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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

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

Author(s): Mona M. Kamel, Mohamed K. Abdel-hameid, Hala B. El-Nassan* and Eman A. El-Khouly

Volume 15, Issue 8, 2019

Page: [873 - 882] Pages: 10

DOI: 10.2174/1573406415666190408125514

Price: $65


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 cellline. 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 μM and 0.34 μM respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1ð/ε, GSK-3α/β, Dyrk1A, Erk2, and CLK1). They exhibited effective inhibition of GSK-3α/β (IC50 = 0.196 μM and 0.246 μM, respectively) and Erk2 (IC50 = 0.295 μM and 0.376 μM, 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.

Keywords: Indole, meridianins, cytotoxic activity, HCT-116 cell-line, GSK-3α/β, Erk2.

Graphical Abstract
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