Design, synthesis and biological evaluation of heterocycle-conjugated styrene derivatives as protein tyrosine kinase inhibitors and free radical scavengers

Abstract

As part of our efforts to develop protein tyrosine kinase (PTK) inhibitors as potential anti-tumor agents, two series of heterocycle-built-in push-pull molecules were designed based on two natural PTK inhibitors, curcumin and resveratrol. Compounds 8-16, 20, 23-26 (A series) and 27-34 (B series) were prepared and evaluated for their ability to inhibit p56lck, p59fyn, epidermal growth factor receptor (EGFR) and HER2 tyrosine kinases. The A series of compounds, with the exceptions of 12 and 13, were effective in inhibiting p56lck, p59fyn, EGFR and HER2. Surprisingly, the compounds in series B with 3,5-dibromo-4-hydroxy substitutions (28, 30, 32 and 34) were almost inactive against the four kinases. Compounds 11-13, 16 and 20 were selected for in vitro screening against 60 NCI human cancer cell lines and displayed significant antiproliferative activity. Compounds 11, 13 and 16 were further evaluated for anticancer activity in the hollow fiber animal model. Compound 11 exhibited good anticancer activity. Compounds 9-13, 15, 16, 20 and 23-34 were also evaluated for their free radical scavenging activity using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. All of the compounds bearing the 3,4-dihydroxystyryl moiety (11, 16, 20, 23, 25, 27, 31 and 33) were more potent than the natural antioxidant curcumin. The three potent DPPH radical scavengers 11, 16 and 20 at 10 μM completely protected LDL from copper ion-induced peroxidation. Our results demonstrate that certain types of designed compounds show promising submicromolar potency against PTKs, and some of these compounds also strongly scavenge free radicals. These compounds may represent lead structures for further development.