Of ansamycin

Murphy P., Sharp A., Shin J., Gavrilyuk V., Dello R. C., Weinberg G., Sharp F. R., Lu A., Heneka M. T., and Feinstein D. L. (2002). Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis. J. Neurosci. Res. 67 461 470. 

The chemistry of the various groups of ansamycins is only discussed briefly, as several excellent reviews have already been published in recent years1,4 s These should be consulted for detailed chemical descriptions and extensive literature references. 

From the biochemical point of view, the unique mode of action of some of the ansamycins, in particular of rifampicin, has aroused much interest. Rifampicin and several other ansamycins have been shown to inhibit bacterial transcription very specifically and at extremely low concentrations by interacting exclusively with DNA-dependent RNA polymerase. This unique action has spurred many investigations on the effects of ansamycins in a variety of viral and eukaryotic systems. More recently maytansine and related compounds have been found to be very potent antimitotic agents and to have interesting antitumour activities. 

The published literature on the biological and medical actions of ansamycins is too vast to be dealt with at length in this article. Several reviews have appeared, however, dealing with the rifamycins51 53 ... 

Most studies about the effects of ansamycins on DNA viruses have been made with vaccinia virus51l It has been found that some derivatives, such as rifampicin, inhibit the growth of this virus. There is no doubt, however, that this inhibition is not due to a block in RNA synthesis, as was found in bacteria, but apparently the assembly... 

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. 

Macrolides and Related Compounds. - Complex phosphonates continue to be used in the construction of carbon skeletons and in cyclisation reactions, as exemplified by the synthesis of didesepoxyrhizoxin, the biogenetic precursor of the antitumour agent rhizoxin, via intramolecular olefination of (225). (+)-Trienomycins A and F, members of a family of ansamycin antibiotics, have been synthesised using a double Wittig reaction of the diphosphonium salt (226) as a key step. The reaction produces a mixture of isomers including 21% of the required (all- ) product. 

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]. 

ABSTRACT The discovery, classification, biosynthesis and biological activities of ansamycin antibiotics are reviewed. 

As a member of the rifamycin group of ansamycin antibiotics, tolypomycin Y (6) was isolated from the culture broth of Streptomyces tolypophorus and its structure was determined. Compound 6 consists of tolypomycinone and tolyposamine [48, 49]. 

As for the other portions of the chromophoric unit, the origins of the substituent(s) at the C-3 and C-4 positions were discussed. A number of ansamycins bear different substituents at C-3 of the aromatic nucleus, e.g. hydroxyl on 3-hydroxyrifamycin S (15) and actamycin (69) thiomethyl in... 

Celmer [200,201] reported a stereochemical and biogenetic model for the lactone ring of macrolide antibiotics such as oleandomycin, erythromycin and leucomycin. On the other hand, the structural similarity between the carbon skeleton (from C-5 to C-14) of the ansa chain of ansamycins, such as the rifamycins and the streptovaricins, and the lactone ring (from C-3 to C-12) of the macrolide antibiotics was also pointed out [1]. 

As implied above, there are two kinds of ansamycins, one that possesses a benzene ring and another that possesses a naphthalene ring in the structure these are known as the benzenoid and naphthalenoid ansamycins, respectively. The m-CyN unit is involved in the biosyntheses of the chromo-phores of both these ansamycins, and the polyketide biosynthetic pathway is also concerned in the biosynthesis of the ansa chains of both types of ansamycin and a part of the chromophore of the naphthalenoid ansamycins. 

About 70 naphthalenoid ansamycins have been reported until now. In most of these ansamycins, the ansa part is composed of 17 carbons, like the rifa-mycins, and in other instances the ansa moiety is composed of 23 carbons, like the naphthomycins [1]. Models for the biosynthesis and stereochemistry (Celmer s model), as applied to macrolide antibiotics [2], have been developed for these two types of ansamycins [3]. 

Sugita M, Natori Y, Sasaki T, Furihata K, Sbimazu A. Seto H, Oiake N. Studies on mycotrienin antibiotics, a novel class of ansamycins. I. Taxonomy, fermentation, isolation and properties of tnycorrienins i and H. J Antibiot 1982 35 1460-1466. 

Lancini GC, Grandi M. Biosynthesis of ansamycins. Corcoran JW, ed. Antibiotics IV— Biosynthesis. New York Springer-Vetlag, 1981 11-40. 

Ghisalba O, Traxter P, Niiesch J. Early intermediates in the biosynthesis of ansamycins. I. Isolation and identification of protorifamycin 1. J Antibiot 1978 31 1124-1131. 

Rifamydns. This family belongs to the large class of ansamycins, molecules characterized by an aromatic nucleus... 

The most unexpected rearrangement of a sugar core was discovered three decades ago by Mootoo and Fraser-Reid. Working on a stereocontrolled synthesis of ansamycin antibiotics, by so-called pyronopyran methodology [30], they observed that bromination of complex derivative 37 did not provide the expected bromohydrin 39 but resulted in the rearrangement of the carbohydrate skeleton (Figure 10.13) [31,32]. 

A new class of ansamycin compounds bearing a ( , , )-triene within a 21-membered ring lactam were recently described. In particular, cytotrienins A-D (175) that were isolated from Streptomyces sp. RK95-74 and are important antitumoral compounds. Their synthesis was disclosed by Panek etal and the cmcial RCM step was performed on polyenic substrate 173. Surprisingly, when using [Ru]-II, the insertion of the ruthenium took place on one of the disubstituted double bonds thus affording the 19-membered ring. On the other... 

Fig. 4. Three-dimensional stereo models of ansamycins and their derivatives A) atropiso-streptovaricin C triacetate cyclic p-bromobenzeneboronate (1), B) rifamycin B p-iodo-anilide (2), C) rifamycin Y p-iodoanilide (3), D) tolypomycinone tri-m-bromobenzoate (5), E) maytansine 3-bromopropyl ether (6), F) geldanamycin. All drawings except that for geldanamycin are from Wang and Paul 148) that for geldanamycin was obtained from Dr. D. J. Duchamp, The Upjohn Company (25)...

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