Molecular design and synthesis of small organic compounds based on optimization of selected scaffolds as targeted anticancer agents

Abstract

This study includes an overview about cancer and the role played by genetic and epigenetic gene modifications in cancer progression, which is controlled by overexpression of tyrosine kinases (EGFR /VEGFR2) and HDACs, respectively. Herein, six novel series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesized as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (XIIc, XVb and XXb) were promising multitarget hits. Whereas (XIIc) exhibited potent VEGFR2 inhibition (IC50 = 185.89 nM), potent EGFR inhibition (IC50 = 1.14 µM), and mild HDAC6 inhibition (23% inhibition). (XVb) exhibited potent EGFR inhibition (98% inhibition), moderate VEGFR2 inhibition (32% inhibition), and moderate HDAC6 inhibition (30% inhibition). Compound (XXb) exhibited potent EGFR inhibition (IC50 = 155.97 nM), moderate HDAC6 inhibition (56% inhibition), and mild VEGFR2 inhibition (25% inhibition). Moreover, compound (XVc) was the most potent dual inhibitor among all the synthesized compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50 = 19.16 nM) and (IC50 = 5.58 µM), respectively. While compounds (XXd) and (VIIc) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesized compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Most of the compounds showed weak to moderate inhibition towards Renal UO-31 and CNS cancer SNB-75 cell lines despite their potent enzyme inhibitory profiles. Additionally, molecular docking studies were carried out to gain further insight into the binding mode to