Synthesis and antiproliferative activity of simplified goniofufurone analogues

Abstract

Several (+)-goniofufurone analogues with simplified structures were designed, synthesized and evaluated for their in vitro antitumour activity, against a panel of human tumour cell lines. Dephenylated compounds 2 and 3 demonstrated remarkable antitumour activities, in the cultures of K562 and Raji cells with IC50 values in the range of 3.0–9.3 nM. Each of goniofufurone analogues lacking the tetrahydrofuran ring (4, 5 and 6) strongly inhibited the growth of at least one malignant cell line, with IC50 values in the range of 11-30 nM. Brief structure–activity relationship (SAR) analysis showed that the simplified goniofufurone analogues, designed by removing the phenyl group from C-7, or by opening the THF ring, could show stronger antiproliferative effects compared to control molecules. It is noticeable that analogues 2–8 are completely inactive with respect to the normal MRC-5 cell line. These findings, together with their potent antitumour activities, provide a suitable basis for the development of new and selective antitumour drugs.

Keywords

• structure simplification based drug design
• goniofufurone mimics
• furanolactones
• cytotoxicity
• wittig olefination
• oxa-michael ring-closure
• sar analysis