Antibiotics chemical modifications

Macrocyclic lactones, stereo-controlled synthesis of 86YGK309 85YZ619. Macrolide antibiotics, chemical modification of 8OYGK395. 

The modem fermentation industries developed from the early era of antibiotics. Over 4000 antibiotics have been discovered since the 1950s. However, only about 100 are produced on a commercial scale and over 40 of these are prepared by a combination of microbial synthesis and chemical modifications. Antibiotics produced by fermentation and used as starting materials in chemical syntheses are given in Table 2. 

A Acetylation, O-Phosphorylation, and O-Adenylylation. A/-Acetylation, O-phosphorjiation, and O-adenyljiation provide mechanisms by which therapeutically valuable aminocyclitol antibiotics, eg, kanamycia [8063-07-8] gentamicin [1403-66-3] sisomicin [32385-11-8], streptomycia [57-92-1], neomycin, or spectinomycin are rendered either partially or completely iaactive. Thus, eg, kanamycia B [4696-78-8] (50) can be iaactivated by modification at several sites, as shown. The elucidation of these mechanisms has allowed chemical modification of the sites at which the iaactivation occurs. Several such bioactive analogues, eg, dibekacia and amikacin have been prepared and are not subject to the iaactivation hence, they inhibit those organisms against which the parent antibiotics are iaeffective (96) (see Antibacterial agents, synthetic). 

Lincomycin. The liacomycias and celesticetins are a small family of antibiotics that have carbohydrate-type stmctures. Clindamycin, a chemical modification of lincomycin, is clinically superior. Antibiotics ia this family inhibit gram-positive aerobic and anaerobic bacteria by interfering with proteia biosyathesis. 

Although the antibacterial spectmm is similar for many of the sulfas, chemical modifications of the parent molecule have produced compounds with a variety of absorption, metaboHsm, tissue distribution, and excretion characteristics. Administration is typically oral or by injection. When absorbed, they tend to distribute widely in the body, be metabolized by the Hver, and excreted in the urine. Toxic reactions or untoward side effects have been characterized as blood dyscrasias crystal deposition in the kidneys, especially with insufficient urinary output and allergic sensitization. Selection of organisms resistant to the sulfonamides has been observed, but has not been correlated with cross-resistance to other antibiotic families (see Antibacterial AGENTS, synthetic-sulfonamides). 

Chemical modification of glycopeptide antibiotics with macrocyclic aglycones 98MI48. 

Chemical modification of monensin, polyether ionophoric antibiotic with bound tetrahydropyran, two tetrahydrofuran, and octahydrospiro-2,2 -furopyran fragments 97YZ583. 

Those drugs that come from natural sources, either directly or after chemical modification, are usually chiral and are generally found only as a single enantiomer rather than as a racemic mixture. Penicillin V, for example, an antibiotic isolated from the Pemcillimti mold, has the 2S,SR,6R configuration. Its enantiomer, which does not occur naturally but can be made in the laboratory, has no antibiotic activity. 

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous tumors. The first anthracyclines, doxorubicin (DOX) and dau-notubicin (DNR), were isolated from Streptomyces var peucetius they were shown to be composed of a tetracyclic ring system with adjacent quinone-hydro-quinone moieties, a short side chain with a carbonyl group, and an aminosugar bound to the C-7 of the four-ring system. DOX and DNR only differed in the side chain terminus (-CH2OH in DOX vs. -CH3 in DNR). Second generation anthracyclines, like epitubicin (EPI) and idatubicin (IDA), were obtained after minor chemical modifications of DOX or DNR, respectively (Fig- 1). 

Over the past few years there have been an increasing number of reports of diseases that are becoming resistant to previously effective drug treatments. This resistance is often due to the presence of enzymes that bring about chemical modification of the drug to an inactive form, e.g. /S-lactamase enzymes deactivate (6-lactam antibiotics by their conversion to penicillanic acid. 

In addition to chemical-based drugs, a range of pharmaceutical substances (e.g. hormones and blood products) are produced by/extracted from biological sources. Such products, some major examples of which are listed in Table 1.2, may thus be described as products of biotechnology. In some instances, categorizing pharmaceuticals as products of biotechnology or chemical synthesis becomes somewhat artificial. For example, certain semi-synthetic antibiotics are produced by chemical modification of natural antibiotics produced by fermentation technology. 

The p-lactams, mainly penicillins and cephalosporins, are by production volume the most important class of antibiotics worldwide, enjoying wide applicability towards a range of infectious bacteria. Most of the key molecules are semi-synthetic products produced by chemical modification of fermentation products. Production of these molecules has contributed significantly to the development of large-scale microbial fermentation technology, and also of large-scale biocatalytic processing. 

In this synthetic strategy, the macrocyclic antibiotic is covalently bonded to the silica matrix in two steps (1) chemical modification of the selector via reaction between suitable groups of the antibiotic and proper groups of the spacer, reacting also as a di- or trialkoxysilane (2) immobilization of the functionalized selector on unmodified silica particles. 

Debono M, Abbott BJ, Malloy RM, Fukuda DS, Hunt AH, Daupert VM, Counter FT, Ott JL, CarreU CB, Howard LC, Boeck LD, Hamill RL. (1988) Enzymatic and chemical modifications of hpopeptide antibiotic A21978C The synthesis and evaluation of daptomycin (LY146032). JAntibiot 41 1093-1105. 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

H). C,8H34N206S. the first lincosaminide antibiotic to which a structure was assigned, is defined chemically as methyl 6,8-dideoxy-6-(l-methyl-fro/M-4-propyl-L-pyrrolidin-2-ylcarbonylamino)-l-thio-D-erythro-L>-gal-actu-octopyranoside. Both lincomycin and the semisynthetic clindamycin (I, R = H, R = Cl), CisH ClNjOsS, are widely used in clinical practice. The trivial name of the sugar fragment of this antibiotic, methyl a-thiolincosaminide, has lent itself to the other members of this family, whether produced as secondary metabolites of soil microorganisms or derived semisynthetically by chemical modification. 

Everninomidn D is the principal component from cultures of Micromonos-pora carbonacae. Chemical modification of the nitro group in everninomicin D has resulted in the formation of amino, mono- and clialky-lamino, Ar-acylamino, and N-hydroxylamino (and its nitrone derivatives) everninomidn D, all of which possess great antibiotic activity against gram-positive bacteria. 

After the first successful attempts in 1928 to identify the active biochemicals found in antibacterial molds, followed the rediscovery of penicillin by Fleming, identification of its chemical structure by Hodgkin, and subsequent synthesis by Chain, Heatley, and Florey, which led to the commercial production of penicillin in the mid 1940s [1], Since then, other families of (3-lactam antibiotics have been developed [2, 3], and their massive use worldwide continues to be a forefront line of action against infectious pathogens [4-6]. In recent years, (3-lactams have found other biomedical applications, such as inhibitors of serine protease ([7, 8] for a review, see [9]) and inhibitors of acyl-CoA cholesterol acyltransferasa (ACAT) [10]. Encouraged by their bioactivity, the synthesis and chemistry of (3-lactam antibiotics have been the focus of active research, and chemical modification of some basic structures available from biosynthesis (semisynthetic approaches) as well as the discovery of fully chemical routes to de novo synthesis of (3-lactam... 

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