Maytansinoid

Compilations of the physical properties of the maytansinoids ate found in two reviews (249,250). 

Several semisynthetic maytansinoids have been prepared by acylating the C-3 hydroxyl group of maytansinol. Some of these derivatives have antiprotozoal and antitumor activity similat to maytansine (104) and ansamitocin P-3 (127) (52,254). 3-Epimaytansinoids have been synthesized and were not biologically active (255). 

Biological Activity. The maytansinoids possess antitumor activity, particulady against P 388 lymphocytic leukemia, B 16 melanocarcinoma, and Lewis lung carcinoma. A number of semisynthetic esters of maytansinol have been prepared and exhibit good antileukemic activity (52,255). The maytansides lack antitumor activity, indicating that the ester at C-3 is a requirement for activity (50,52). The carbinolamide also appears to be necessary for... 

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

In a synthesis of maytansinoids, a 10 1 ratio of adducts results from the reaction of ethyl lithiodithioacetate with the enantiomerically pure aldehyde ( + )-(2S, 3S, 4S)-3,4-epoxy-2,4-dimethyl-5-trimethylsilyloxypentanal°. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

Maytansine 588 is a macrocyclic tetrahydro-l,3-oxazin-2-one derivative isolated from higher plants, mosses, and an actinomycete, kctinosynnema pretiosum. Despite the extraordinary antitumor activity found for many maytansine derivatives, the Phase II clinical trials with maytansine turned out to be disappointing. The chemistry and biology of maytansinoids have recently been reviewed <2004CPB1>. 

The potential of this sequence was applied in Meyers s total synthesis of antibiotic maytansinoids such as (-)-maysine [345]. 

Isolation and Structure Proof. The maytansinoids were (lie first ansamacrolides to be found in plants. The term maytansinoids refers to those ansamacrolides related to maytansinc, whereas the term maytansides refers to maytansinoids lacking the ester side chain at C-3 as well as the corresponding elimination products. Maytansine was first isolated from the alcoholic extract of Maytenus ovatus Loes. Several other maytansinoids and maytansides have been isolated from this species. The structure of niaytan-sine was established by x-ray crystallographic analysis, and the structures of the other maytansinoids and maytansides were arrived at by comparative nmr studies using maytansine. The absolute configuration of maytansine is 3(5), 4(5), 5(5), 6(R), 7(5), 10(5), and 2 (5). 

Another large group of maytansinoids are produced by the microorganism Nocardia sp. C-25003 N-1) and are designated ansamitodns. The structures of the ansamitodns were determined by spectral analysis. By comparison of reported physical data, it was concluded that ansamitodns P-0, P-1, and P-2 were identical to maytaiisiiiol, may tanadue. and may-tansinol propionate, respectively. 

Chemical Properties and Derivatives. Procedures for the total synthesis of several of the maytansinoids have been thoroughly reviewed. A variety of bacte.ua, actinomycetes, yeasts, and fungi weie scieened foi tlieii ability to modify the ansamitodns. 

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis, whereas RNA synthesis is not affected. The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. 

Recently Kupchan et al.219 isolated two Maytansinoids Maytanacine and Maytansinol. They differ from the previously described Maytansinoids by different substituents at C-3, both being without an amino acid residue at that position. Semisynthetic Maytansinoids have also been prepared by esterification of the 3-OH group of Maytansinol. 

Oxazines without a nitro group have also been suggested as antitumor compounds.56 Maytansinoids possess antileukemic and antitumor activity275"279,288 with the exception of Maytansinol.279... 

It contains alkaloids among which are (he maytansinoids, which have had considerable interest as antitumor agents. Samples (165) of 92 species gave the following as positives previously known Calha edulis (2/3), Euonymus atropurpureus, Hippocratea indica, Maylenus mossamhicensis. 

Larson GM, Schaneberg BT, Sneden AT (1999) Two New Maytansinoids from Maytenus buchananii. J Nat Prod 62 361... 

Yu T-W, Bai L, Clade D, Floffmann D, Toelzer S, Trinh KQ, Xu J, Moss SJ, Leistner E, Floss FIG (2002) The Biosynthetic Gene Cluster of the Maytansinoid Antitumor Agent Ansamitocin from Actinosynnema pretiosum. Proc Natl Acad Sci USA 99 7968... 

Liu C, Tadayoni BM, Bourret LA, Mattocks KM, Derr SM, Widdison WC, Kedersha NL, Ariniello PD, Goldmacher VS, Lambert JM, Blattler WA, Chari RVJ (1996) Eradication of Large Colon Tumor Xenografts by Targeted Delivery of Maytansinoids. Proc Natl Acad Sci U S A 93 8618... 

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