Mona Monir Kamel, Mohamed Kamal Abdel-hameid, Hala Bakr El-Nassan* and Eman Adel El-Khouly Pages 1 - 11 ( 11 )
Background: The oceans cover more than 70% of the earth’s surface, which represent over 95% of the biosphere. Therefore, oceans provide a wealth of marine invertebrates, especially sponges, ascidians, bryozoans and molluscs that produce structurally unique bioactive metabolites such as alkaloids. The bioactive scaffolds of marine alkaloids exhibit cytotoxic activities against human cancer cell lines.
Objective: To prepare analogues of the marine alkaloid nortopsentin [having 2,4-bis(3'-indolyl)imidazole scaffold] as cytotoxic agents via structural modification of the core imidazole ring and one of the side indole rings.
Method: Four series of nortopsentin analogues were synthesized in which the imidazole ring was replaced by pyrazole, pyrido[2,3-d]pyrimidinone and pyridine rings. Furthermore, one of the side indole rings was replaced by substituted phenyl moiety. The target compounds were tested for their in vitro cytotoxic activity against HCT-116 cell-line and the most potent compound was subjected to further investigation on its effect on HCT-116 cell cycle progression.
Results: The cytotoxic screening of the synthesized compounds revealed that bis-indolylpyridine-dicarbonitriles 8a-d exhibited the most potent cytotoxic activity with IC50=2.6-8.8 µM. Compound 8c was further tested by flow cytometry analysis to explore its effect on HCT-116 cell cycle progression that in turn indicated its anti-proliferative effect.
Conclusion: Marine-derived bis-indole alkaloids (nortopsentins) have emerged as a new class of indole-based antitumor agents. The design of new analogues involved several modifications in order to obtain more selective and potent cytotoxic agents. Indole derivatives bearing a pyridine core displayed more potent cytotoxic activity than those containing pyrido[2,3- d]pyrimidin-4(1H)-one moiety.
3-Indolyl pyrazoles, 3-indolyl pyrido[2, 3-d]pyrimidines, bis-indole derivatives, Nortopsentins, Anticancer activity, Cell cycle analysis.
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