Ansamycins rifamycins

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... 

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]. 

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),... 

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). 

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. 

Ghisalba O (1985) Biosynthesis of Rifamycins (Ansamycins) and Microbial Production of Shikimate Pathway Precursors, Intermediates, and Metabolites. Chimia 39 79... 

Ansamycins are a class of macrocyclic compounds in which non-adjacent positions on an aromatic ring system are spanned by the long aliphatic bridge (Latin ansa = handle). The aromatic portion may be a substituted naphthalene or naphthaquinone, or alternatively a substituted benzene ring. The macrocycle in the ansamycins is closed by an amide rather than an ester linkage, i.e. ansamycins are lactams. The only ansamycins currently used therapeutically are semi-synthetic naphthalene-based macrocycles produced from rifamycin B. 

The rifamycins are ansamycin antibiotics produced by cultures of Amycolatopsis mediterranei (formerly Nocardia mediterranei or Streptomyces mediterranei). The crude antibiotic mixture was found to contain five closely related substances rifamycins A-E, but if the organism was cultured in the presence of sodium diethyl barbiturate (barbitone or barbital), the product was almost entirely rifamycin B (Figure 3.71). Rifamycin B has essentially no antibacterial activity, but on standing in aqueous solution in the presence of air, it is readily transformed by oxidation and intramolecular nucleophilic addition into rifamycin O, which... 

The evidence then is that, for rifamycin and other ansamycins, biosynthesis diverts at a so-far unidentified (but early) compound in the shikimic acid pathway to give 3-amino-5-hydroxybenzoic acid (91) (as its CoA ester). This compound then yields, on the one hand, the mitomycins [e.g. porfiromycin (88)1 and, on the other, the CoA ester of P8/1-OG (92), which then affords diverse metabolites such as rifamycin B (87) and actamycin (86) (cf. ref. 83 for a detailed scheme). 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

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. 

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. 

The ansamycins have a very broad spectrum of biological effects which are of great significance for both scientific and practical reasons. One member of the rifamycins,... 

The rifamycins, streptovaricins and tolypomycins are very effective antibacterial agents. They all inhibit the synthesis of RNA by inactivating the DNA-dependent RNA polymerase. This effect occurs at low concentrations (0.01 jug/ml, 10-8 M) and is highly specific. It is the most thoroughly investigated and clearly defined biological action of the ansamycins. 

The potent antibacterial activity of the rifamycins, streptovaricins and tolypomycins is a consequence of the specific inhibition of DNA-dependent RNA polymerase, the enzyme responsible for most of the transcription of DNA to RNA. The interaction between these ansamycins and the enzyme has accordingly been studied in great detail. Because of its easy availability, rifampicin has been used most often as the model compound in such studies, but it is reasonable to assume that the data obtained with rifampicin also hold true, at least qualitatively, for the other rifamycins, the streptovaricins and tolypomycins. 

The structure of the ansamycins determines not only their activity on RNA polymerase, but also other important characteristics such as their ability to penetrate into bacteria and their pharmacokinetics and absorption in the host. To cite just a few examples rifamycin B, containing a free carboxylic acid group, has no antibacterial activity, although it inhibits RNA polymerase as strongly as rifampicin. Damavaricin C behaves similarly to rifamycin B, whereas its 6-methyl ether inhibits RNA polymerase to a lesser extent, but has good antibacterial activity23. Rifampicin owes its widespread clinical use to the fact that, in contrast to most other rifamycin derivatives, it is well absorbed when given orally. 

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. 

Martinelli, E., Gallo, G.G., Antonini, P. White, R.J. Structure of rifamycin W. A novel ansamycin from a mutant of Nocardia mediterranei. Tetrahedron 30, 3087 (1974)... 

S White, R.J., Martinelli, E. Ansamycin biogenesis incorporation of (1-13C) glucose and (1- 13C) glycerate into the chromophore of rifamycin S. FEBS Letters 49, 233 (1974)... 

Wehrli, W., Staehelin, M. Rifamycins and other ansamycins. In Antibiotics Vol. 3. Mechanism of action of antimicrobial and antitumor agents. Corcoran, J. W. and Hahn, F. E., (ed). Berlin-Heidclberg-New York Springer 1975, p. 252... 

A,A-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride (BOP-Cl, 64) has been found to be an efficient macrolactamization reagent [69]. Tatsuta and coworkers [69c] used it in the synthesis of the ansamycin antibiotic rifamycin W 123). As shown in Scheme 41, amino acid 121 was cyclized to 122 using 4 equiv of BOP-Cl and 10 equiv of diisopropylethylamine in toluene at 85 °C for 3 h. Upon deprotection and oxidation 123 was obtained in 30% yield from 121. 

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

An example of the utilization of a bridged bicyclic ketone for preparation of an acyclic moiety is the stereoselective synthesis of the C-21 to C-27 segment of rifamycin-S, a member of the ansamycin family of antibiotics (Scheme 18). Rao et alP used ketone (61), derived from furan, to prepare lactone (62). Exhaustive reduction of (62) provided the segment (63), which contains five chiral centers of lifamycin-S. 

Ansamycins - The structures, reactions, physical properties and biosynthe-sis of these antibiotics were reviewed.98 Protostreptovaricins I-IV were described as precursors of the streptovaricins.99 Also, the biosynthetic sequence damavaricin D - SvD -> SvC SvB, SvJ was determined.100 The isolation and structure of actamycin was reported.101 An immunosuppresent effect in mice of rifamycin and streptovaricin a..alogues correlated with toxicity but not with in vitro activity.102 The plasma decline of ethynyl-estradiol after administration of rifamycin was quantified in humans.103... 

Macrocyclic antibiotics The multiple chiral atoms and several functional groups allow multiple interactions with the analytes to enable chiral recognition. The primary interaction is ionic secondary interactions include hydrogen bonding, dipole-dipole, n-n, hydrophobic interactions, and steric repulsion. Rifamycin B, rifamycin SV, ristocetin A, teicoplanin, fradiomycin, kanamycin, ansamycins, avoparcin, and vancomycin. Amephoterin, a-aminoadipic acid, flurbiprofen, fenoprofen, methionine, methotrexate, ketoprofen, and suprofen, etc. 

Polyketide and non-ribosomal peptides produced by bacteria and fungi often attain the conformations that establish biological activity by cychzation constraints introduced by tailoring enzymes. This includes heterocychzation of cysteines, serines and threonines in non-ribosomal peptides. The second cychzation constraint is macrocychzation in polyketides, such as the above-mentioned antibiotic erythromycin and the antitumor epothilones. Regio- and stereospecific macrocychzation usuaUy occurs at the end of the polyketide and non-ribosomal peptide assembly hnes during chain release by thioesterase domains [49]. However, in the case of antibiotics of the ansamycin class, like the antitubercular drug rifamycin, the final... 

Ning, S., Muller, R.,Yu,T.W.,Taylor, M., Hoffmann, D., Kim, C. G., Zhang, X., Hutchinson, C. R., Floss, H. G., Biosynthesis of the ansamycin antibiotic rifamycin deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699, Chem Biol. 1998, 5, 69-79. 

---