Ansamycin derivative

Certain ansamycin derivatives, such as rifampicin, inhibit the growth of these organisms at high drug concentration. The underlying mechanism of action is poorly unterstood at present, but it does not seem to be related to RNA or DNA synthesis. 

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]. 

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... 

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. 

Lactone 227 has been converted in several steps into aldosulose derivative 228, a degradation product from the ansamycin antibiotic (+ )-trienomycin A.441... 

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. 

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. 

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... 

As a consequence, intramolecular and intermolecular interactions lead to unexpected chemical properties. In particular, those derivatives with lipophilic side chains tend to aggregate and behave like detergents even in dilute solutions. This property should be taken into account, when ansamycins are used at high concentrations in biological systems. The ansamysins do not contain lactone bonds in their ansa ring, which sets them clearly apart from the macrolide antibiotics. 

Aminopolyhydroxynaphthalenes. This NH, synthon was used to convert the protected bromopolyhydroxynaphthalene derivative I to the protected aminopolyhydroxy-naphthalene derivative 2, the aromatic nucleus of an ansamycin. One advantage of this amination is the satisfactory yield, which occurs in spite of the steric factors usually observed in the reaction of bromides with potassium azide. 

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. 

Further antibiotics, mainly derived from actinomycetes, are used for special applications in human and veterinary medicine [20]. These compounds have numerous chemical structures. The macrolides, tetracyclines, aminoglycosides, glycopeptides, and ansamycins for instance are used in antibacterial treatment whereas the anthracyclines reached the market to supplement anticancer chemotherapy. The fairly toxic polyether-type antibiotics are preferably used as anticoccidial agents. Due to the dramatically increasing resistance of clinical important bacterial strains new targets for the discovery of novel types of antibacterial agents are urgently needed. 

Rifamycin B, produced by Amycolatopsis mediterranei, is one of the most notable members of the ansamycin family [36, 37, 64, 65] (Fig. 14). It has been used clinically in a synthetically modified form called rifampicin and it is still one of the first-line therapies effective in the treatment of tuberculosis and other mycobacterial infections. The starter unit for rifamycin polyketide assembly is part of the chromophore and is derived from 3-amino-5-hydroxybenzoic acid. Five polyketide synthases are involved in the formation of rifamycin chromophore and the first polyketide synthase contains at the N terminus the loading domain for 3-amino-5-hydroxybenzoic acid, which consists of an acyl-CoA ligase linked to ACP, and module 1-3. The rifamycin polyketide synthase lacks a TE domain at the C terminus. The release of polyketide chain from polyketide synthase and the formation of amide to generate the macrocyclic lactam will be catalyzed by RifF, which is very similar to arylamine A-acetyltransferase. 

Ansamycins. Synthesis of 25-deacetoxy-25-epi-hydroxy rifenycin S (RF S) was reported. The additional hydroxyl function introduced by the transformation did not have the expected effect on antibacterial activity, although the proper conformation for interaction with the target enzyme was proved. RF derivatives containing 3-amidino and 4-aminoimidazolo [4,S-c] moieties were prepared and some showed good antinycobacterial activity in mice. LM 427, a spiropiperidyl RF, was particularly effective in mouse tubercular infection models. Microbial transformation of RF B to RF O and RF S, a intermediate in the thesis of rifempicin,... 

Among others, the ansamycin antibiotics have displayed antibacterial, antitumor and herbicidal activities. For many years, rifampicin, a semisynthesized antibiotic derived from rifamycin B, has been utilized for the treatment of tuberculosis. 

Among the naphthalenoid and benzenoid ansamycin antibiotics, some ansamycins possess a 1,4-naphthoquinone or a 1,4-quinone unit as a chromophore, and others possess a 1,4-hydroxynaphthalene or a 1,4-hydroquinone units (or their derivatives) as a chromophore. Since these two types of chromphore are in most cases reversible, it is not appropriate to classify by the difference of the oxidation stage of the chromophore. In this review, benzenoid and naphthalenoid ansamycins are further divided according to the difference of the length of their ansa chains. Thus, naphthalenoid ansamycins are divided into 3 groups, i.e., naphthalenoid ansamycins with C17 ansa chains, naphthalenoid ansamycins with C23 ansa chains, and naphthalenoid ansamycins with C9 ansa chains. The benzenoid ansamycins are divided into 2 groups, i.e., benzenoid ansamycins with C15 ansa chains and benzenoid ansamycins with Ci7 ansa chains. The relationships between, and the antibiotics within these groups are indicated in Scheme 2. 

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