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.
Synthesis and cytotoxic activity of 3-[2-(1H-Indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[3,2-c]pyridine hydrobromides , analogues of marine alkaloid nortopsentin
