DESIGN, SYNTHESIS AND IN VITRO ANTI-CANCER ACTIVITY OF NOVEL 1,2,4-TRIAZOLE DERIVATIVES
Keywords:DNA Topoisomerase, Bis-triazole, Cytotoxicity, DNA fragmentation, Apoptosis
Objective: DNA topoisomerase is one of the important targets for anticancer agents. Many triazole derivatives have been shown to possess cytotoxic activity. In this paper, we present the design and in silico docking of a virtual library of molecules with DNA topoisomerase II along with their synthesis and In vitro cytotoxicity profile.
Methods: Sybyl X 2.1 programmesss were used to perform the docking experiments on DNA topoisomerase II using etoposide as ligand. In vitro anticancer activity was carried out by trypan blue exclusion assay against EAC cells. DNA fragmentation studies were performed by Gel electrophoresis to identify the cause of cell death induced by these compounds.
Results: Among the compounds studied for docking, 12c generated the highest docking score (13.66) and showed hydrogen bonding interactions with glycine 778 at a distance of 1.879 AËš. the compounds 12c & 12g showed the highest level of cytotoxicity with IC50 value of 0.55 Î¼M and 0.62 Î¼M respectively. Compounds 12c and12g were subjected to DNA fragmentation studies to identify the cause of cell death induced by these compounds. Gel electrophoresis of these compounds showed a typical feature of apoptosis ladders in agarose gel. Compound 12c was able to induce apoptosis at a concentration of about 3 Î¼M.
Conclusion: A series of bis-triazoles were synthesized targeted to DNA topoisomerase II and evaluated their In vitro cytotoxicity. The compound 12c was found to be most active and also exhibited apoptosis inducing potential.
Reck F, Zhou F, Girardot M, Kern G, Eyermann CJ, Hales NJ, Ramsay RR, et al. Identification of 4-Substituted 1,2,3-triazoles as novel oxazolidinone antibacterialagents with reduced activity against monoamine oxidase. J Med Chem 2005;48:499â€“506.
Qu W, Kung MP, Hou C, Oya S, Kung HF. Quick assembly of 1,4-diphenyltriazoles as probes targeting b-amyloid aggregates in Alzheimer's disease. J Med Chem 2007;50:3380â€“7.
Wuest F, Tang X, Kniess T, Pietzsch J, Suresh M. Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives. Bioorg Med Chem 2009;17:1146â€“51.
Purohit MN, Pujar GV, Manohar KV, Udupi RH, Vijayakumar GS. Synthesis and Antimicrobial Activity of 4-substituted-5-mercapto 3-carboxamido triazoles. Indian J Heterocyclic Chem 2006;16:93-4.
Romagnoli R, Baraldi PG, Lopez OC, Cara CL, Carrion MD, Brancale A, et al. Synthesis and Antitumor Activity of 1,5-Disubstituted 1,2,4-Triazoles as Cis-Restricted Combretastatin Analogues. J Med Chem 2010;53:4248â€“58.
Al-Soud YA, Al-Masoudi NA, El-Rahman A, Ferwanah S. Synthesis and properties of new 1,2,4 triazoles: potential antitumor agents. Bioorg Med Chem 2003;11:1701-8.
Kumar D, Narayanam MK, Chang KH, Shah K. Synthesis of novel indolyl-1,2,4 triazoles as potent and selective anticancer agents. Chem Bio Drug Des 2011;77:182-8.
Sunil D, Shetty P. Synthesis, characterization and anticancer activity of 1,2,4-Triazolo[3,4-b]-1,3,4 thiadiazoles on Hep G2 cell lines. Der Pharm Chemica 2009;1:19-26.
Holla BS, Veerendra B, Shivananda MK, Poojary B. Synthesis characterization and anticancer studies on some Mannich bases derived from 1,2,4 triazoles. Eur J Med Chem 2003;28:759-67.
Amin KM, El-Zahar MI, Anwar MM, Kamel MM, Mohamed M. Synthesis and anticancer activity of novel tetraline-6-yl-pyrimidine derivatives. Acta Polon Pharm Drug Res 2009;66:279-91.
Issa RM, Gaber M, Adb-Elhamed Al-Wakiel N, Fathalla SK. Synthesis, spectral, thermal and biological studies of Mn(II), Co(II), Ni(II) and Cu(II) complexes with 1-(((5-Mercapto-1H-1,2,4-triazol-3-yl)imino)-methyl)naphathalene-2-ol. Chinese J Chem 2012;30:547-56.
