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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