Tổng hợp và thử hoạt tính sinh học của một số dẫn chất acid hydroxamic mang khung quinazolin

Abstract

To find novel histone deacetylase inhibitors, a series of 9 novel hydroxamic acids incorporating quinazoline heterocycles (4a-i) were synthesized with moderate yields (76-62%) via a 3 step pathway: the first one was a Niementowski condensation of substituted-2-aminobenzoic acids (1a-i) and formamide to obtain quinazoline-4(3H)-on derivatives (2a-i), The second one was a one-pot phosphonium mediated amination at the C-4 position of 2a-i using PyBOP, DBU and an excess amount of amine. The conversion proceeded smoothly in acetonitrile as solvent at room temperature gave the ester intermediates 3a-i. The formation of the hydroxamic acids in the final step was afforded through a nucleophilic acyl substitution of hydroxylamine hydrochloride with the esters 3a-i under alkaline conditions. The obtained quinazoline-based hydroxamic acids proved potent cytotoxicity against the foliowing three human cancer cell lines: SW620, colon; PC-3, prostate; NCI-H23, lung. Several compounds, e.g. 4b, 4c, 4g-i. displayed the cytotoxical potency from 5- up to 10-fold higher than that of the reference SAHA (suberoylanilidehydroxamic acid, vorinostat). Moreover, the synthesized compounds appeared comparable to SAHA in inhibiting HDACs, with IC₅₀ values at sub-micromolar range. Even, as an HDAC inhibitor, compound 4g showed more potent than SAHA in Hela extract assay and as a promising candidate for anticancer drug.