Ansamycin compound

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... 

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]. 

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). 

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. 

Ansamycin antibiotics are probably the most complex organic compounds produced by the genus Streptomyces. In addition to the antibacterial, they also exhibit antiviral effects. Ansamitocin P-3 shows a potent cytotoxicity against the human solid tumor cell lines A-549 and HT-29. The compound exhibits a significant activity against P-388 lymphocytic leukemia in mice and both 9PS (murine lymphocytic leukemia) and 9KB (human nasopharyngeal carcinoma) in cell culture systems. [38]. 

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... 

Naphthomycin has been isolated from a Streptomyces species28. Its structure has been elucidated and shown to belong to the class of naphthalenic ansamycins (Fig. 3)29 In contrast to these compounds, however, the skeleton of the ansa chain contains six additional C-atoms. Very recent structural studies of the chromo-phore have shown that naphthomycin possesses a hydroxyl group in position 6 and is unsubstituted in position 8 (W. Keller Schierlein, personal communication). It thus resembles the streptovaricin precursor protostreptovaricin I (Fig. 8). A further characteristic of naphthomycin is that it contains a halogen in the chromophore. 

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 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. 

Very interesting effects on eukaryotic cells result after treatment with ansamycins containing a benzene chromophore, especially with compounds of the maytan-sine group which are the only ansamycins found so far to occur in plants. 

The ansamycins are a remarkable group of natural compounds varying widely in both their chemical structure and their biological activities. They have mostly been isolated from prokaryotic microorganisms, but one group, the maytansines, occurs in plants. 

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. 

The vicinal and allylic four-bond proton-proton couplings for ribafutinol, a reduced form of a naphthalenic ansamycin (ribafutin) have been applied by Santos et al in the elucidation of the three-dimensional structure of this compound. Full sets of the Jhh couplings have been reported for both ribafutin and ribafutinol. 

The specific and proximate precursor of the mCyN unit in ansamycin polyketides is 3-amino-5-hydroxybenzoic acid 59 (AHBA) [94]. The biosynthesis of AHBA has recently been described by Floss and co-workers from the initial branch point of the shikimic acid pathway prior to 3-deoxy-D-flra/jzno-heptulo-sonic acid 7-phosphate (DAHP) [95]. The pathway shown in Scheme 25 was delineated by feedings of the proposed AHBA precursors, in labelled forms, to cell-free extracts of both the rifamycin B producer A. mediterranei S699 and the ansatrienin A producer S. collinus Tul892. In these experiments each of the compounds 61-64 was converted into AHBA with generally increasing efficiency. Most importantly the shikimate pathway compound DAHP cannot replace phosphoenolpyruvate 61 and erythrose 4-phosphate 60, or aminoDAHP 62 as the precursor of AHBA 59. 

A similar strategy has been followed for the preparation of the naphthoquinone nucleus (118) [202], a precursor of awamycin (119), another ansamycin antibiotic isolated from several Streptomyces species and active against Gram-positive bacteria, protozoa and marine tumors in vivo. The compound is also cytotoxic to Hela cells in vitro [203]. The structure of awamycin (119) has been determined by X-ray analysis [204] and it is structurally similar to damavaricin D (120), a degradation product and biosynthetic precursor of streptovaricin D (108). 

The compounds were shown to possess potent inhibition of oncostatin M signaling activity. The ethylene containing mycotrienins and mycotrienols are another class of related triene ansamycins. Much synthetic effort has been recently focused on the synthesis of these compounds. Historically, the maytansines, a family of chlorobenzenoid... 

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. 

Macrocyclic lactam antibiotics consist of the ansamycin antibiotics and a number of other compounds which are classified as non-ansamycin macrocyclic lactams (Scheme 1). 

The structures of the ansamycins which have provided the name for these antibiotics are remarkably complex, as we shall review in the following sections. However, it is the bioactivities of these compounds which first attracted the greatest attention. 

---