An improved partial synthesis of corosolic acid and its conversion to highly cytotoxic mitocans

Ursolic acid was used as a convenient starting material for a three-step partial synthesis of corosolic acid. Corosolic acid was acetylated, and an amide linker was attached followed by a rhodamine B unit at the distal end of the linker. Especially compounds holding a piperazinyl or homopiperazinyl linker held exceptional cytotoxicity for several human tumor cell lines. For example, homopiperazinyl spacered 11 showed EC50 = 2 nM for A2780 cells combined with high tumor cell/non-tumor cell selectivity (compound 11: EC50 = 0.122 mu M for non-malignant NIH 3T3). Thus, compound 11 currently represents one of the most cytotoxic triterpene derivatives holding both superior cytotoxicity combined with high selectivity (SI (A2780 vs NIH 3T3) > 60). Staining experiments showed this compound to act as a mitocan. This makes 11 an interesting compound for further studies or as a lead substance.

Automated summary

Ursolic acid was used for the synthesis of corosolic acid, and the synthesized compounds showed significant cytotoxicity against human tumor cells with high selectivity.