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 MHESR - Ministère de l'Enseignement Supérieur et de la Recherche Scientifique
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.
Shchepinov M. S. Korshun V. A. Recent applications of bifunctional trityl groups Chem. Soc. Rev. 2003 32 170 180 https://dx.doi.org/10.1039/b008900l
Montes De Oca M. N. Vara J. Milla L. Rivarola V. Ortiz C. S. Physicochemical properties and photodynamic activity of novel derivatives of triarylmethane and thiazine Arch. Pharm. 2013 346 255 265 https://dx.doi.org/10.1002/ardp.201200437
Dong J. Aulestia F. J. Assad Kahn S. Zeniou M. Dubois L. G. El-Habr E. A. Daubeuf F. Tounsi N. Cheshier S. H. Frossard N. Junier M. P. Chneiweiss H. Néant I. Moreau M. Leclerc C. Haiech J. Kilhoffer M. C. Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling Biochim. Biophys. Acta, Mol. Cell Res. 2017 1864 1018 1027 https://dx.doi.org/10.1016/j.bbamcr.2017.01.010
Zeniou M. Fève M. Mameri S. Dong J. Salomé C. Chen W. El-Habr E. A. Bousson F. Sy M. Obszynski J. Boh A. Villa P. Kahn S. A. Didier B. Bagnard D. Junier M. P. Chneiweiss H. Haiech J. Hibert M. Kilhoffer M. C. Heeschen C. Chemical library screening and structure-function relationship studies identify bisacodyl as a potent and selective cytotoxic agent towards quiescent human glioblastoma tumor stem-like cells PLoS One 2015 10 1 35 https://dx.doi.org/10.1371/journal.pone.0134793
Sylla-Iyarreta Veitía M. Siverio-Mota D. Lerari V. Marin M. Giner R. M. Vicet Muro L. Rivero Guerra Y. Dumas F. Ferroud C. A. M de Witte P. Crawford A. D. Aran V. J. Marrero Ponce Y. Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues Curr. Top. Med. Chem. 2017 17 2866 2887 https://dx.doi.org/10.2174/1568026617666170817161953
Ricco C. Abdmouleh F. Riccobono C. Guenineche L. Martin F. Goya-Jorge E. Lagarde N. Liagre B. Ben Ali M. Ferroud C. El Arbi M. Sylla-Iyarreta Veitía M. Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies Bioorg. Chem. 2020 96 103591 https://dx.doi.org/10.1016/j.bioorg.2020.103591
Mibu N. Yokomizo K. Uyeda M. Sumoto K. Synthesis and antiviral activities of some 4,4′- dihydroxytriphenylmethanes Chem. Pharm. Bull. 2003 51 1325 1327 https://dx.doi.org/10.1248/cpb.51.1325
Sumoto K. Mibu N. Yokomizo K. Uyeda M. Synthesis of 2,2′-dihydroxybisphenols and antiviral activity of some bisphenol derivatives Chem. Pharm. Bull. 2002 50 298 300 https://dx.doi.org/10.1248/cpb.50.298
Ikarashi N. Baba K. Ushiki T. Kon R. Mimura A. Toda T. Ishii M. Ochiai W. Sugiyama K. The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE2 secretion from macrophages Am. J. Physiol. 2011 301 G887 G895 https://dx.doi.org/10.1152/ajpgi.00286.2011
Fujita T. Karaki S. Tateoka T. Kuwahara A. Desacetyl bisacodyl-induced epithelial Cl(-) secretion in rat colon and rectum Biomed. Res. 2016 37 13 20 https://dx.doi.org/10.2220/biomedres.37.13
Chemama M. Fonvielle M. Arthur M. Valéry J. M. Etheve-Quelquejeu M. Synthesis of stable aminoacyl-tRNA analogues containing triazole as a bioisoster of esters Chem. - Eur. J. 2009 15 1929 1938 https://dx.doi.org/10.1002/chem.200801563
Silverman S. M. Moses J. E. Sharpless K. B. Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE Chem. - Eur. J. 2017 23 79 83 https://dx.doi.org/10.1002/chem.201604765
Bourne Y. Kolb H. C. Radić Z. Sharpless K. B. Taylor P. Marchot P. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation Proc. Natl. Acad. Sci. U. S. A. 2004 101 1449 1454 https://dx.doi.org/10.1073/pnas.0308206100
