Synthesis and cytotoxic activity of 1,2,3-triazoles derived from 2,3-seco-dihydrobetulin via a click chemistry approach

National Science Centre, Poland (grant No. 2016/21/B/ST5/02141) Czech Science Foundation No. 20-25308S.

In search of new cytotoxic derivatives based on the lupane scaffold, the seco-lupane azides were coupled with a number of alkynes under the 1,3-dipolar cycloaddition (CuAAC) conditions to afford 1,2,3-triazoles. Phenylalkynes having different substituents at the para position were used as starting materials. Similarly, coupling of the seco-lupane thiocyanate with sodium azide gave 5-thiotetrazole. The cytotoxicity of thir- teen derivatives were investigated, as well as the effect of substituents in the phenyl ring on the activity of 1,2,3-triazoles. Limited activity was observed for some of these products. Most of the studied com- pounds were inactive in cancer cell lines and healthy fibroblasts. Triazole 46 exhibited cytotoxic activity against CEM and MCF-7 cancer cell lines, however, it was also toxic to normal human BJ fibroblasts. Two other derivatives – triazole 45 and tetrazole 49 – exhibited low cytotoxicity. Compound 49 showed good selectivity towards tumor cell lines compared to normal fibroblasts. This compound did not affect the growth of normal human fibroblasts and therefore has a wide therapeutic window.