Biochemistry; Molecular Medicine; Pharmacology; Pharmaceutical Science; Drug Discovery; Organic Chemistry
Abstract :
[en] Triarylmethanes and triazoles constitute privileged structures extensively used in drug discovery programs. In this work, 12 novel triarylmethanes linked to a triazole ring were designed, synthesized, and chemically characterized aiming to target colorectal cancer. The synthetic strategy for triarylmethanes mono- and bi-substituted by a functionalized triazole ring involved a 1,3-dipolar cycloaddition. A preliminary screening in human colorectal cancer cells (HT-29 and HCT116) and murine primary fibroblasts (L929) allowed the selection of the best candidate 9b based on its high inhibition of cancer cell proliferation with an IC50 of 11 μM on HT-29 and 14 μM on HCT116 and its non-cytotoxic effects on murine fibroblasts (<100 μM). A deep mechanistic study on various pathways showed that compound 9b induces caspase-3 cleavage, and its inhibitory effect on PARP activity is correlated with the increase of DNA fragmentation in cancer cells. Moreover, 9b induced apoptosis promoted by the inhibition of anti-apoptotic cell survival signaling pathways demonstrated via the downregulation of phosphorylated Akt and ERK proteins. Finally, the predicted binding modes of compounds 8c and 9b to five potential biological targets (i.e., AKT, ERK-1 and ERK-2, PARP and caspase-3) was evaluated using molecular modeling, and the predictions of the SuperPred webserver identified ERK2 as the most remarkable target. Also predicted in silico, 9b displayed appropriate drug-likeness and good absorption, distribution, metabolism and excretion (ADME) profiles.
Hadj Mohamed, Ameni ; Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (GBCM, EA 7528), Conservatoire national des arts et métiers, HESAM Université, Paris, France ; Laboratoire de Chimie Hétérocyclique, Produits Naturels et Réactivité (LR11ES39), Monastir, Tunisia
Pinon, Aline; Université de Limoges, LABCiS, UR 22722, Faculté de Pharmacie, Limoges, France
Lagarde, Nathalie; Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (GBCM, EA 7528), Conservatoire national des arts et métiers, HESAM Université, Paris, France
Ricco, Christophe; Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (GBCM, EA 7528), Conservatoire national des arts et métiers, HESAM Université, Paris, France
Goya-Jorge, Elizabeth ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Mouhsine, Hadley; Peptinov, Pépinière Paris Santé Cochin, Hôpital Cochin, Paris, France
Msaddek, Moncef; Laboratoire de Chimie Hétérocyclique, Produits Naturels et Réactivité (LR11ES39), Monastir, Tunisia
Liagre, Bertrand; Université de Limoges, LABCiS, UR 22722, Faculté de Pharmacie, Limoges, France
Veitía, Maité Sylla-Iyarreta ; Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (GBCM, EA 7528), Conservatoire national des arts et métiers, HESAM Université, Paris, France
Language :
English
Title :
Colorectal anticancer activity of a novel class of triazolic triarylmethane derivatives
CAMPUS France [FR] MHESR - Ministère de l'Enseignement Supérieur et de la Recherche Scientifique [TN]
Funding text :
The authors gratefully acknowledge the CAMPUS France (PHC Program, UTIQUE 2017 37094W) and the Ministère de l'Enseignement Supérieur et de la Recherche Scientifique of Tunisia for providing financial support. A. Hadj Mohamed specially acknowledges the Excellence Eiffel program of Campus France, for her PhD scholarship 964896H (2019–2020). The authors are also grateful to Pr. Jean François Zagury for allowing them to conduct the cell viability studies in the Peptinov laboratories.
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