Synthesis of Lincomycin

The stereoselective allylation of aldehydes is one of the most important, and intensively investigated, reactions in synthetic chemistry [113]. Nowadays, one of the most efficient 

Allylation using tethered nucleophiles has been investigated by other groups and has been shown to typically exhibit excellent levels of stereocontrol [117], which in some cases are complementary to those obtained in the corresponding intermolecular process. A Glaxo group used such an approach in the synthesis of a key intermediate for the preparation of tricyclic ]3-lactam antibiotics [118]. 

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Golebiowski A., Jurczak J. Total Synthesis of Lincomycin and Related Chemistry... 

A. Gotebiowski and J. Jurczak, Total synthesis of lincomycin and related chemistry. Recent Progress in the Chemical Synthesis of Antibiotics, (G. Lukacs and M. Ohno, eds.). Springer Verlag, Heidelberg, 1990, p. 365. 

Mechanism of Action. THie earliest studies on the mechanism of action of lincomycin showed that lincomycin had the immediate effect on Staphjlococcus aureus of complete inhibition of protein synthesis (23). TThis inhibition results from the blocking of the peptidyltransferase site of the SOS subunit of the bacterial ribosome (24). Litde effect on DNA and RNA synthesis was observed. 

Clindamycin is a chlorine-substituted derivative of lincomycin. However it is more potent and is better absorbed from the gastrointestinal tract and has therefore replaced lincomycin in most situations. Clindamycin is in principle a bacteriostatic agent. Its indications are mainly limited to mixed anaerobic infections. As mentioned above it has a similar mechanism of action as erythromycin. It selectively inhibits bacterial protein synthesis by binding to the same 50s ribosomal subunits. Erythromycin and clindamycin can interfere with each other by competing for this receptor. Also cross-resistance with erythromycin frequently occurs. Resistance is rather chromosomal rather than plasmid mediated and is especially found in cocci and Clostridium difficile. 

The Synthesis of N-Acetyl-lincosamine (6-Acetamido-6,8-dideoxy-D-ert/fhro-D-ga-lacto-octose), a Derivative of the Free Carbohydrate Moiety in Lincomycin, G. B. Howarth, W. A. Szarek, and J. K. N. Jones, Chem. Commun., (1969) 1339-1340. 

Lincomycin, an antibiotics produced by Streptomyces lincolnensis, has been used widely in the treatment of infections caused by gram positive organisms. Lincomycin inhibited microbial protein synthesis by interacting strongly and specifically with the 50 S ribosomal subunit at mutually related sites. The results show that such interaction was not influenced by any of the chemical modifications of lincomycin structure. One molecule of antibiotic bound per 50 S subunit. It inhibited peptide bond formation, a mixture of protein synthesis which was catalyzed by a peptidyl transferase centre on the 50 S subunit. It interfered with substrate binding at the P- or A- site on the catalytic centre. It probably bound to the ribosome in positions at or close to the peptide transferase centre. 

Gryaznova et al (73) studied the effect of lincomycin on metabolism of Actinomyces reseolus producing lincomycin. The results show that lincomycin inhibited protein synthesis by 50 % at 1000ug/l. When mycelio were cultured for 24 69 hours, their sensitivity to lincomycin decreased. 

Lincomycin is a natural product isolated from fermentations of Streptomyces lincolnensis var. lincolnensis. It is active against Gram-positive organisms, including some anaerobes. It is indicated for the treatment of serious infections caused by sensitive strains of streptococci, pneumococci, and staphylococci. It generally is reserved for patients who are allergic to penicillin because of the increased risk of pseudomembranous colitis (described below). It also serves as the starting material for the synthesis of clindamycin (by a Sn-2 reaction that inverts the R stereochemistry of the C-7 hydroxyl to a C-7 S-chloride). 

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