Tumor inhibitors. 122. The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides

Abstract

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-

Antibody Conjugate Therapeutics: Challenges and Potential

“…The development of dolastatin 10 was terminated in 1995 when it failed to demonstrate efficacy in a phase II trial in prostate cancer patients. The maytansinoids are exquisitely potent cytotoxic agents (31). Maytansinoids are 19-membered macrocyclic lactams that are related to ansamycin antibiotics.…”

Ansamitocin analogs from a mutant strain of Nocardia II. Isolation and structure.

“…NMR spectra were obtained using a Varian XL-100-12 and a Varian EM-390 instrument; chemical shifts (6) are reported in ppm downfield from TMS. Mass spectra were determined on a JEOL JMS-OISC spectrometer equipped with a direct inlet system.…”

Biosynthesis and Accumulation of Ergoline Alkaloids in a Mutualistic Association between Ipomoea asarifolia (Convolvulaceae) and a Clavicipitalean Fungus

“…The disjointed distribution of natural products has not only been observed in the case of ergoline alkaloids, but also with other natural products, such as maytansinoids, which are bacterial products (Higashide et al, 1977), but occur also in plants belonging to the family Celastraceae (Kupchan et al, 1977). The distribution of maytansinoids in nature suggests that they are products of microorganisms (bacterium or fungus) that are associated with Celastraceae plants (Pullen et al, 2003;Cassady et al, 2004).…”