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.