Anti-Proliferative Effect of Synthesized Bakuchiol Analogues on Cultured Human Tumor Cell Lines

Abstract

Bakuchiol (1) is an unique prenylated phenolic meroterpene found exclusively in the seeds of Psoralea corylifolia L. P. corylifolia is an annual plant of the Leguminosae family and distributed over Southeast Asian countries. Numerous biological actions of the whole extract of the plant or purified constituents have been reported as antioxidant, antiinflammatory and antibacterial activities. Compound 1 has been introduced firstly to be isolated from the species by G. Mehta et al. and the chemical structure of 1 was fully determined including the absolute configuration of C-6 as (S)-chirality, even the total synthesis was accomplished in 1973. 1 is the main constituent of the species and reported to exert antidiabetic, antitumor effects, BACE-1 inhibitory activity, and hepatoprotective activities. In the previous study, we had reported that the seeds extract of P. corylifolia exhibited a marked inhibitory effect on the proliferation of cultured human tumor cell lines and the inhibitory effect was mainly ascribed to 1, a major component of the extract. As a trial for optimizing the chemical structure of 1 for improved antitumor activity, several analogues (2-8) of 1 were prepared according to the synthetic routes illustrated in Scheme 1. Briefly, 1 was treated with an equivalent amount of H2O2 and (NH4)2Ce(NO3)6 (ammonium cerium nitrate; CAN) in acetic acid to give 2. It seemed that the Δ double bond of 1 was oxidized to give a corresponding diol, which was further acetylated to produce 2. Compound 3 was prepared by the epoxidation of 1 with m-chloroperbenzoic acid in CH2Cl2 at 0 C. The treatment of