Ferreira S. Sodero A. C. R. Cardoso M. F. C. Lima E. S. Kaiser C. R. Silva F. P. Ferreira V. F. Synthesis, Biological Activity, and Molecular Modeling Studies of 1H-1,2,3-Triazole Derivatives of Carbohydrates as a-Glucosidases Inhibitors J. Med. Chem. 2010 53 2364 2375 https://dx.doi.org/10.1021/jm901265h
Tron G. C. Pirali T. Billington R. A. Canonico P. L. Sorba G. Genazzani A. A. Click chemistry reactions in medicinal chemistry: Applications of the 1,3-dipolar cycloaddition between azides and alkynes Med. Res. Rev. 2008 28 278 308 https://dx.doi.org/10.1002/med.20107
Valverde I. E. Bauman A. Kluba C. A. Vomstein S. Walter M. A. Mindt T. L. 1,2,3-Triazoles as amide bond mimics: Triazole scan yields protease-resistant peptidomimetics for tumor targeting Angew. Chem., Int. Ed. 2013 52 8957 8960 https://dx.doi.org/10.1002/anie.201303108
Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN, 2022, https://www.iarc.who.int/fr/news-events/global-burden-of-colorectal-cancer-in-2020-and-2040-incidence-and-mortality-estimates-from-globocan/
Berscheid R. Vögtle F. Nieger Z. Mehrfach verbrückte Triphenylmethane Chem. Ber. 1992 125 1687 1695 https://dx.doi.org/10.1002/cber.19921250726
Li N. Wang C. Georgiev M. I. Bajpai V. K. Tundis R. Simal-gandara J. Lu X. Xiao J. Tang X. Qiao X. Trends in Food Science & Technology Advances in dietary polysaccharides as anticancer agents: Structure-activity relationship Trends Food Sci. Technol. 2021 111 360 377 https://dx.doi.org/10.1016/j.tifs.2021.03.008
Wang M. Chen W. Chen J. Yuan S. Hu J. Abnormal saccharides affecting cancer multi-drug resistance ( MDR ) and the reversal strategies Eur. J. Med. Chem. 2021 220 113487 https://dx.doi.org/10.1016/j.ejmech.2021.113487
Hossain F. Andreana P. R. Developments in Carbohydrate-Based Cancer Therapeutics Pharmaceuticals 2019 12 84 https://dx.doi.org/10.3390/ph12020084
Nagy A. Csordás B. Zsoldos-Mády V. Pintér I. Farkas V. Perczel A. C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies Amino Acids 2017 49 223 240 https://dx.doi.org/10.1007/s00726-016-2346-5
Görmen M. Sylla-Iyarreta Veitía M. Trigui F. El Arbi M. Ferroud C. Ferrocenyl analogues of bisacodyl: Synthesis and antimicrobial activity J. Organomet. Chem. 2015 794 274 281 https://dx.doi.org/10.1016/j.jorganchem.2015.07.016
Hadj Mohamed A. Pinon A. Lagarde N. Goya Jorge E. Mouhsine H. Msaddek M. Liagre B. Sylla-Iyarreta Veitía M. Novel Set of Diarylmethanes to Target Colorectal Cancer: Synthesis, In Vitro and In Silico Studies Biomolecules 2023 13 54 https://dx.doi.org/10.3390/biom13010054
Goel P. Alam O. Naim M. J. Nawaz F. Iqbal M. Alam M. I. Recent advancement of piperidine moiety in treatment of cancer- A review Eur. J. Med. Chem. 2018 157 480 502 https://dx.doi.org/10.1016/j.ejmech.2018.08.017
Abdelshaheed M. M. Fawzy I. M. El-Subbagh H. I. Youssef K. M. Piperidine nucleus in the field of drug discovery Future J. Pharm. Sci. 2021 7 188 https://dx.doi.org/10.1186/s43094-021-00335-y
Chen Q.-S. Li J.-Q. Zhang Q.-W. Application of Chiral Piperidine Scaffolds in Drug Design Pharm. Front. 2023 05 e1 e14 https://dx.doi.org/10.1055/s-0043-1764218
Khajeh E. Rasmi Y. Kheradmand F. Malekinejad H. Aramwit P. Saboory E. Daeihassani B. Nasirzadeh M. Crocetin suppresses the growth and migration in HCT-116 human colorectal cancer cells by activating the p-38 MAPK signaling pathway Res. Pharm. Sci. 2020 15 592
