Affiliation:
1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
Abstract
Background:
The oceans cover more than 70% of the earth’s surface, which represents
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.
Methods:
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-indolylpyridinedicarbonitriles
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.
Publisher
Bentham Science Publishers Ltd.
Cited by
1 articles.
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