Tetracyclines polyketide derivatives

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

The tetracyclines bind ribosomal proteins and inhibit bacterial protein synthesis. The first tetracycline was discovered in 1948. Tetracyclines are classified as polyketides, and all are either isolated from bacteria or derived from other tetracyclines. Common examples include tetracycline (A.30) and doxycycline (A.31) (Figure A.8). 

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

Feeding studies using deuterated [1- 13C] acetate and subsequent location of the deuterated sites by the nmr isotope shift effects showed labeling at carbons 7 and 9. The absence of a detectable p-2H isotope shift at carbon 4a indicates that only one of the carbon-5 hydrogens is acetate-derived and that this is stereospecifically eliminated by carbon-5 a hydroxylation. 8-Methoxychlortetracydines, with and without hydroxyl substitution at carbon-4a, have been isolated. These tetracyclines retain the original oxygen at C-8 from the polyketide chain (79—81). 

Acetate/malonate Fatty acid derivatives (n-alkanes, acetylene derivatives). Polyketides (anthracene derivatives, tetracyclines, griseofulvin, phenolcarboxylic acids from fungi and lichens, pyridine derivatives). 

The most important polyketides of this type are the tetracyclines (Table 35) and derivatives of glutarimide, e.g., cycloheximide, which both are formed in Strepto-mycetes. 

---