Macrolides and Related Compounds

5 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. 

4 Macrolides and Related Compounds.- Complex phosphonates continue to be used in the construction of the carbon framework in syntheses of macrocyclic compounds, for example (187), (188), and (189) in syntheses of the immunosuppressant FK-S06, a high affinity ligand for the immunophilin FKBP,94 and the bis-macrolide (-)-colletol,95 respectively. In the case of the immunophilin FKBP intramolecular phosphonate-based olefination is also used as the cyclization step.  

A recently reported asymmetric synthesis of the macrocyclic lactam macebecin uses selective (Z)-olefination with the fluoroethyl phosphonate ester (190) to introduce the (E,Z)-dienic amide residue. A Wittig reaction of ylides (191) with biphenyl aldehydes (192) has been used to link rings C and D in new convergent synthesis of the macrocyclic bis(biphenyls), plagiochin C and D.  

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Macrolides and Related Compounds.- Phosphorus-based methods have... 

Macrolides and Related Compounds.- The total synthesis of amphoteronolide B (166) and amphotericin B (167) has been reported in a series of papers by Nicolaou s group.The method uses the phosphonate-based olefination of (164) with (165) to form the basic carbon skeleton which is cyclised by an intramolecular phosphonate-based olefination. A Wittig reaction of the ylide (168) is a key step in the synthesis of the cytotoxic macrocycle riccardin C (169). 

Wise, R. (1989). The development of macrolides and related compounds—Leading article. J. 

Major classes of antibiotics include more than 200 peptides such as the gramicidins, bacitracin, tyrocidines and valinomycin (Fig. 8-22)k more than 150 penicillins, cephalosporins, and related compounds tetracyclines (Fig. 21-10) the macrolides, large ring lactones such as the erythromycins (Fig. 21-11) and the polyene antibiotics (Fig. 21-10). 

Marine sponges of the genus Haliclona contain a diverse array of active secondary metabolites, including highly potent cytotoxic macrolides, e g., halichondrin and related compounds, Fig. (56) [468], and salicylihalamides A and B, Fig. (57) [469], New macrolides chemically related to salicylihalamides, apicularens A and B, were recently isolated from the myxobacteria Chondromyces sp. [470], From marine bacteria, other cytotoxic macrolides have been isolated, such as octalactin A, Fig. (58) and B, which have been shown as a cell cycle-specific anticancer drug [471], and swinholide, Fig. (59), isolated from symbiotic cyanobacteria with the marine sponge Theonella swinhoei [472]. 

Mallams, A. K., and Rossman, R. R. (1989). Semisynthetic macrolide antibacterials derived tylosin. Synthesis of 23-O-demycinosyl tylosin and related compounds. J. Chem. Soc. Perkin Trans. /, 775-785. 

Franklin, M.R. (1991). Cytochrome P450 metabolic intermediate complexes from macrolide antibiotics and related compounds. Meth. Enzymol. 206, 559-573. 

Dipyridyl disulfide and related compounds have also been used as a method for macrolide formation the addition of thio-philic metal cations and/or pyridine derivatives has been found to assist this process. This oxidation-reduction condensation, using 2,2 -dipyridyl disulfide, constitutes an excellent strategy for the solid-phase synthesis of peptides. This method does not affect amino acids sensitive to oxidation, proceeds under mild conditions without the requirement of basic or acid catalysts, and has the advantages of minimizing both racemization of carboxyl component and side-reactions of certain amino acids. Furthermore, it has been successfully applied to phosphorylation reactions, such as the synthesis of coenzyme A, oligothymidilates, and nucleotide cyclic phosphates, and nucleotides from G ,2 -cyclouridine. ... 

Hydroxy acids H0-(CH2)n-C02H with n>3 react with DEAD and TPP to afford the corresponding lactones. This procedure can be utilized in the preparation of macrolide antibiotics and related compounds. Macrolactonization by the use of DEAD-TPP depends on the reaction conditions and the structure of the seco acids. Thus dropwise addition of the hydroxy acid (18) over a period of 10 h to a mixture of DEAD (7.7 equiv) and TPP (7.5 equiv) affords the lactone (19) in 59% yield as well as the unwanted di-lactide (20) in a yield of <1%. On the other hand, the reaction of... 

