Synthesis and Cytotoxic Activity of Novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indole Derivatives

Abstract

A series of novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indoles (3a–l) were synthesized and their cytotoxicities were analyzed against 3 different human cell lines, including liver (HUH7), breast (MCF7) and colon (HCT116). The Mannich reaction of 3-methylindole (1) with 4-substitutedpiperazines (2) and formaldehyde resulted to the 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indoles (3a–l) in 38–69% yields. The investigation of anticancer screening revealed that the tested compounds showed comparable activity to the reference drug 5-fluorouracil and compounds 3g, 3h, 3i and 3k, had lower 50% inhibition (IC₅₀) concentration than reference drug. Moreover, the cytotoxic effect of the most potent compound 3h on HUH7 and MCF7 cells through apoptosis was visualized by Hoechst staining and compared with paclitaxel, which is a mitotic inhibitor acting on microtubules. The morphological features of apoptosis were observed as condensed and fragmented nuclei that are similar to paclitaxel.

Key words

anticancer - apoptosis - indole - Mannich base - 1,4-disubstitutedpiperazines

• References

• 1 Waring MJ. The Search for New Anticancer Drugs. Dordrecht, The Netherlands: Kluwer Academic Publishers; 1992: 1-18
• 2 Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71-96
• 3 Bacher G, Beckers T, Emig P et al. New small-molecule tubulin inhibitors. Pure Appl Chem 2001; 73: 1459-1464
• 4 Buolamwini JK, Addo J, Kamath S et al. Small molecule antagonists of the MDM2 oncoprotein as anticancer agents. Curr Cancer Drug Targets 2005; 5: 57-68
• 5 Dass CR, Choong PFM. Targeting of small molecule anticancer drugs to the tumour and its vasculature using cationic liposomes: lessons from gene therapy. Cancer Cell International 2006; 6: 17
• 6 Downing KH, Nogales E. Tubulin and microtubule structure. Curr Opin Cell Biol 1998; 10: 16-22
• 7 Brancale A, Silvestri R. Indole, a core nucleus for potent inhibitors of tubulin polymerization. Med Res Rev 2007; 27: 209-238
• 8 Duflos A, Kruczynski A, Barret JM. Novel aspects of natural and modified vinca alkaloids. Curr Med Chem Anticancer Agents 2002; 2: 55-70
• 9 Kumar D, Sundaree S, Johnson EO et al. An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles as potent anticancer agents. Bioorg Med Chem Letters 2009; 19: 4492-4494
• 10 Marchand P, Antoine M, Le Baut G et al. Synthesis and structure-activity relationships of N-aryl(indol-3-yl)glyoxamides as antitumor agents. Bioorg Med Chem 2009; 17: 6715-6727
• 11 Ziedan NI, Stefanelli F, Fogli S et al. Design, synthesis and pro-apoptotic antitumour properties of indole-based 3,5-disubstituted oxadiazoles. Eur J Med Chem 2010; 45: 4523-4530
• 12 Dimmock JR, Kandepu NM, Hetherington M et al. Cytotoxic Activities of Mannich Bases of Chalcones and Related Compounds. J Med Chem 1998; 41: 1014-1026
• 13 Aboraia AS, Abdel-Rahman HM, Mahfouz NM et al. Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents. Bioorg Med Chem 2006; 14: 1236-1246
• 14 Ivanova Y, Momekov G, Petrov O et al. Cytotoxic Mannich bases of 6-(3-aryl-2-propenoyl)-2(3 H)-benzoxazolones. Eur J Med Chem 2007; 42: 1382-1387
• 15 Reddy MVB, Su CR, Chiou WF et al. Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents. Bioorg Med Chem 2008; 16: 7358-7370
• 16 Solomon VR, Hu C, Lee H. Hybrid pharmacophore design and synthesis of isatin-benzothiazole analogs for their anti-breast cancer activity. Bioorg Med Chem 2009; 17: 7585-7592
• 17 Chen J, Lou J, Liu T et al. Synthesis and in-vitro antitumor activities of some Mannich bases of 9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones. Arch Pharm Chem Life Sci 2009; 342: 165-172
• 18 Shaw AY, Chang CY, Hsu MY et al. Synthesis and structure-activity relationship study of 8-hydroxyquinoline-derived Mannich bases as anticancer agents. Eur J Med Chem 2010; 45: 2860-2867
• 19 Dimmock JR, Kumar P. Anticancer and Cytotoxic properties of Mannich bases. Curr Med Chem 1997; 4: 1-22
• 20 Yarim M, Koksal M, Schepmann D et al. Synthesis and in vitro evaluation of novel indole-based sigma receptors ligands. Chem Biol Drug Des 2011; 78: 869-875