A late-stage diversification via Heck-Matsuda arylation: Straightforward synthesis and cytotoxic/antiproliferative profiling of novel aryl-labdane-type derivatives

Abstract

In the current study a late-stage diversification of unactivated olefins labd-8(17)-en-15-oic acid (1a) and methyl labd-8(17)-en-15-oate (1b) via Heck-Matsuda arylation is described. The reaction provided straightforward and practical access to a series of novel aryl-labdane-type derivatives (HM adducts 3a-h) in moderate to good yields in a highly regio- and stereoselective manner at room temperature under air atmosphere. The cytotoxic activity of these compounds was investigated in vitro against three different human cell lines (THP-1, K562, MCF-7). Of these, HM adduct 3h showed a selective effect in all cancer cell lines tested and was selected for extended biological investigations in a leukemia cell line (K562), which demonstrated that the cytotoxic/antiproliferative activity observed in this compound might be mediated by induction of cell cycle arrest at the sub-G1 phase and by autophagy-induced cell death. Taken together, these findings indicate that further investigation into the anticancer activity against chronic myeloid leukemia from aryl-labdane-type derivatives may be fruitful.

Keywords: Anticancer activity; Heck-Matsuda reaction; Labdanes; Late-stage diversification; Moldenhawera nutans; Palladium.