The details of the isolation and structural elucidation of the potent antileukemic ansa macrolide principles maytansine (I), maytanprine (Z), maytanbutine (3), maytanvaline (4), and maytanacine (IZ), and the companion maytansides, maysine (5), normaysine (6), maysenine (7), and maytansinol (13), are reported. The isolation and characterization of a new antileukemic principle, maytanbutacine (a), is also reported. 1,2,3, and 4 were shown to be Nacyl amino acid esters of 13, and 12 was found to be the acetate ester of 13. Reductive cleavage of 3 and 12 afforded 13 as well. 8 was found to contain two acyl ester groups, a C-3 isobutyrate ester and a C-15 acetate ester. 5,6, and 7 all lack the C-3 ester moiety, but retain the ansa macrolide ring system.In the course of a continuing search for tumor inhibitors from plant sources, we found that an alcoholic extract of Maytenus serrata (Hochst. ex A. Rich.) R. W i l c~e k~~~~ showed significant inhibitory activity in vitro against cells derived from human carcinoma of the nasopharynx (KB) and in vivo against five standard animal tumor systems.4 Our preliminary c o m m~n i c a t i o n s~-~ described the isolation and structural elucidation of the potent antileukemic (PS) maytanside esters, maytansine (l), maytanprine (2), maytanbutine (3), and maytanvaline (4), as well as the maytansides, maysine (5), normaysine (6), and maysenine (7). Chemica18t9 and biologicaI1O-l7 interest in the maytansinoids continues and maytansine is currently undergoing clinical trials under the auspices of the National Cancer Institute. In this paper we present in detail the isolation and structural elucidation of the maytansinoids, and, in addition, the characterization of a new maytanside diester, maytanbutacine (S), is described.Fractionation (Chart I) of the ethanolic extract, guided by assay against KB tissue culture and PS leukemia in mice, revealed that the inhibitory activity was concentrated, successively, in the ethyl acetate layer of an ethyl acetate-water partition and in the methanol layer of a 10% aqueous metha-

An ethanolic extract of Psorospermum febrifugum was fractionated with antileukemic activity in vivo in the P388 lymphocytic leukemia in mice and in vitro in the KB cell culture system used as a guide. The new antileukemic xanthone psorospermin 1 was isolated, and its structure was elucidated. The chlorohydrin of O-methylpsorospermin 2 was also isolated after treatment of the fraction containing psorospermin chlorohydrin 6 with diazomethane. Psorospermin 1 was demonstrated to have significant antitumor activity in the P388 in vivo system as well as cytotoxicity against the KB in vitro system.

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.

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