The discovery of the anticancer drugs erlotinib and gefitinib in the early 2000’s prompted intensive research on 4-anilinoquinazoline compounds. The main biomolecular target for this class of compounds remains the Epidermal Growth Factor Receptor (EGFR), although some compounds do not show high selectivity for it. Cell cycle experiments with our previously reported 4-biphenylaminoquinazolines multi-tyrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. While previous compounds acted as dual inhibitors, the new heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. On the contrary, the absence of a dioxygenated fused ring led to compounds inactive against tubulin polymerization. The most interesting compounds were cytotoxic in both OVCAR-8 (human ovarian carcinoma) and NCI/ADR-RES (human ovarian carcinoma P-glycoprotein overexpressing) cell lines at nanomolar concentration.

Biphenylaminoquinazolines as novel dual inhibitors of tyrosine kinases and tubulin polymerization: synthesis, SARs and anticancer properties

DALLA VIA, MARTINA;CHILIN, ADRIANA;MARZARO, GIOVANNI
2015

Abstract

The discovery of the anticancer drugs erlotinib and gefitinib in the early 2000’s prompted intensive research on 4-anilinoquinazoline compounds. The main biomolecular target for this class of compounds remains the Epidermal Growth Factor Receptor (EGFR), although some compounds do not show high selectivity for it. Cell cycle experiments with our previously reported 4-biphenylaminoquinazolines multi-tyrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. While previous compounds acted as dual inhibitors, the new heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. On the contrary, the absence of a dioxygenated fused ring led to compounds inactive against tubulin polymerization. The most interesting compounds were cytotoxic in both OVCAR-8 (human ovarian carcinoma) and NCI/ADR-RES (human ovarian carcinoma P-glycoprotein overexpressing) cell lines at nanomolar concentration.
SIMCC 2015 Spanish-italian medicinal chemistry congress
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3189365
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