Papaliagkas V. Anogianaki A. Anogianakis G. Ilonidis G. The proteins and the mechanisms of apoptosis: a mini-review of the fundamentals Hippokratia. 2007 11 108 113, https://pubmed.ncbi.nlm.nih.gov/19582203
Sulzyc-Bielicka V. Domagala P. Hybiak J. Majewicz-Broda A. Safranow K. Domagala W. Colorectal cancers differ in respect of PARP-1 protein expression Pol. J. Pathol. 2012 2 87 92
Occhiuzzi M. A. Lico G. Ioele G. De Luca M. Garofalo A. Grande F. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents Eur. J. Med. Chem. 2023 246 114971 https://dx.doi.org/10.1016/j.ejmech.2022.114971
Revathidevi S. Munirajan A. K. Akt in cancer: Mediator and more Semin. Cancer Biol. 2019 59 80 91 https://dx.doi.org/10.1016/j.semcancer.2019.06.002
Zekri O. Hillard E. A. Top S. Vessières A. Pigeon P. Plamont M.-A. Huché M. Boutamine S. Mcglinchey M. J. Müller-Bunz H. Role of aromatic substituents on the antiproliferative effects of diphenyl ferrocenyl butene compounds Dalton Trans. 2009 4318 4326
Guo Y. Pan W. Liu S. Shen Z. Xu Y. Hu L. ERK/MAPK signalling pathway and tumorigenesis Exp. Ther. Med. 2020 19 1997 2007
Sun Y. Liu W.-Z. Liu T. Feng X. Yang N. Zhou H.-F. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis J. Recept. Signal Transduction 2015 35 600 604
Ye Q. Cai W. Zheng Y. Evers B. M. She Q.-B. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer Oncogene 2014 33 1828 1839
Loesch M. Chen G. The p38 MAPK stress pathway as a tumor suppressor or more? Front. Biosci. 2008 13 3581
Nickel J. Gohlke B.-O. Erehman J. Banerjee P. Rong W. W. Goede A. Dunkel M. Preissner R. SuperPred: update on drug classification and target prediction Nucleic Acids Res. 2014 42 W26 W31 https://dx.doi.org/10.1093/nar/gku477
Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays J. Immunol. Methods 1983 65 55 63 https://dx.doi.org/10.1016/0022-1759(83)90303-4
Bretin L. Pinon A. Bouramtane S. Ouk C. Richard L. Perrin M.-L. Chaunavel A. Carrion C. Bregier F. Sol V. Chaleix V. Leger D. Y. Liagre B. Photodynamic Therapy Activity of New Porphyrin-Xylan-Coated Silica Nanoparticles in Human Colorectal Cancer Cancers 2019 11 1474 https://dx.doi.org/10.3390/cancers11101474
Rioux B. Pinon A. Gamond A. Martin F. Laurent A. Champavier Y. Barette C. Liagre B. Fagnère C. Sol V. Pouget C. Synthesis and biological evaluation of chalcone-polyamine conjugates as novel vectorized agents in colorectal and prostate cancer chemotherapy Eur. J. Med. Chem. 2021 222 113586 https://dx.doi.org/10.1016/j.ejmech.2021.113586
Saur I. M. L. Panstruga R. Schulze-Lefert P. NOD-like receptor-mediated plant immunity: from structure to cell death Nat. Rev. Immunol. 2021 21 305 318 https://dx.doi.org/10.1038/s41577-020-00473-z
Pettersen E. F. Goddard T. D. Huang C. C. Couch G. S. Greenblatt D. M. Meng E. C. Ferrin T. E. UCSF Chimera - A visualization system for exploratory research and analysis J. Comput. Chem. 2004 25 1605 1612 https://dx.doi.org/10.1002/jcc.20084
Allouche A. Software News and Updates Gabedit — A Graphical User Interface for Computational Chemistry Softwares J. Comput. Chem. 2012 32 174 182 https://dx.doi.org/10.1002/jcc
Wolber G. Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters J. Chem. Inf. Model. 2005 45 160 169 https://dx.doi.org/10.1021/ci049885e
https://chemaxon.com/, (n.d.)
Adasme M. F. Linnemann K. L. Bolz S. N. Kaiser F. Salentin S. Haupt V. J. Schroeder M. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA Nucleic Acids Res. 2021 49 W530 W534 https://dx.doi.org/10.1093/nar/gkab294
