Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids.
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D007942:Leukemia, Experimental / Q000188:drug therapy; D008453:Maytansine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010063:Ovum / Q000187:drug effects; D010078:Oxazines / Q000494:pharmacology*; D012617:Sea Urchins; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D010078:Oxazines; D014404:Tubulin; C562224:maytansinol; D008453:Maytansine