazine, imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline and pyrazolo[1,5-a]quinoxaline derivatives. Nour Bou Karroum 1,3 , Cindy Patinote 1,2 , Adrien Chouchou 1 , Georges Moarbess 3 , Mona Diab-Assaf 3 , Pierre Cuq 1 , Carine Deleuze-Masquéfa 1 , Issam Kassab 3 , Pierre-Antoine Bonnet 1 .

  The transcription factor NF-κB plays a key role in multiple cellular processes, including immune signaling, inflammation, development, proliferation and survival. Disregulated NF-κB activation is associated with autoimmunity 1 , chronic inflammation 2 and cancer3 . Activation of NF-κB requires IκB kinases: IKKα and IKKβ. Representation of NF-κB-dependent genes involved in inflammation and cancer (published by Mike Menkes listed in cancer, originally published in issue 220 -February 2015). Stimulation of the surface receptors by different inducers initiates several proximal signaling events resulting in activation of the IκB kinase complex 4.BMS-345541 was identified as a selective inhibitor of the catalytic subunits of IKK (IKKβ : IC 50 = 0.3 µM, IKKα: IC 50 = 4 µM).5

  (a) SOCl 2 , reflux, 18 h ; (b) NaHMDS, THF, 5 h ; (c) NaH, DMA, reflux, 48 h ; (d) POCl 3 , DEA, MW (130°C, 15 min) ; (e) EtOH, NHCH 3 , MW (150°C, 20 min) ; (f) NBS, CHCl 3 , reflux, 2 h ; (g) arylboronic acid R 3 -B(OH) 2 or trimethylboroxine, Pd(PPh 3 ) 4 , Na 2 CO 3 , DME, MW (140 °C, 20 min).(a) R 1 = H : NH 4 OH, CH 3 CN, MW (130°C, 2h) ; R 1 = CH 3 : CH 3 NH 2, EtOH, MW (140°C, 20 min) ; (b) Trimethylboroxine (R 2 =CH 3 ), K 2 CO 3 , PdCl 2 (dppf) . CH 2 Cl 2 , THF, MW (140°C, 20 min) or 3,4-dimethoxyphenylB(OH) 2 (R 2 =3,4-dimethoxyphenyl), Na 2 CO 3 , Pd(PPh 3 ) 4 , DME/H 2 O (1/1), MW (140°C, 20 min) ; (c) BBr 3 , CH 2 Cl 2 , 0°C to RT, 2h. (a) MeCN, reflux, 24h ; (b) NH 2 -NH 2 .H 2 O, Pd/C, EtOH, reflux, 1h ; (c) CDI, PhCl 2 , reflux, 4 h ; (d) POCl 3 , DEA, MW (130 o C, 15 min) ; (e) CH 3 NH 2 , EtOH, MW (150 o C, 30 min).(a) SOCl 2 , reflux, 18h ; (b) NaHMDS, THF, 5h ; (c) NaH, DMA, reflux, 48h ; (d) POCl 3 , DEA, MW (130°C, 15 min) ; (e) CH 3 NH 2 , EtOH, MW (150°C, 30 min) ; (f) NBS, CHCl 3 , reflux, 2h. (a) SOCl 2 , reflux, 18h ; (b) NaHMDS, THF, 5h ; (c) NaH, DMA, reflux, 48h ; (d) POCl 3 , DEA, MW (130°C, 15 min) ; (e) CH 3 NH 2 or (CH 3 ) 2 NH, EtOH, MW (150°C, 30 min) ; (f) NBS, CHCl 3 , reflux, 2h .

  Société d'Accélération du Transfert de Technologies (SATT AxLR), CSU, 950 rue Saint Priest, 34090 Montpellier, France.3 Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, EDST, BP 90656, Fanar Jdeideh, Lebanon.

1

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 F16, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue

Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, France.

2