Erythromycins derivatives

These reactions liberate carbonyl fluonde and fluorotnmethylsilane and thus require no hydrolysis A fluorinated erythromycin derivative is obtained from fluorination of 3 O raycarosyl-8 9-anhydroerythronolideB 6,9 hemiacetal, an enol ether [iS] (equation 16)... 

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]. 

Allopurinol, amoxicillin/clavulanic acid, dicloxacillin, erythromycin derivatives, halothane, phenytoin, and trimethoprim/sul-famethoxazole... 

Ruan, X., Pereda, A., Stassi, D.L. et al. (1997) Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. Journal of Bacteriology, 179, 6416. 

Stassi, D.L., Kakavas, S.J., Reynolds, K.A. cl al. (1998) Ethyl-substituted erythromycin derivatives produced by directed metabolic engineering. Proceedings of the National Academy of Sciences of the United States of America, 95, 7305. 

Figure 8.3 Erythromycin derivatives obtained by gene inactivation.

Figure 8.4 Erythromycin derivatives generated by using the OleGII glycosyltransferase of the oleandomycin pathway.

Gaisser S, Lill R, Wirtz G et al (2001) New erythromycin derivatives from Saccharopoly-spora erythraea using sugar O-methyltransferase from the spinosyn biosynthetic gene cluster. Mol Microbiol 41 1223-1231... 

DL Stassi, SJ Kakavas, KA Reynolds, G Gunawardana, S Swanson, D Zeidner, M Jackson, H Liu, A Buko, L Katz. Ethyl-substituted erythromycin derivatives produced by directed metabolic engineering. Proc Natl Acad Sci (USA) 95 7305-7309,... 

Ruan, X., Pereda, A., Stassi, D. L., Zeidner, D., Summers, R. G., Jackson, M., Shivakumar, A., Kakavas, S., Staver, M.J., Donadio, S., and Katz, L. (1997). Acyl transferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives./. Bacteriol., 179, 6416-6425. 

Benzoxazoles have been prepared by intramolecular reaction of a phenolic —OH groiq) with a Beckmann intermediate (equation 30). A cyclic imidate was isolated in high yield from tosylation and in situ Beckmann reaction of the erythromycin-derived oxime (4[Pg.698]

Although spiramycin is used to treat toxoplasmosis, more potent inhibitors of Toxoplasma gondii have been reported [183-185]. In contrast to derivatives of erythromycin, activity was not observed from several 16-membered macrolides against Mycobacterium avium complex [186]. Similar trends have been noted with several other bacterial and parasitic pathogens in which 16-membered macrolides have not matched the promising activity shown by erythromycin derivatives [177]. 

Cholestatic hepatitis, which is associated primarily with erjdhromycin estolate, can be caused by all forms of erythromycin, including the base, estolate, ethylsuccinate, propionate, and stearate (39,41). Although it was originally speculated that a hypersensitivity reaction to the estolate ester rather than to the erjdhromycin itself was responsible for this adverse reaction (42), erythromycin does inhibit bile flow (43). Most probably the differences in hepatotoxicity between the various erythromycin derivatives are of a quantitative rather than a qualitative nature (44,45), perhaps because of better intestinal absorption of the estolate. Potentially severe but rare cholestatic liver injury occurs in perhaps up to 2-4% of... 

The accumulation of novel erythromycin-derivatives has been reported after replacing the loading domains (AT and ACP) of module 1 of DEBS with the loading domains from the avermectin producer. As expected, and again due to the broad substrate specificity of AT and ACP from S. avermitils, the hybrid enzyme was producing a number of new antibiotics (72-80)) [53] (Fig. 12.14). 

Weber, J.M., J.O. Leung, S.J. Swanson, K.B. Idler and J.B. McAlpine (1991). An erythromycin derivative produced by targeted gene disruption in Saccharopolvspora erythraea. Science 252 114-117. 

In addition to the contribution derived from protein-protein interactions, modular recognition and discrimination of incoming substrates also plays a role in controlling the specificity of PKSs, as determined in the DEBS system. The KS domains of DEBS modules 2-6 were shown to have surprising tolerance in vivo to a series of substrates fed diffusively, and were able to incorporate these substrates into novel 6dEB or erythromycin derivatives [59]. In vitro studies on the KS domain of DEBS module 2 likewise showed this domain to be tolerant to a broad range of substrates [60]. Nevertheless, the DEBS modules do not accept all substrates. In vitro studies of module 2, module 3, module 5, and module 6 for acceptance of various diketide substrates showed that all four modules have similar substrate preference, and while all diketide compounds with sy stereochemistry across the a- and /9-posi-tions were accepted by the modules, those compounds with anti stereochemistry were not accepted. It is particularly interesting that all four DEBS modules have similar substrate specificity, despite the fact that their natural substrates differ widely [61]. 

This chapter deals with recent progress in the chemical modification and structure-activity relationships of 14- and 15-membered macrolides (mainly erythromycin derivatives), 16-membered macrolides (mainly the leucomycin and tylosin families), and the avermectin family of macrolides, showing nematocidal, insecticidal, and arachnidicidal activities. Previous reviews of these macrolides were given by Sakakibara and Omura in the first edition of this book in 1984 [1]. 

Morimoto, S., Adachi, T., Kashimura, M., Matsunaga, T., Asaka, T., Yoshida, T., Amano, T., Watanabe, Y, and Hatayama, K. (1992). Synthesis of erythromycin derivatives. IX. Novel procedure of clarithromycin (6-0-methylerythromycin A) synthesis. Presented at 112th Ann. Meet. Pharm. Soc. Jpn. (March 29-31, Fukuoka). Abstr. No. ZH 9-14. 

Luger, P., and Marier, R. (1979). Molecular structure of 9-deoxy-ll-deoxy-9,ll-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-(9S)-erythromycin, a new erythromycin derivative. J. Cryst. Mol. Struct. 9, 329-338. 

Ackland, M. J., Atkins, P. J., and Jones, N. B. (1991). Approaches to novel water-soluble prodrags of erythromycin A. Synthesis of 2 -0-(iV-alkylsuccinamoyl)-erythromycin derivatives incorporating anionic and cationic groups. J. Chem. Res. (M), 1265-1278. 

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