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

Abstract

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.

Total synthesis of racemic, natural (+) and unnatural (−) scorzocreticin

“…1 In particular, 3-substituted 3,4-dihydroisocoumarin derivatives have attracted considerable interest in medicinal chemistry as they show remarkable antibacterial, anticancer, antifungal or antimalarial properties. 2 Mellein (see Fig. 1) is one of the most interesting example in such a class of compounds known for having antibacterial activity.…”

Enantiopure 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines via chemoenzymatic asymmetric transformations

“…2 In addition, dihydroisocoumarins are a class of naturally occurring biologically active lactones possessing remarkable antibacterial, anticancer, antifungal or antimalarial properties. 3 Asymmetric synthesis and isolation from plant extracts of 3-substituted-3,4-dihydroisocoumarins have particularly attracted attention. 4 However, only a few chemoenzymatic routes have been reported until now, among which biocatalytic methods for the preparation of 3-methyl-3,4-dihydroisocoumarins only include chemoenzymatic pathways involving ketone transformations such as Baeyer-Villiger oxidations 5 or bioreduction processes.…”

Synthesis, spectroscopic and structural study of trans- and cis-(±)-3-phenyl-4-(pyrrolidine-1-carbonyl)-isochroman-1-ones

“…3,4-Dihydroisocoumarins possess an aryl substituent in position 3 are the core of various natural [1][2][3] and synthetic [4][5][6][7] compounds which exhibit a wide variety of pharmacological activities [8][9][10][11]. Because C-3 and C-4 carbon atoms are stereogenic centers, both diastereomers (cis-and trans-) are possible for this type of compounds (Scheme 1).…”