Maytansinoids antitumor activity

Other Sources of Imidazole Alkaloids Lythraceae alkaloids Maytansinoids Antitumor Activity Other Biological Activity Muscarine Alkaloids Naphthylisoquinoline Alkaloids Peptide Alkaloids Purine or Xanthine Alkaloids Biosynthesis... 

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). 

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 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. 

The first report of in vivo antitumor activity of a bryophyte appeared in 1986 in a review of results of screening of bryophytes in the National Cancer Institute s antitumor screening program by Spjut, Suffness, Cragg and Norris [20]. Subsequent studies, however, led to the conclusion that this bryophyte species, Claopodium crispifolium, was contaminated with a microorganism which contained maytansinoids, a well known class of antitumor macrolides [21]. 

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