Geldanamycin antitumor activity

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). 

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. 

Biochemical Studies Geldanamycin shows antitumor activity in vitro and in situ [1,3]. Uehara et al. found that geldanamycin and other benzoquinonoid ansamycins reversibly decrease the autophosphorylation of p60 and reverse the cell morphology from the transformed to the normal phenotype [4]. 

The growth inhibition of virus-transformed cells in vitro and antitumor activity in vivo of geldanamycin (85) and its derivatives [230,231], and the inhibition of DNA synthesis in murine tumor cells by 85 were reported [232,233]. Geldanamycin (85) is an antibiotic that preferentially inhibits Gl/S transition and causes G2/M arrest in human leukemia HL-60 cells. Also, it was found that 85 selectively inhibited recombinant Src tyrosine kinase without significantly inhibiting protein kinase A. The perturbation of cell cycling by 85 was accompanied by marked suppression of c-MYC expression [234]. 

Herbimycin was found to have potent herbicidal activity against most mono- and dicotyledonous plants, especially against Cyperus microiria STEUD but strong resistance by Oryza saliva [173]. It was also reported that herbimycins showed cytocidal activity on both HeLa cells and Ehrlich cells in vitro and could convert the transformed morphology of Rous sarcoma virus-infected rat kidney cells to the normal ones [177]. However, interest in geldanamycin and herbimycin increased greatly upon the discovery of their potent antitumor activity at nanomolar concentrations [178, 179]. 

This section covers compounds that were reported relatively recently. The mechanism of action of these compounds is reasonably understood. The compounds in this section have been sorted by their biological activity and their potential utility in the clinic. The class of compounds include immunosuppressants (rapamycin and FK506), antitumor agents (geldanamycin to echinomycin), antiinflammatory agents (efomycin), antiobesity agents (lipstatin), and antibiotics (streptogramins to platensimycin). 

Ansamycins with the ansa bridge bound to a benzene ring are macbecin I (121) and II (122), geldanamycin (123) and herbimycin A (124), B (125) and C (126) and show a significant range of antitumor, antifungal,herbicidal, angiostatic, antiviral and antiprotozoal activity [205]. 

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