Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.
Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.
Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France; Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculté des Sciences, Université Mohammed V, B.P. 1014 Rabat, Morocco.
Soukaina
S
Alaoui
Université Côte d'Azur, CNRS UMR 7284 and INSERM U 1081, Institute for Research on Cancer and Aging (IRCAN), 28 Avenue de Valombrose, 06107 Nice, France.
Maeva
M
Dufies
Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculté des Sciences, Université Mohammed V, B.P. 1014 Rabat, Morocco.
Mohsine
M
Driowya
Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France; Département de Chimie, Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Pharmaceutiques, 4 avenue de l'Observatoire & UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, Paris Fr-75006, France.
Luc
L
Demange
Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculté des Sciences, Université Mohammed V, B.P. 1014 Rabat, Morocco.
Khalid
K
Bougrin
Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 Route de Saint-Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex 3, France.
Guillaume
G
Robert
Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 Route de Saint-Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex 3, France.
Patrick
P
Auberger
Université Côte d'Azur, CNRS UMR 7284 and INSERM U 1081, Institute for Research on Cancer and Aging (IRCAN), 28 Avenue de Valombrose, 06107 Nice, France.
Gilles
G
Pagès
Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France. Electronic address: Rachid.benhida@unice.fr.
Rachid
R
Benhida
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D061565:Cycloaddition Reaction; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012265:Ribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D009705:Nucleosides; D012265:Ribonucleotides; D013449:Sulfonamides; D014230:Triazoles; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide
Antitumor agents; Dipolar cycloaddition; Nucleoside analogues; Sequential reactions