Background: Fused heterocyclic containing pyrazolopyridine systems have several medicinal activities
including cytotoxic and carcinostatic activities.
Objective: To investigate the antiproliferative activity and associated mechanism(s) of a novel series of
Method: The series has been synthesized by the reaction of hydrazonoyl chlorides with each of 4-(4-
methoxyphenyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 2-amino-4-(4-
methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile in dioxane in basic medium. The assigned
structures for each of the new products were identified via elemental and spectral data. Moreover, the cytotoxic
activity for some selected products was screened.
Results: Derivatives 5g, 7i, 8 and 9 had their IC50 at ~ 1-3 µM and derivatives 7b, 7d, and 7f were similar to 5-
fluorouracil and had their IC50 at ~ 5 µM against breast (MCF-7) and colon (HCT-116) cell lines. All derivatives
were specific in action and safe to normal fibroblasts (WI38). Only derivative 9 caused some toxicity but at high
concentration of 93 µM. These derivatives exerted strong antiproliferative activity through inducing intrinsic
apoptosis as indicated from the significant induction of caspases 9 and 3 by 3-6 folds in colon cells and/or inhibiting
tyrosine kinase (TK) and hence arresting the cell cycle.
Conclusion: Compounds 8 and 5g were the most potent anticancer agents inhibiting the TK by 86 and 89% and
their IC50 of the enzyme were 311 and 352 nM, respectively. We believe that these derivatives deserve further
investigation and these chemical moieties could offer promising anticancer drugs.