Novel pyrano[2,3-c]pyrazolopyrimidines as promising anticancer agents: Design, synthesis, and cell cycle arrest of HepG2 cells at S phase

Abstract

The poor selectivity, significant toxicity, high cost, and emergence of resistance of conventional chemotherapies are driving motive for the ongoing search for novel anticancer agents. New pyrano[2,3-c]pyrazolopyrimidines were synthesized and examined as antiproliferative agents, and the possible molecular mechanism(s) of action were explored. The mass and elemental analyses, alongside the IR,¹H, and ¹³C NMR spectra, confirmed the proposed structures of the obtained compounds. Derivatives 4 and 7 demonstrated the best antiproliferative profile against HepG2 cancer cells at 4 µM, with a high selectivity index of ∼7–9 folds. They increased the S phase cell population by 51% and 40% and caused a 5- and 11-fold increase in the p21 protein. Compound 7 was superior in inhibiting HepG2 cell migration and delayed wound healing, reducing migration rates by 55% and 90%, respectively. Future studies on the pharmacokinetics, pharmacodynamics, antimetastatic, and antitumor activities in animal models would be a robust advance.

Graphical Abstract

Keywords:

• β-Enaminonitrile
• metastasis
• pyrano[2,3-c]pyrazoles
• S phase
• wound healing

Author contribution

D.S.A.H., M.H.H., W.S.I.A., W.M.E. designed the study. D.S.A.H., M.H.H., W.S.I.A. performed the chemistry experiments. W.M.E. performed the biological evaluation of the new compounds. D.S.A.H., M.H.H., W.S.IA., W.M.E. analyzed the data and prepared the draft manuscript. W.M.E., revised the manuscript. All authors approved the final version.

Data availability statement

Full experimental detail; IR, ¹H, ¹³C NMR, and MS spectra. This material can be found via the “Supplementary Content” section of this article’s webpage.