Ansamycins geldanamycin

Studies using 14C-labelled precursors and C-l3 carbon magnetic resonance have suggested that the biosynthesis of the benzenic ansamycin geldanamycin follows essentially the same pathway as that of the rifamycins and streptovaricins50. Geldanamycin is composed of 3 acetate and four propionate units which are attached to a C7N unit in the same direction of growth as is found in rifamycins and streptovaricins. The incorporation of three acetate units into the ansa chain, as opposed to two in the naphthalenic ansamycins, excludes the existance of a common precursor. 

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]. 

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). 

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... 

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. 

Schulte, T. W., and L. M. Neckers. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol. 42 273-9.1998. 

Maroney, A.C. et al. 2006. Dihydroquinone ansamycins toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives. Biochemistry 45, 5678-5685. McLaughlin, S.H., H.W. Smith, and S.E. Jackson. 2002. Stimulation of the weak ATPase activity of human hsp90 by a client protein. J. Mol. Biol. 315, 787-798. 

Investigations of the biosynthesis of the rifamycins, streptovaricins and geldanamycin proved that the ansa chain of the ansamycins is synthesized as proposed by Woodward. The isolation of the precursors rifamycin W, damavaricin C and D and the protostreptovaricins, together with the fact that rifamycin B and tolypomycin Y are cosynthesized by Streptomyces tolypophorus26 make it probable that the rifamycins, streptovaricins and tolypomycin Y have a common progenitor. 

Nothing is known about the biosynthesis of the maytansine group, the only ansamycins so far identified as being of plant origin. Their similarity to the bacterial metabolite geldanamycin has led to the hypothesis that despite their occurrence in plants, microorganisms might be involved in their production. 

Finally, there remain some effects of ansamycins of which the significance and the biochemical targets are as yet unknown these include the combined action of rifamycin and amphotericin B on fungal cells, and the antibacterial and antifungal activity of naphthomycin and geldanamycin. 

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]. 

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]. 

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... 

Streptovaricin B (307), tolypomycin and geldanamycin are examples of ansamycins which are chemically related to rifamycins. The streptovaricins and tolypomycins resemble rifamycins in RT-inhibitory activity [18]. Streptovaricin B inhibits the replication of poxviruses by inhibiting early stages of mRNA synthesis [18]. Inhibition of focus formation of MSV by streptovaricins is also reported [18]. 

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. 

The biosynthetic precursor of the chromophoric moiety was studied vigorously by several research groups. As a result it was established that during the biosynthesis of the ansamycins, a W-C7N unit (Fig. 4) was incorporated into the chromophores of both the benzenoid ansamycins, such as geldanamycin (85) [177, 178] and ansamitocin P-3 (81) [179], and also the naphthalenoid ansamycins, such as the rifamycins [22,180-182] and actamycin (69) [183]. 

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. 

Geldanamycin ( 3) is the first member of a new benzoquinone subgroup of the ansamycins.2 28... 

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... 

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