The Design Synthesis and Biological Evaluation of Conformationally Restricted 4-Substituted-26-dimethylfuro23-dpyrimidines as Multi-targeted Receptor Tyrosine Kinase and Microtubule Inhibitors as Potential Antitumor Agents

摘要

A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound >1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds >2, 3, 7 and >10 showed microtubule depolymerizing activity comparable to or better than the lead >1, some with nanomolar EC50 values. While compound >8 had no effect on microtubules, >8 and >10 both showed potent RTK inhibition with nanomolar IC50s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog >10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-β). Compound >10 is highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies.