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

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.

Automated summary

This study demonstrated a late-stage diversification of unactivated olefins through Heck-Matsuda arylation to synthesize a series of novel aryl-labdane-type derivatives, showing significant cytotoxic activity against cancer cell lines, with one compound exhibiting selective effects. Further biological investigations suggested that the observed cytotoxic activity might be mediated by cell cycle arrest and autophagy-induced cell death, indicating potential for anticancer activity against chronic myeloid leukemia from aryl-labdane-type derivatives.