Ansamycin

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 reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Wehrli, W. Ansamycins Chemistry, Biosynthesis and Biological Activity. 72, 21-49 (1977). 

Wehrli, W. Ansamycins Chemistry, Biosynthesis and Biological Activity. 72, 21-49 (1977). Weiss, A. Crystal Field Effects in Nuclear Quadrupole Resonance. 30, 1-76 (1972). 

Rifamycin B (136), a macrocyclic antibiotic of the ansamycin class, associates enan-tioselectively with amino alcohols. As 136 bears a carboxyl group, it can be used as a host molecule to resolve enantiomeric mixtures by CE. This was applied to analyze a variety of drugs, including terbutalin (137), bamethan (138), norphenylephrine (139),... 

The ansamycins (rifamycin B and rifamycin SV) are produced by certain strains of Nocardia mediterranei and act by inhibition of messenger RNA (m-RNA) synthesis, and consequently of bacterial protein synthesis. Structurally, they present a characteristic ansa structure, made of a ring containing a naphthohydroquinone system spanned by an aliphatic chain. The two ansamycins differ in the type of substituent on the... 

Vancomycin was the first macrocyclic antibiotic evaluated as selector for the synthesis of HPLC chiral stationary phases (CSPs) [7], along with rifamycin B (among ansamycins) and thiostrepton (among polypeptides). 

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... 

Miller, P., C. DiOrio, M. Moyer, R. C. Schnur, A. Bruskin, W. Cullen, and J. D. Moyer. Depletion of the erbB-2 gene product pI85 by benzoquinoid ansamycins. Cancer Res. 54 2724-2730.1994a. 

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. 

Supino-Rosin, L., A. Yoshimura, Y. Yarden, Z. Elazar, and D. Neumann. Intracellular retention and degradation of the epidermal growth factor receptor, two distinct processes mediated by benzoquinone ansamycins. J Biol Chem. 275 21850-5.2000. 

Whitesell, L., E. G. Mimnaugh, B. De Costa, C. E. Myers, and L. M. Neckers. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 91 8324-8.1994. 

Pharmacology Rifabutin, an antimycobacterial agent, is a semisynthetic ansamycin antibiotic derived from rifamycin S. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in Mycobacterium... 

Ansamycins, like the macrolides, are synthesized by condensation of a number of acetate and propionate units. These antibiotics, which are produced by several genera of the Actinomy-cetales, display a characteristic core aromatic ring structure. Amongst the best-known family members are the rifamycins, which are particularly active against Gram-positive bacteria and mycobacteria. They have been used, for example, in the treatment of Mycobacterium tuberculosis. 

Chemistry of / -Lactam Antibiotics and Ansamycins D. Zivanov-Stakic, Arh. Farm., 1979, 29, 311-328. 

AnsamacroHdes. Antibiotics in the ansamacrolide family are also referred to as ansamycins. They are benzenoid or naphthalenoid aromatic compounds in which nonadjacent positions are bridged by an aliphatic chain to form a cyclic structure One of the aliphatic-aromatic junctions is always an amide bond, Rifampin is a semisynthetically derived member of this family and has clinical importance, it has selective antibacterial activity and inhibits RNA polymerase. 

A novel ansamycin, naphthomycin K (1641), was isolated from a Streptomyces strain of the medicinal plant Maytenus hookeri (1616). This compound was cytotoxic (P388 and A-549 cell lines) but inactive against Staphylococcus aureus and Mycobacterium tuberculosis. An Amycolatopsis sp. has furnished the ansacarbami-tocins A-F, Al, B1 (1642-1649), which are similar to the ansamitocins (1617). 

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