Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives as Potential Anti-Cancer Agents

Background: Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids show in vitro cytotoxic and antineoplastic activities against a wide range of cancer cell lines. Objective: Three series of bioisosteres of marine indole alkaloids (meridianins) were synthesized and the compounds were tested for their in vitro anti-proliferative activity against HCT-116 cell-line. In the design of the targeted analogues, the 2-aminopyrimidine ring of merdianins was replaced with 5-aminopyrazole, pyrazolo[1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings. Results: The cytotoxic screening of the synthesized compounds revealed that pyrazolo[1,5-a]pyrimidines (compounds 9c and 11a) had the most potent cytotoxic activity with IC50 = 0.31 mu M and 0.34 mu M respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1 partial derivative/epsilon, GSK-3 alpha/beta, Dyrk1A, Erk2, and CLK1). They exhibited effective inhibition of GSK-3 alpha/beta (IC50 = 0.196 mu M and 0.246 mu M, respectively) and Erk2 (IC50 = 0.295 mu M and 0.376 mu M, respectively). Conclusion: Meridianins emerged as promising lead structures that need further development to obtain more selective and potent cytotoxic agents. One of these modifications involved the replacement of 2-aminopyrimidinyl ring of meridianins with other heterocyclic rings. Both pyrazolo[1,5-a] pyrimidine and pyrazolo[3,4-b] pyridine rings showed promising cytotoxic activity compared to the five membered 5-aminopyrazole.