(Iso)quinoline amides derived from corosolic acid exhibit high cytotoxicity, and the potential for overcoming drug resistance in human cancer cells

Abstract

Previous research on acetylated pentacyclic triterpenes had demonstrated the excellent cytotoxic action and, in certain situations, very surprising selectivity of (iso)-quinolinyl amides, in particular. Specifically, compounds derived from asiatic acid or maslinic acid had demonstrated promising outcomes. To investigate the influence of the different arrangement of the two methyl groups in ring E (compared to maslinic acid) and the absolute configuration of the hydroxyl groups in ring A (compared to asiatic acid), corosolic acid was chosen as starting material. Corsolic acid was acetylated and transformed into the corresponding quinolinyl amides 3–7 and isoquinolinyl amides 8–13 using various amino–(iso)–quinolines for a systematic investigation. Their analysis using SRB assays revealed that several of the synthesized amides exhibited significant cytotoxicity against a range of human cancer cell lines. Notably, compound 6, a 7-amino-quinoline derivative, emerged as the most potent, demonstrating not only high cytotoxicity but also good selectivity for tumor cells and a remarkable ability to overcome drug resistance. The highest selectivity index was obtained for compound 4 – a 5-amino-quinoline derivative - and HT29 colorectal carcinoma cells with SI > 74.6, and compound 13 – a 8-isoquinoline derivative – with a SI = 58.5 while under the same conditions standard doxorubicin showed only SI = 2.9.

Keywords

• Corosolic acid
• Cytotoxicity
• Amides
• Quinoline
• Isoquinoline