Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds

•We investigated hydroxamates and carbamates of betulin and betulinic acid.•The compounds showed antitumor activity on different human cancer cell lines.•Many of the compounds are cytotoxic even in a low micro molar concentration.•Highest cytotoxicity was found for a betulinic acid derived hydroxamate.•Highest selectivity was established for a betulin derived N-hexylcarbamate.

The betulinic acid-derived hydroxamates 5–18, the amides 19–24, and betulin-derived bis-carbamates 25–28 as well as the carbamates 31–40 and 44–48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 μM were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16–20 μM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 μM for A2780 human ovarian carcinoma cells and EC50 > 30 μM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19–24 and of betulin derived bis-carbamates 25–28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 μM (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined.

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