Erythromycins modifications

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macroHdes some of the derivatives ate being commercially launched (116). 

Another successhil strategy for derivatization of erythromycin employed modification of functional groups involved in intramolecular cyclizations. The C-9 ketone, C-6 hydroxyl group, C-8 proton, and/or C-ll,12-diol of erythromycin were converted into functional groups which participate poorly, if at all, in intramolecular cyclizations. Some derivatives which have been extensively evaluated in preclinical and clinical trials exhibit such desirable properties as better stabiUty under acidic conditions, greater oral bioavadabihty, and higher and more prolonged concentrations of antibiotic in semm and tissues. 

The 2-chlorobenzyl group has been used in the protection of an oxime during the modification of erythromycin K ... 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

McDaniel, R., Thamchaipenet, A., Gustafsson, C. et al. (1999) Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel unnatural natural products. Proceedings of the National Academy of Sciences of the United States of America, 96, 1846. 

Another basic drug where minor structural modification results in a dramatic increase in volume of distribution is the macrolide antibiotic, azithromycin. The traditional agent in this class is erythromycin, which contains one basic nitrogen, in the sugar side-chain. 

Another example of solid phase DOS involves post-modification of the natural product macrolide antibiotic erythromycin (34) [77]. Erythromycin was first converted to analogue 32 which resembles a third generation macrolide antibiotic with high activity against resistant strains (ABT-773, 35), but is attached to solid phase-bound amino acids by reductive amination. Two further reductive amination steps and cleavage from solid support form a library of compounds of type 33 (Fig. 10). 

Weishlum B. (1995). Erythromycin resistance by ribosome modification. Antibiotic Agents and Chemotherapy 39 577-585. 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macrolides some of the derivatives are being commercially launched. Derivatives of erythromycin and oleandomycin include 2-U-nee ly I erythromycin (C331129NO t. 2 -O-propionylerythromycin (QoHtiNOm), erythromycin ethyl carbonate (C/0H71NO15), erytliromydn ethyl succinate (C 3H75NOi2), tn-O-acetyloleandomycin (C4iHc7NOi5), erythromycin-11,12-carbonate... 

Penicillin, erythromycin, tetracycline, and cephalosporins are among the most widely used. Synthetic modifications of the naturally occurring antibiotic compounds have produced many variations that have the necessary clinical properties. 

Enzymatic detoxification or modification AGAC antibiotics /(-Lactams Chloramphenicol Erythromycin Tetracyclines Mercury compounds Formaldehyde Modification by acetyltransferases, adenylylases or phosphotransferases Inactivation (/(-lactamases) Inactivation (acetyltransferases) Esterases produce anhydroerythromycin Enzymatic inactivation Inactivation (hydrolases, lyases) Dehydrogenase... 

McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M, Ashley G (1999) Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel Unnatural Natural Products. Proc Natl Acad Sci USA 96 1846... 

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