Chemical modification of ansamitocines. III. Synthesis and biological effects of 3-acyl esters of maytansinol

DOI: 10.1248/cpb.32.3441

Source and publish data:

Chemical and Pharmaceutical Bulletin p. 3441 - 3451 (1984)

Update date:2022-08-03

Topics:

Authors:

Kawai Kawai

Akimoto Akimoto

Kozai Kozai

et al. et al.

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Article abstract of DOI:10.1248/cpb.32.3441

Several semisynthetic maytansinoids that differ in the structure of the acyl group at the C₃ position were prepared by acylation of maytansinol (3) using appropriate carboxylic acids or their active derivatives, and the effects of the compounds on the growth of Tetrahymena pyriformis and the survival of tumor-bearing mice were determined. Among these analogs, the C₃ esters having a straight chain aliphatic acyl (11, 12), cycloalkanecarbonyl (18-20) or phenylacetyl group (22), and those having a 2-(N-acetyl-N-methyl)aminohexanoyl (7) or (2-(N-acetyl-N-methyl)aminophenylpropionyl group (8), strongly inhibited the growth of T. pyriformis and exhibited potent activity against B16 melanoma in mice. The potencies were similar to those of maytansine and ansamitocin P-3. The most striking result was the finding that the phenylglycinate (31) was superior to maytansine in terms of its broader effective dose range against ip B16 melanoma and P388 leukemia in mice; however, higher doses of the phenylglycinate were required.