Asymmetric synthesis and anti-tumor properties of conformationally constrained analogues of (S)-and (R)-goniothalamin

Abstract

Naturally isolated 5-substituted-a,B-unsaturated-.-lactones gained great attention of researchers due to their cytotoxic and anti-tumor properties. Styryl lactones are the most interesting members of this group of naturally available compounds. One of the well-known and important example for styryl lactone is goniothalamin, which shows cytotoxicity against variety of cancer cell lines. This cytotoxic property was shown to be selective for cancer cell lines with no significant cytotoxicity toward non-malignant cells. Recent structure activity relationship (SAR) studies on goniothalamin shows that R configuration on its stereogenic center, trans double bonded linker and Michael acceptor parts of the molecules are essential for its cytotoxic activity. In this study conformationally constrained analogues of (S)- and (R)-goniothalamin were synthesized. Syntheses were started with the catalytic asymmetric allylation of benzaldehyde, naphthaldehyde and quinaldehyde derivatives in the first step, then formed alcohols were acrylated with acryloyl chloride to yield the corresponding esters, in the last step, ring closing metathesis with Grubbs. catalyst yielded the target molecules. Meanwhile, in this study the synthesized 5-aryl-substituted-a,B-unsaturated-S-lactones were tested to determine their cytotoxicity against MCF-7, PC-3, DU-145 and LNCAP cancer cell lines.