Anticancer 2-aminoquinazolines were evaluated by their photophysical properties responding to media changes. By binding to the colchicine binding site of β-tubulin, the fluorescence emission of 2-N-morpholino-derivative (1) was blue-shifted with enhanced intensity. These distinguished features were used for the development of a β-tubulin colchicine site competition assay and visualization of the intracellular distribution of 1 by fluorescence microscopy.Download high-res image (260KB)Download full-size image

A quinazoline derivative PVHD121 (1a) was shown to have strong antiproliferative activity against various tumor-derived cell lines, including A549 (lung), NCI-H460 (lung), HCT116 (colon), MCF7 (breast), PC3 (prostate), and HeLa (cervical) cells with IC50 values from 0.1 to 0.3 μM. A structure–activity relationship (SAR) study at the 2- and 4-position of the quinazoline core lead to the discovery of more potent anticancer agents (14, 16, 17, 19, 24, and 31). The results of an in vitro tubulin polymerization assay and fluorescent-based colchicine site competition assay with purified tubulin indicated that 1a inhibits tubulin polymerization by binding to the colchicine site.Keywords: anticancer; colchicine binding site; Quinazoline; structure−activity relationship study; tubulin inhibitor