Synthesis and in vitro and in vivo evaluation of a series of dihydroisocoumarin derivatives conjugated with fatty acids, alcohols, and amines as potential anticancer agents.

In this paper, we report the synthesis and biological activity of a series of dihydroisocoumarin analogues conjugated with fatty acids, alcohols, or amines, of varying hydrocarbon chain length and degree of unsaturation, to the dihydroisocoumarins, kigelin and mellein, at the C-7 and C-8 positions on the core dihydroisocoumarin structure. These compounds were evaluated for their antiproliferative activity against human breast cancer (MCF-7 and MDA-MB-468) and melanoma cells (SK-MEL-28 and Malme-3M) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Two compounds conjugated with gamma-linolenyl alcohol (18:3 n-6) demonstrated potent antiproliferative activity in vitro with one of these 4-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-5-carboxylic acid octadeca-6,9,12-trienyl ester, demonstrating significant antitumor activity in vivo in a number of human tumor xenograft models.