Ansa-Macrolides

Kupchan, S.M., Komoda, Y., Thomas, G.J., Hintz, H.PJ. Maytanprine and maytanbutine, new antileukaemic ansa macrolides from Maytenus buchananii. J. Chem. Soc. Chem. Comm. 1972, 1065... 

Wani, M.C., Taylor, H.L., Wall, M.E. Plant Antitumor agents colubrinol acetate and colubrinol, antileukaemic ansa macrolides from Colubrina texensis. J. Chem. Soc. Chem. Comm. 1973, 390... 

Wolpert-Dufilippes, R.K., Adamson, R.H., Cysyk, R.L., Johns, D.G. Initial studies on the cytotoxic action of maytansine, a novel ansa macrolide. Biochem. Pharmacol. 24, 751 (1975)... 

Karim A, Gilmore CJ, Haltiwanger RC, Bryan RF. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J. 

An important consideration in the agricultural production of plants containing medicinally active components is that they are sometimes produced by, or in consequence of, microbial agents present in or on the plant. These also constitute part of the biodiversity regulated by law, may be pathogenic to other economic crops and are not always easily cultured. Production in the natural habitat raises no problems. As an example one may notice that the maytansinoids, ansa-macrolides, which form part of the chemical make-up of Maytenus ilicifolia and M. aquifolia, Celastraceae, the two species most highly considered for stomach ulcer treatment, have been shown to be produced by bacteria associated with the plants. ... 

Classes of Useful Antibacterial Antibiotics Penicillin Cephalosporin -C Steroid Aminoglycoside Polymyxin Chloramphenicol Cycloserine Tetracycline Macrolide Ansa macrolide Lincomycin Cycloserine Novobiocin... 

The structure and absolute configuration of maytansine (72 R = H) has been established by V-ray crystallographic analysis of its 3-bromopropyl ether [72 R = (CH2)3Br]. °° Maytansine represents the first ansa macrolide-type compound that shows in vivo tumour inhibitory properties. ... 

The first benzenoid ansa macrolide maytansine (73) was isolated from the bark of the Celastraceae plant Maytenus ovatus as an antileukemic principle [119, 120]. 

As described above, the first benzenoid ansa macrolides were isolated from a higher plant. On the other hand, the first ansa macrolide from a microorganism was isolated from the culture filtrate of Streptomyces hygroscopicus var. geldanus and named as geldanamycin (85) [137]. Geldanamycin (85) showed an inhibitory effect on the growth and multiplication of protozoa and possessed potent cytocidal activities in vitro. 

Maytansine (73), the first benzenoid ansa macrolide isolated from the higher plant Maytenus ovatus was obtained as an antileukemic ansa macrolide [119,120]. The cytotoxic action of 73 was reported in a preliminary communication [122]. Several other maytansinoids, such as normaytancyprine (75) [123], 10-epitrewiasine (76) and nortrewiasine (78) [124], were isolated from Putterlickia verrucosa and Trewia nudiflora. The structural requirements for the antileukemic activity of naturally and semisynthetic maytansinoids were reported [120,125]. 

Maytansine (218) was the first ansa macrolide shown to contain a 19-membered lactam ring with carbinolamine, epoxide, or aryl halide functions and appears to be the first member of the series reported to show significant in vivo tumor inhibitory activity [116]. 

Maytansine s ansa macrolide structure shows noteworthy similarities to those of the rifamycins [255], streptovaricins [256], tolypomycins [257], and geldanamycin [258]. The ansamycin antibiotics and their derivatives have aroused considerable interest as antiviral and antimicrobial agents, and as inhibitors of RNA tumor virus reverse transcriptases. 

Kupchan proposed that the generic term maytansinoids be used for all ansa macrolide derivatives structurally related to maytansine, and... 

In the same year Kupchan et al. [259] described two new and potent antileukemic ansa macrolides isolated from the alcoholic extract of stems of Maytenus buchananii. Thus, maytanprine (222) and maytanbutine (223) were the new principles which showed lymphocytic leukemia over a 50-100-fold dosage range at the pg/kg level. Fig. (56). 

Unfortunately, work with these compounds has been impeded by the remoteness of source materials and their exceedingly low maytansinoid content. The ansamitocins may be converted by chemical manipulation to maytansine, but yields are not high. In order to solve this problem, Kupchan et al. searched methods for improving the isolation of these compounds from the active extracts of M. serrata, M. buchananii and P. verrucosa. Thus, the details of the isolation, of the species mentioned above, and the structural elucidation of the ansa macrolide principles maytansine (218), maytanprine (222), maytanbutine (223), ma anvaline... 

The full account of the work by the late S. M. Kupchan and his collaborators on the maytansinoids includes details of the isolation, structural elucidation, and chemical inter-relationships of those novel ansa macrolides. Of the ten macrolides isolated from Maytenus serrata, only maytansine [35 =... 

A series of novel ansa-macrolides has been isolated from plants of several genera of the Celastraceae, as well as othei families. The macrolide alkaloid, maytansine (11), was firsi... 

Higher Plant Alkaloids, Amides, and Ansa Macrolides... 

Maytansine, an ansa macrolide (D 4), which occurs in a Nocardia strain... 

Fig. 33. The C7N unit of ansa macrolide and mitomycin antibiotics and its origin from the shikimate pathway. Reprinted, with modifications, from Reference 68 with permission of the Federation of European Microbiological Socieites.

Ansa-macrolides - Extensive progress in the study and clinical use of rifampin (rifampicin) and other rifamycins is reflected in the more than a hundred publications dealing with their antibacterial anti-viral (see Chapter 11). pharmacokinetic and therapeutic qualities . Characteristically, ansa-macrolides (ansa-mycinsZ J ). the rifamycins. streptovaricin. and tolypomycin. are thought to exert their antibacterial action through suppression of RNA-polymerase function,... 

Ansa Macrolides. Rifampicin s (rifampin) potential in the treatment of pulmonary tuberculosis has been further strengthened by laboratory 3 and clinical3 Investigations while its merit in the therapy of staphylococcal 3 and other inf actions remains to be established. 

While several prominent antibioti synthesis at the level of the bacterial rifamycins, streptovaricins 3a5h macrolides, e.g., tolypomycin, 30 in ce well as ln vlro " 3 specifically inhibit polymerase of sensitive--but not of res Bubtilis and coli. Unlike actinomyc inhibit this enzyme in the mammalian ce template DNA, the ansa macrolides do so... 

Kupchan S M, Komoda Y, Branfman A R, Sneden A T, Court W A, Thomas G J, Nagao Y, Daley R G, Zimmerly V A, Sumner W C 1977 The maytansinoids, isolation, structural elucidation and chemical interrelation of novel ansa macrolides. J Org Chem 42 2349-2357... 

Sneden AT, Beemsterboer GL 1980 Normaytansine, a new antileukemic ansa macrolide from Maytenus buchananii. J Nat Prod 43 637-640... 

Sneden AT, Sumner WC Jr, Kupchan SM 1982 Normaytancyprine, minor antileukemic ansa macrolide from Putterlickia verrucosa. J Nat Prod 45 624-628... 

Maytansine and Homologues. Three potent anti-leukaemic ansa macrolides, designated maytansine, maytanprine, and maytanbutine, have been isolated from Maytenus ovatus Loes. Spectral and A -ray crystallographic analysis showed that maytansine had structure (151a) and the homologous structures... 

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