Geldanamycin and Herbimycins

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]. 

SEVEN-, EIGHT-MEMBERED AND LARGER HETEROCYCLIC RINGS 

As anticipated, AHBA biosynthesis genes were not found in the gdm gene cluster but are clustered elsewhere in the gdm genome. Thus the geldanamycin producer has two different AHBA clusters, ahba-B and ahba-N, whereas the herbimycin producer 

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A significant breakthrough in identifying protein clients of Hsp90 was the realization that the chaperone is inhibited by benzoquinone ansamycins like geldanamycin and Herbimycin A (Whitesell et al. 1994). The first... 

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

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]. 

Other benzenoid ansamycins, geldanamycin [9,10] and herbimycin [11,12], are also known. Herbimycin was first isolated as a herbicidal antibiotic and was subsequently found to normalize tumor cells [13]. 

In the benzenoid ansamycin antibiotics, the ansa chains of herbimycin A, geldanamycin, and macbecin I [7] are similar. It was shown that the ansa moiety of geldanamycin consisted of four molecules of propionic acid (P), two... 

Sakagami, M., P. Morrison, and W. J. Welch. Benzoquinoid ansamycins (herbimycin A and geldanamycin) interfere with the maturation of growth factor receptor tyrosine kinases. Cell Stress Chaperones. 4 19-28.1999. 

The closely related members of the ansamycin family include the herbimycins and macbecin I (Scheme 3). Structural differences compared to geldanamycin include the absence of a methoxyl at C17 on the quinone portion and the presence of methoxyls at Cl5 and at Cl 1 (R , R =OMe). Total syntheses of macbecin I have been reported by Baker and Castro in 1990, Evans and co-workers in 1992, and Panek and Xu in 1995. The total synthesis of herbimycin A was reported in 1992 by Nakata and... 

Among other benzenoid ansamycins with C15 ansa chains, geldanamycin, the macbecins and the herbimycins are classified in this category. These compounds possess a 1,4-quinone or a 1,4-hydroquinone moiety as a chromophore. 

Other geldanamycin (85) related compounds, the macbecins I (93) and II (94), were isolated from the fermentation broth of Nocardia sp. No. C-14919 (N-2001) and their structures reported [147-150]. Macbecin I (93) possessed a quite similar chemical structure to that of herbimycin A (86), except that 93 possessed a methyl group at the C-6 position instead of a methoxyl group, as in 86. Macbecin II (94) possessed a hydroquinone moiety as a chromophoric unit. 

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