Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin

A series of new triphenylphosphonium (TPP) derivatives of the triterpenoid betulin (<b>1</b>, 3-lup-20(29)-ene-3β,28-diol) have been synthesized and evaluated for cytotoxic effects against human breast cancer (MCF-7), prostate adenocarcinoma (PC-3), vinblastine-resistant human breast cancer (MCF-7/Vinb), and human skin fibroblast (HSF) cells. The TPP moiety was applied as a carrier group through the acyl linker at the 28- or 3- and 28-positions of betulin to promote cellular and mitochondrial accumulation of the resultant compounds. A structure–activity relationship study has revealed the essential role of the TPP group in the biological properties of the betulin derivatives produced. The present results showed that a conjugate of betulin with TPP (<b>3</b>) enhanced antiproliferative activity toward vinblastine-resistant MCF-7 cells, with an IC₅₀ value as low as 0.045 μM