A tormentic acid-homopiperazine-rhodamine B conjugate of single-digit nanomolar cytotoxicity and high selectivity for several human tumor cell lines

Abstract

Tormentic acid and euscaphic acid were isolated from plant material and transformed into amides holding an extra rhodamine B moiety; these compounds were screened for their cytotoxic activity employing a panel of human tumor cell lines and non-malignant fibroblasts. Prerequisites for both high cytotoxicity and tumor cell selectivity seem to be the combination of an amide (from a secondary amine but not from a primary), the use of homopiperazine rather than piperazine as a spacer together with rhodamine B (as a cationic center) and – most important-a triterpene holding a (2α, 3β) configuration of the substituents in ring A of the triterpenoid skeleton. All these features are found in tormentic acid derived compound 15; it acts as a mitocan; it is approximately 190 times more cytotoxic for ovarian carcinoma cells than for non-malignant fibroblasts, and 15 displayed an EC50 as low as 1 ​nM for several human cancer cell lines.

Keywords

• Tormentic acid
• Pentacyclic tritepene
• Euscaphic acid
• Rhodamine B
• Cytotoxicity