Cytotoxic triterpenoid-safirinium conjugates target the endoplasmic reticulum

Abstract

Safirinium P and Q fluorescence labels were synthesized and conjugated with spacered triterpenoic acids to access hybrid structures. While the parent safirinium compounds were not cytotoxic at all, many triterpenoid safirinium P and Q conjugates showed moderate cytotoxicity. An exception, however, was safirinium P derived compound 30 holding low EC₅₀ = 5.4 μM (for A375 cells) to EC₅₀ = 7.5 μM (for FaDu cells) as well as EC₅₀ = 6.6 μM for non-malignant fibroblasts NIH 3T3. Fluorescence imaging showed that the safirinium core structures cannot enter the cells (not even after a prolonged incubation time of 24 h), while the conjugates (as exemplified for 30) are accumulating in the endoplasmic reticulum but not in the mitochondria. The development of safirinium-hybrids targeting the endoplasmic reticulum can be regarded as a promising strategy in the development of cytotoxic agents.

Keywords: Betulinic acid; Cytotoxicity; Endoplasmic reticulum; Safirinium.