Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling.

Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling. Bioorg Chem. 2020 Aug 26;103:104222 Authors: AbdelHaleem A, Mansour AO, AbdelKader M, Arafa RK Abstract VEGFR-2 is a key regulator in cancer angiogenesis. This research displays the design and synthesis of novel 3-cyano-6-naphthylpyridine scaffold-based derivatives as selective VEGFR-2 inhibitors and cytotoxic agents. In vitro percent kinase activity inhibition screening against a panel of 23 kinases at a single high dose (30 nM) affirmed that VEGFR-2 was selectively the most responsive to inhibition by the investigated chemotypes. IC50 values determination demonstrated kinase inhibitory activities of the test compounds at the sub-nanomolar level. In vitro testing of the new compounds against two prostate cancer cell lines namely PC3 and DU145 and two breast cancer cell lines namely MCF-7 and MDA-MB435 confirmed their potent cytotoxic activity with IC50s at the nanomolar level. The most active compound against MCF-7 viz.11d was subjected to an in vivo examination against a xenograft mouse model and was found effective. Studying the tissue mRNA expression levels of various cell cycle controlling biomolecules in 11d-treated MCF-7 cells demonstrated (i) upregulation of p53, p21 and p27, (ii) cleavage of PARP protein, (iii) activation of caspase-3, -8 and -9, (iv) downregulation of the anti-apoptotic protein Bcl, (v) upregula...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Tags: Bioorg Chem Source Type: research