Tumor inhibitors. 124. Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids

Abstract

In an effort to determine the structural requirements for the significant antileukemic, cytotoxic, antitubulin, and antimitotic activity exhibited by the novel ansa macrolide, maytansine (1), four new C-3 ester and six new C-9 ether homologues were synthesized. The biological activities of these compounds were assayed and compared to the activities of previously reported, naturally occurring maytansinoids. From the data, it is apparent that presence of the C-3 ester is necessary for significant activity, and variations in the ester group are not accompanied by marked changes in activity. However, elimination of the ester group, as in maytansinol (7), maysine (8), normaysine (9), and maysenine (10), results in a significant decrease in biological activity. Blockage of the C-9 carbinolamide via etherification markedly reduces antileukemic and cytotoxic activity and slightly reduces antitubulin activity but has relatively little effect on antimitotic activity against sea urchin eggs. Thus, a free carbinolamide at C-9 is advantageous for optimal activity.

Recent Developments in the Maytansinoid Antitumor Agents

“…Maytansinol esters, such as maytansine and ansamitocin P3 or P4, are highly active antileukemic agents, whereas compounds carrying a double bond (maysine, normaysine and maysenine) or hydroxy function (maytansinol) at C3 lack antileukemic activity and show only 1/10000 the cytotoxicity of maytansinol esters. 51,59) The importance of the ester group is also evident from the observation that a change from the a to the b configuration at C3 leads to loss of the inhibitory ac-tivities. 45) Twenty-nine semisynthetic maytansinoids bearing a variety of C3 acyloxy side chains were prepared synthetically from maytansinol.…”

“…Interestingly, blockage of the carbinol amide by etherification of the C9 alcohol results in a marked decrease in antitumor activity and cytotoxicity against KB cells when compared to maytansine and maytanbutine. 59) Epimerisation at C10, e.g., in trewiasine to give 10- epitrewiasine, has little influence on the biological activity 58) and a hydroxy group at C15, as in colubrinol, is compatible with potent antitumor activity. 35,55) Neither the amide N-methyl group 60) nor the 20-O-methyl group 34) seem to be necessary for biological activity; in fact, 20-O-demethylansamitocin P3 is more active against P-388 and L-1210 leukemia in vivo than AP-3.…”

The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum

“…Based on the results of feeding experiments with 13 C-and 14 C-labeled precursors (16,17), the biosynthesis of the maytansinoids can be predicted to involve the assembly of the carbon framework on a type I modular polyketide synthase (PKS) from 3-amino-5-hydroxybenzoic acid (AHBA) as the starter unit. Chain extension proceeds by incorporation of three propionates, three acetates, and an unusual hydroxylated two-carbon extender unit (''glycolate'' unit) to give a 19-membered macrocyclic lactam.…”

Maytenus ovatus (schweinf.) An African Medicinal Plant Yielding Potential Anti-cancer Drugs

“…United States Patent Number 3,896,111 of July 22, 1975, awarded to Kupchan [9], it was disclosed that certain African woods, in particular Maytenus ovatus and M. buchananii contain certain factors which demonstrated significant anti-leukemic activity in microgram/kilogram level. One of these factors, the chemical structure of which was disclosed in the patent was identified as "maytansine".…”

“…One of these factors, the chemical structure of which was disclosed in the patent was identified as "maytansine". The starting material for the development of maytansine based drugs by the procedures of the invention of Kupchan [9] is maytansine containing plant material, suitably woody portions of stem and bark. The preferred sources are wood from Maytenus ovatus, Maytenus buchananii and Putterlickia verrucosa.…”