Murty MSR, Ram KR, Venketeswara RR, Yadav JS, Rao JV, Velattoru LR. Synthesis of new S-alkylated-3-mercapto-1,2,4 triazole derivatives bearing cyclic amine moiety as potent anti-cancer agents. Lett Drug Des Discov 2012;9:276-81.
Purohit M, Rajendra Prasad VVS, Mayur YC. Synthesis and Cytotoxicity of bis-1,3,4-oxadiazoles and bis-pyrazoles derived from 1,4-bis[5-thio-4-substituted-1,2,4-triazol-3-yl]-butane and their DNA binding. Arch Pharm Chem Life Sci 2011;11:248-54.
Purohit M, Mayur YC. Synthesis, In vitro Cytotoxicity, and Anti-microbial studies of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butanes. Med Chem Res 2012;21(2):174-84.
Giraud F, Guillon R, Loge C, Pagniez F, Picot C, Borgne M, et al. Synthesis and structure-activity relationships of2-phenyl-1-[(pyridinyl-and piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents. Bioorg Med Chem Lett 2009;19:301â€“4.
Al-Soud Y, Al-Dweri M, Al-Masoud N. Synthesis, antitumor and antiviral properties of some 1, 2, 4-triazole derivatives. Farmaco 2004;59:775â€“83.
Eswaran S, Adhikari AV, Shetty NS. Synthesis and antimicrobial activities of novel quinoline derivatives carrying 1,2,4-triazole moiety. Eur J Med Chem 2009;44:4637â€“47.
Alanine A, Anselm L, Steward L, Thomi S, Vifian W, Groaning MD. Synthesis and SAR evaluation of 1,2,4-triazolesas A2A receptor antagonists. Bioorg Med Chem Lett 2004;14:817â€“21.
Navidpour L, Shafaroodi H, Abdi K, Amini M, Ghahremani MH, Dehpour AR, Shafiee A. Design, synthesis, andbiological evaluation of substituted 3-alkylthio-4,5-diaryl-4H-1,2,4-triazoles as selective COX-2 inhibitors. Bioorg Med Chem Lett 2006;14:2507â€“17.
Sun H, Xu X, Wu X, Zhang X, Liu F, Jia J, et al. Discovery and design of tricyclic scaffolds as protein kinase ck2(ck2) inhibitors through a combination of shape-based virtualscreening and structure-based molecular modification. J Chem Inf Model 2013;53:2093âˆ’102.
Marino JP, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, et al. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J Med Chem 2007;50:3777-85.
Hou YP, Sun J, Pang Z, Pang L, Li D, Yan L, et al. Synthesis and antitumor activity of 1,2,4-triazoles having 1,4-benzodioxanfragment as a novel class of potent methionine aminopeptidase type II inhibitors. Bioorg Med Chem 2011;19:5948â€“54.
Dugan BJ, Gingrich DE, Mesaros EF, Milkiewicz KL, Curry MA, Zulli AL, et al. A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-a]pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of CEP-33779. J Med Chem 2012;55:5243âˆ’54.
Shultz MD, Majumdar D, Chin DN, Fortin PD, Feng Y, Gould T, et al. Structure Efficiency Relationship of [1,2,4]Triazol-3-ylamines as Novel Nicotinamide Isosteres that Inhibit Tankyrases. J Med Chem 2013;56:7049âˆ’59.
Voronkov A, Holsworth DD, Waaler J, Wilson SR, Ekblad B, Perdreau-Dahl H, et al. Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor. J Med Chem 2013;56:3012âˆ’23.
Zhang Q, Peng Y, Wang XI, Keenan SM, Arora S, Welsh WJ. Highly potent triazole-based tubulin polymerization inhibitors. J Med Chem 2007;50:749-54.
Purohit M, Chandrashekhar VM, Mayur YC. Synthesis and in vitro cytotoxicity studies of certain novel heterocycles derived from bis 1, 2, 4-triazoles and their dna damage studies. Med Chem 2013;9:1063-72.
Reddy SK, Purohit MN, Pujar GV. Synthesis and pharmacological activity of some novel bis-heterocycles encompasssing pyrrole. Int J Pharm Pharm Sci 2012;4(5):153-7.
Paul DA, Adrian CN. Electrophoretic DNA analysis for the Detection of Apoptosis. Mol Biotech 1998;9:247-52.