A convergent synthesis of novel alkyne-azide cycloaddition congeners of betulinic acid as potent cytotoxic agent

- Synthesis of 22 betulinic acid/betulonic acid derivatives.
- Several derivatives were active against human cancer cell lines.
- The molecule 11h is apoptotic inducer on HCT-116 cells.

In an endeavour to develop potent anti-tumor agents from betulinic acid (BA), a series of C-28 derived 1,2,3-triazolyl derivatives were designed and synthesized by employing Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition reaction. All the derivatives were evaluated for cytotoxic activity by MTT assay against five different human cancer cell lines: lung (A549), colon (HCT116), prostate (PC3), pancreatic (MIA PaCa-2) and breast (T47D). The data revealed that compounds 11c, 11d, 11g, 11h and 13a possess most promising cytotoxic potential. The compound 11h was one of the most active compounds, with IC50 values in the range of 4-6 µM against all the five cancer cell lines. The results of this study suggested that derivatives with free -OH (11c, 11d and 11g) and free -COOH (11h and 13a) substitutions in the triazole moiety introduced at the C-28 position significantly improved the anti-tumor activity and may be the favourable position to synthesize potent anticancer leads from BA. Introduction of a non polar alkyl groups at C-28 position (10, 12 and 14) resulted in the significant loss of the activity. Further, DAPI staining, ROS generation and wound healing experiments revealed that compound 11h induces apoptosis in HCT-116 cells.

Design and synthesis of C-28 derived 1,2,3-triazolyl betulonic acid as apoptotic agents.212