Molecular Design and Synthesis of Fused Pyrimidine-Based Scaffolds as Cancer Targeting Agents

Abstract

Two series of pyrimidine-based derivatives namely the furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine series, linked to either biarylamide or biarylurea via an NH or ether linker, were designed, synthesized and evaluated for their in vitro VEGFR-2 inhibitory activity as well as their anti-proliferative activity against NCI 60 cell line panel. Most of the biarylurea-based derivatives linked to either of the fused pyrimidine scaffolds exhibited good to potent VEGFR-2 inhibition at 10 µM concentration, with derivatives bearing an ether linkage generally exhibited better VEGFR-2 inhibition compared to their aniline analogues. Seven urea-based derivatives namely; The furo[2,3-d]pyrimidines (XVb, XVIc, XVIe) and the thieno[2,3-d]pyrimidines (XXIa, XXIb, XXIc, XXIe) exhibited potent dose-related VEGFR-2 inhibitory activity with IC50 values in nanomolar range. The thieno[2,3-d]pyrimidine derivative (XXIe) bearing 1-(3-chloro-4-methylphenyl)-3-phenyl urea via an ether linker at 4-position, exhibited a highly potent single digit nanomolar inhibition of VEGFR-2 kinase (IC50 1.3 nM). In addition, compounds (XVb) (IC50 946 nM), (XXIb) (IC50 33.4 nM) and (XXIc) (IC50 47 nM) manifested in vitro good to potent ability to inhibit VEGF-induced HUVEC cell line proliferation with inhibition percent of 99.5%, 81.97% and 79.15% respectively. On the other hand, the amide-based derivatives (XIIIa-b, XIVa-e) showed weaker VEGFR-2 inhibition (5-15%) at 10 µM concentration. These results were further explained using molecular docking studies which revealed the ability to the urea-based derivatives to form a network of key interactions, known to be essential for type II VEGFR-2 inhibitors. However, their amide-based analogues missed one key interaction with Glu 885 residue.