Ansamycin macrolides

These compounds are identified by having a medium to large macroUde or macrolactam handle fused to a mono- or bicychc aromatic core [25]. Although macrolactams do not belong to the macrolides in the correct sense, they are included here because of the close similarity of the aliphatic chain in structure and stereochemistry to that of the polyoxo macrolides. Most prominent representatives are 

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This renaissance was by no means limited to aminoglycoside antibiotics. Indeed new polypeptides, ansamycins, macrolides and other novel chemical types have been discovered in recent years. 

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. 

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. 

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. 

In specific antibiotic research areas, development of improved e-lactams (see Chapter li) and work on aminocyclitol antibiotics represented a significant portion of the effort. Advances were also made in areas of interest on other antibiotics of importance in medicine or agriculture, such as the macrolides, tetracyclines, lincomycins, ansamycins, novobiocins, polyethers, and peptides. 

The widespread occurrence and biological significance of the macrolide ansamycin and polyether antibiotics, and of polyhydroxylated natural products, including rare carbohydrates, among others, has stimulated considerable interest in the development of concise, efficient synthetic methodology for the stereo-and enantio-selective construction of stereochemically adorned acyclic molecules.Indeed, considerable effort has been devoted towards the development of highly stereoselective syntheses of the so-called propionate (e.g.—CHMe—CHOH—CHMe—CHOH—), acetate (c.g.—CHOH—CH2CHOH—CH —)... 

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. 

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]. 

Maytansine s ansa macrolide structure shows noteworthy similarities to those of the rifamycins [255], streptovaricins [256], tolypomycins [257], and geldanamycin [258]. The ansamycin antibiotics and their derivatives have aroused considerable interest as antiviral and antimicrobial agents, and as inhibitors of RNA tumor virus reverse transcriptases. 

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]. 

The very largest of the polyketides are the macrolide antibiotics, e.g. nystatin 3.106). Further examples are the ansamycins which derive by a mixed acetate-propionate pathway (Section 7.6.1). Intermediate in size are the cytochalasins which derive by an acetate (malo-nate) pathway (Section 7.6.2). Where propionate units account for C3 fragments in the ansamycins, methionine and acetate serve in the cytochalasins. The macrolide antibiotics discussed below all follow the former way of generating C3 units. It is clear that, if methyl groups are introduced by two different pathways, this is not adventitious. The methyl groups must have a function possibly like the double bonds in dictating the conformation of the macrocycle. 

Large family of natural macrolactones commonly referred to as macrolides can be grouped into polyoxo macrolides, polyene macrolides, ionophoric macrohdes, and ansamycin macrohdes. 

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