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

Author(s):

Mona Monir Kamel, Mohamed Kamal Abdel-hameid, Hala Bakr ElNassan* and Eman Adel El-Khouly  

Abstract:


Background: Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids showed in vitro cytotoxic and anti-neoplastic activities against 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 µM and 0.34 µM respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1ð/ɛ, 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 5aminopyrazole.

Keywords:

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

Affiliation:

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562



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