Tetracyclines oxygenation

In the tetracyclines, oxygen appears on a series of alternate carbon atoms. Robinson pointed out that the naphthalene ring system could be derived from octaketostearic acid and that the latter could be formed from 9 moles of acetate i. The addition of single carbon atoms and an amino... 

Tetracyclines are produced by various Streptomyces strains and are extensively applied in human and veterinary medicine. They display a broad spectrum of antimicrobial activity in combination with low toxicity and can be applied orally. The most commonly prescribed tetracycline drugs are tetracycline itself and oxytetracycline, an oxygenated derivative, which are directly isolated from fermentation liquors, and doxycycline whose partial synthesis from oxy-... 

UV irradiation (335 nm) at pH 7.3 showed that some tetracyclines produced significant concentrations of the superoxide anion radical. Demeclocycline (122), oxytetracycline (123) and chlortetracycline (124) were the most active in this. These are all potent photosensitizers and probably give the observed exaggerated sunburn as a result of superoxide production in the skin [90]. Other photochemical experiments demonstrated the production of singlet oxygen. Yields obtained by luminescence measurements in alkaline ethanol were in the order (122) > (120) > (124) > (121) > (125). Chlortetracycline... 

Several classes of antibiotics, e.g., tetracyclines [86], fluoroquinolones [87, 88], and p-lactams [89] were observed to react with chemical oxidants such as chlorine dioxide (CIO2) and free chlorine. Oxidation with CIO2 yields hydroxylated and oxygenated products in the case of tetracyclines, and leads to dealkylation, hydroxylation, and intramolecular ring closure at the piperazine moiety of the fluoroquinolones [86, 88]. 

The JACS paper describes the total synthesis of the more highly oxygenated (-)-tetracycline 16. To this end, the alcohol S was carried on to the enone 10. Opening of the cyclobutane 11 to the o-quinone methide followed by Diels-Alder cycloaddition to 10 delivered the endo adduct 12. 

Stereospecific ene reaction. Singlet oxygen (meso-tetraphenylporphine) reacts with anhydrotetracycline (1) to give the hydroperoxide 2 in 97% yield. Hydrogenation of 2 provides the antibiotic tetracycline (3).2... 

Tetracyclines have many effects on cells involved in inflammatory reactions, including inhibition of neutrophilic functions, such as migration, phagocytosis, degranulation, and the production of free oxygen radical (1). Most of these effects are supposed to be due to chelation of divalent ions and can be partly reversed by the addition of calcium ions or zinc ions. Their ability to inhibit synthesis... 

For example, tetracycline (506), a broad-spectrum antibiotic, and its derivatives are known to induce phototoxic or photoallergic reactions that involve photosensitization of biomolecules by the drug or the formation of one or more photoproducts and their subsequent photoreactions.1383 Singlet oxygen is probably involved. 

In 1963, McFarland [69] investigated the preparation of tetracycline derivatives by U-4CRs and found that besides its expected products, which depend on the reaction conditions, different concentrations of a great variety of by-products were formed [71-73] in addition to the usual by-products, autoxidized compounds may be formed, particularly if aldehydes of the U-4CR proceed slowly, and oxygen is present [74],... 

Two drugs, chloramphenicol and tetracycline, interact with rRNA through atoms that are coordinated by both the drugs and the RNA phosphate oxygens (11, 14). Shared metal coordination is not a common interaction between drug and proteins it remains to be seen if this is a common phenomenon for RNA/antibiotic complexes or not. 

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). 

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