Maytansine, at 6x10(-8)M, irreversibly inhibits cell division in eggs of sea urchins and clams. It causes the disappearance of a mitotic apparatus or prevents one from forming if added at early stages. Maytansine does not affect formation of the mitotic organizing center but does inhibit in vitro polymerization of tubulin. Maytansine and vincristine inhibit in vitro polymerization of tubulin at about the same concentrations, but vincristine is about 100 times less effective as an inhibitor of cleavage in marine eggs.
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.
Aus Maytansinol (I) werden durch Umsetzung mit Carbonsäureanhydriden in Gegenwart von Pyridin die Ester (II) und mit entsprechenden Alkoholen in Gegenwart Vvon Trifluoressigsäure aus Maytansin (III) die Ether (IV) hergestellt.
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