Synthesis of Furocoumarin Derivatives as Anti-cancer Agents

Abstract

Furocoumarin derivatives such as bergamottin, 8-hydroxypsoralen, and methoxsalen are one of the interesting compounds which showed potential as a core structure for further development in the areas of anti-cancer agents. Literature shows that the anticancer activity especially the amide group at the C-5 position of methoxsalen. On the other hand, furocoumarin derivatives have been reported to cause DNA crosslink when stimulated by light, leading to high cytotoxicity towards normal cells. Therefore, in this work, we have synthesized various functional groups of furocoumarin derivatives especially the amide group to further enhance the anticancer activity. We also aim to reduce the side effects by synthesising the tetracyclic furocoumarin derivatives. Twenty-two novel of furocoumarin derivatives were successfully synthesized. All final products were characterized by nuclear magnetic resonance spectroscopy (NMR), high-resolution mass spectrometry (HRMS), and fourier-transform infrared spectroscopy (FTIR). The synthesized novel products (1, 2, 3a-3k and 3m) and methoxsalen were evaluated for anticancer activity; breast cancer (MDA-MB-231 cell and T47-D cell), liver cancer (HepG2 cell and S102), leukemia (HL-60 and MOLT-3), lung cancer (A549 and H69AR), cholangiocarcinoma (HuCCA-1), HeLA cell and normal embryonic lung cell (MRC-5) by MTT assay and XTT assay at Chulabhorn Research Institute. According to the results, bromophenyl containing compound 3d has significantly greater anticancer activity. For the structure-activity relationship (SAR), the compounds containing electron withdrawing group had better anticancer activity than electron donating group in most cancer cells. This information could become valuable for the drug discovery and the development of anticancer drug in the future.