Erythromycin, a macrolide antibiotic, lacks a significant chromophore. Detection sensitivity was enhanced by using a wavelength of 200 nm and selecting an injection solvent of lower conductivity than the BGE. In order to facilitate the separation of erythromycin and its related substances, 35% (v/v) ethanol was incorporated into a 150 mM phosphate buffer pH 7.5. Resolution of all of the compounds was achieved in approximately 45 min. The method was employed as an assay method for erythromycin and for impurity determination. Peptide antibiotics, such as colistin and polymyxin, are mixtures of many closely related compounds. A validated CZE method for impurity analysis of polymyxin B was described, employing 130 mM triethanolamine-phosphate buffer at pH 2.5 to reduce the adsorption of analyte onto the capillary wall. Methyl-/l-cyclodextrin (M-/1-CD) and 2-propanol were found to be necessary for selectivity enhancement. Using similar buffer additives, the same group developed and validated a method for colistin analysis. ... 

The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. 

Macrolide and lincosamide antibiotics are weakly basic compounds slightly soluble in water but readily soluble in common organic solvents. They are most composed of several closely related components that may vary in proportion depending upon the source of the formulation. Macrolides other than oleandomycin are stated to be unstable at both acidic and basic aqueous solutions. 

Extensive early studies of in vitro and in vivo structure-activity relationships within the leucomycin family revealed correlations between the number and type of O-acyl substituents and the compounds antibacterial potency, efficacy in treating experimental infections, and serum antibiotic concentrations [26]. Consequently, esterification of all hydroxyl groups within several leucomycin-related macrolides was conducted to find derivatives with better antibiotic activity and pharmaceutical properties (such as greater water solubility and masking their extremely bitter taste). From such investigations with midecamycin, miokamycin was synthesized and characterized as a useful new macrolide antibiotic [24, 27]. It has now been commercially launched in several countries [5]. 

Among the many antibiotics isolated from the actinomycetes isthe group of chemically related compounds called the mac-mlides. In I9S0, picromycin, the first of this group to be identified as a macrolide compound, was first reported. In 1952. erythromycin and carbomycin were reported us new antibiotics, and they were followed in subsequent years by other macrolides. Currently, more than 40 such compounds ate known, and new ones are likely to appear in the future. Of all of these, only two, erythromycin and oleandomycin, have been available consistently for medical use in the United States. In recent years, interest has shifted away from novel macrolides isolated from soil samples (e.g.,. spiramycin, josamycin, and rosamicin), all of which thus far have proved to be clinically inferior to erythromycin and semisynthetic derivatives of erythromycin (e.g., clarithromycin and azithromycin), which have superior pharmacokinetic properties due to their enhanced acid stability and improved distribution properties. 

The chemical nature and related physicochemical properties largely govern the distribution and elimination, which refers to biotransformation (metabolism) and excretion, of antimicrobial agents. The majority of antimicrobial agents are weak organic electrolytes, either weak acids (penicillins, cephalosporins, sulphonamides) or weak bases (aminoglycosides, lincosamides, macrolides, diaminopyrimidines, metronidazole), while fluoroquinolones, tetracyclines and rifampin are amphoteric compounds, and chloramphenicol and its... 

Natural Products. 16-Membered macrolides are divided into leucomycin- and tylosin-related groups, which differ in the substitution pattern of their aglycones. Multi-factor complexes are usually produced and some compounds have been isolated from culture broths of different organisms and then been given different names. 

The following discussion will briefly outline two categories of macrolide (large ring system) antibiotics the lactone macrolides that include clinically useful erythromycins and several related compounds and the ansamacrolides, the most prominent members being the rifamcyins. 

Fig. 13. Structures of macrolide lactams and a related compound produced by actinomycetes.

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