Mitochondria-Targeted TPP-Meroditerpenes Based on Quinopimaric and Dehydroquinopimaric Acids: Synthesis and Evaluation of Cytotoxicity and Antibacterial Activity.

A convenient approach to the synthesis of quaternary phosphonium salts, bearing a diterpenoid fragment is proposed. This highly regioselective synthesis is based on the reaction of quinopimaric and dehydroquinopimaric acids with P─H-phosphonium salts. The structures of obtained quaternary phosphonium salts based on quinopimaric and dehydroquinopimaric acid were confirmed by NMR and IR spectroscopy, mass spectrometry, and XRD. Compounds possess both antibacterial activity and in vitro cytotoxicity against human cancer cell lines. Selectivity of cytotoxic action depends on substituents in the aromatic moieties of phosphonium salts. Also, phosphonium derivatives of quinopimaric acid, possessing a hydroxyvinyl fragment bound directly to the phosphorus atom, show a higher cytotoxicity than dehydroquinopimaric acid phosphonium derivatives. Highest cytotoxicity is for the phosphonium derivatives of quinopimaric acid, containing 4-methoxyphenyl substituents (IC50 = 1.5-2.8 µM). Apoptosis test suggests that the cytotoxic mechanism involves a substantial contribution of the mitochondrial pathway of apoptosis.