Natural vancomycin

Table 4. Naturally Occurring Vancomycin-type Dalbaheptides...

As recently as 1970, only about 30 naturally occurring organohalogen compounds were known. It was simply assumed that chloroform, halogenated phenols, chlorinated aromatic compounds called PCBs, and other such substances found in the environment were industrial pollutants. Now, only a third of a century later, the situation js quite different. More than 5000 organohalogen compounds have been found to occur naturally, and tens of thousands more surely exist. From a simple compound like chloromethane to an extremely complex one like vancomycin, a remarkably diverse range of organohalogen compounds exists in plants, bacteria, and animals. Many even have valuable physiological activity. Vancomycin, for instance, is a powerful antibiotic produced by the bacterium Amycolatopsis orientalis and used clinically to treat methicillin-resistant Staphylococcus aureus (MRSA). 

Teicoplanin is a naturally occurring complex of five closely related tetracyclic molecules. Its mode of action and spectrum of activity are essentially similar to vancomycin, although it might be less active a inst some strains of coagulase-negative staphylococci. Teicoplanin can be administered by intramuscular injection. 

Progress in defining new treatments for C. difficile infection has been hindered by the heterogeneous nature of hospital-acquired diarrhea, and in particular by whether colitis and/or pseudomembranous colitis is present in individual cases. Study groups have usually been poorly defined in this context, and given the spontaneous resolution of symptoms in a proportion of cases the true efficacy of treatment approaches often remains uncertain. Enthusiasm to explore new treatment possibilities for C. difficile has been largely fuelled by the apparently high relapse rate of conventional (metronidazole or vancomycin) treatment [138],... 

Brush-type, proteins, CDs, natural molecular imprint-based polymers (MIP), and macrocyclic antibiotics have been immobilized as chiral selectors on packed-CEC columns. Zheng and Shamsi demonstrated the possibility of using chiral CEC—ESI/MS with a commercially packed column for the determination of warfarin enantiomers in human plasma using coumachlor as an internal standard (IS). Robustness of this chiral CEC capillary was recently improved by a novel procedure and applied for the simultaneous enantiosepara-tion of height /1-blockers with multimodal CSP using different combinations of vancomycin and teicoplanin, as presented in Figure 5. ... 

Figure 2 Summary of NRP natural product biosynthesis, exemplified by vancomycin.

Some research groups have derivatized biological active and very important natural products (Scheme 3.30) like Indolactam V (207) [297], Sarcodictyin (208) [298] Taxol (209) [299] and Vancomycin (210) [123]. For example, the soHd-phase synthesis of Indolactam derivatives (213) with three points of diversity has been reported by Waldmann et al. in 1999 (Scheme 3.31) [297]. 

Even newer is the natural product daptomycin (Cubicin), a complex cyclic lipopeptide structure, approved for use in the United States in 2003. Daptomycin has a spectrum similar to that of linezolid and specifically includes MRSA and VRE. In contrast to linezolid, daptomycin is bactericidal for these Gram-positive organisms. It is, like vancomycin, a parenteral antibiotic and is given intravenously. It is indicated for treatment of complicated skin and skin structure infections and for some cases of bacteremia, including endocarditis. Daptomycin may be thought of as an alternative to vancomycin. 

Many other reactions have been used to construct macrocycles, and many are related to specific bond formations and therefore not very widely applicable. Since bisaryl ethers and biphenyl units are relatively common in naturally occurring macrocycles [4] (both units can be found in the important antibiotic vancomycin, 20, Fig. 7), some approaches to their synthesis will... 

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