Of tetracycline

Figure 7-15 shows the time evolution of the temperature, total energy, and potential energy for a 300 ps simulation of the tetracycline repressor dimer in its induced (i.e., hgand-bound) form. Starting from the X-ray structure of the monomer in a complex with one molecule of tetracycline and a magnesium ion (protein database... 

The numbering system of tetracyclines is used for synthetic intennediates. 

Antibiotics were used in folk medicine at least as early as 2500 years ago when the Chinese reported the medicinally beneficial effects of moldy bean curd. Evidence for some type of tetracycline antibiotic usage by the Sudanese-Nubian civilization (350 AD) was reported in 1980 (6). Fluorescent areas in human bones from this eta were observed that were identical in location and characteristics to modern bone from patients treated with tetracyclines. Identification of tetracycline in the ancient bones was further substantiated by fluorescence spectmm measurements and microbiological inhibition studies (7). 

An on-line concentration, isolation, and Hquid chromatographic separation method for the analysis of trace organics in natural waters has been described (63). Concentration and isolation are accompHshed with two precolumns connected in series the first acts as a filter for removal of interferences the second actually concentrates target solutes. The technique is appHcable even if no selective sorbent is available for the specific analyte of interest. Detection limits of less than 0.1 ppb were achieved for polar herbicides (qv) in the chlorotriazine and phenylurea classes. A novel method for deterrnination of tetracyclines in animal tissues and fluids was developed with sample extraction and cleanup based on tendency of tetracyclines to chelate with divalent metal ions (64). The metal chelate affinity precolumn was connected on-line to reversed-phase hplc column, and detection limits for several different tetracyclines in a variety of matrices were in the 10—50 ppb range. 

Under acidic conditions, dehydration to an anhydrotetracycline [20154-34-1] (8), C22H22N20y, occurs under basic ones, ring C opens to an isotetracycline [3811-31-2] (9), C22H24N20g. The anhydrotetracyclines, such as (8), appear to exhibit a mode of antibacterial action, but it is unlike that of tetracycline (24). Epimerization (23,25,26) at C-4 occurs in a variety of solvents within the pH range 2—6, particularly in acetic acid (25). A number of anions (27) facihtate this reaction. The reverse process, from 4-epitetracycline [79-85-6] C22H24N20g, to tetracycline, is promoted by chelation with ions such as calcium and magnesium (28). 

The isolation of the 6-deoxytetracyclines (44) led to other chemical modifications of (1). 6P-Deoxytetracycline [5614-03-9] (13), prepared by catalytic hydrogenolysis of tetracycline (1), resulting ia an iaversion (45) of the configuration at the C-6 position, but retention of antibacterial activity. Catalytic reduction (7,8) of the 6-methylene derivative (14) yields both the 6a-methyl (15) and 6P-methyl compound (13). The 6a-isomer (15) is reported (7,45) to be more active than the 6P isomer (13). The a-isomer, doxycycline (6), is an example of a semisynthetic tetracycline that has become commercially useful. 

X = NH2, Y = H). Oxidation (54) of tetracyclines usiag the Udenfriend reagent has yielded 9-hydroxytetracyclines and disubstituted (C-7 and C-9) products (48) can also be obtained. Substituent assignments are made from nmr spectral iaterpretations. The 7- and 9-methyl tetracyclines have been prepared and reported to retain biological activity (55). 

Fig. 3. Conformations of tetracycline (1) (a) lipophilic nonionized form, and (b) polar 2witterionic form (59).

The unexpected biological activities of tetracyclines, such as 5a-epi-6-epitetracychne [19543-88-5] C22H24N20g, and 7-chloro-5a,lla-dehydro-6-epitetracycline [22688-60-4] C22H22ClN20g, make predicting stmcture-activity relationships difficult (64). Aside from the C-2 amide Mannich-base derivatives, variation at other centers in the molecule, ie, C-4, 4a, 5a, 12a, decreases the biological activity. 

The total U.S. antibiotic market for 1990 was about 4.73 biUion, 233 million of that was tetracyclines. The development of the semisynthetic P-lactam antibiotics (see Antibiotics, P-LACTAMs) and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. 

Fig. 4. Comparison of the three types of tetracycline resistance where T represents the tetracycline molecule O, a tetracycline transporter and aaa/, the ribosome A shows the effect of tetracycline exposure on a sensitive cell B, the efflux of resistance where a cytoplasmic membrane protein ( D) pumps tetracycline out of the cell as fast as the tetracycline transporter takes it up C, the ribosomal protection type of resistance where the ribosome is modified by ( ) to block productive binding and D, the tetracycline modification type of resistance where t is an inactive form of tetracycline. Reproduced with...

Tetracyclines are used as alternative dnigs in a variety of circumstances when the patient is unable to take the dnig of choice, eg, in patients allergic to penicillin (88,89). Tetracyclines are widely known to cause staining of teeth (and are therefore contra-indicated in children developing permanent teeth), photosensitivity, and, in the case of minocycline, vestibular toxicity. Details of these adverse effects and others associated with administration of tetracyclines have been comprehensively reviewed (96—101). 

Table 2. Classification and Distribution of Tetracycline Resistance Determinants in Microorganisms ...

Tetracycline antibiotics have found wide application in animal industries for treatment, preventive maintenance and stimulation of growth of large horned livestock owing to what their residue amounts can be present at milk and meat of animals. Residue amounts of antibiotics are not toxic, however, capable to cause allergic reactions and to promote development of tolerance of the some people pathogenic bacterias. According with the legislative requirements of a number of the European countries it is forbidden to deliver to the population production polluted residual contents of tetracyclines. 

For detection residue amounts of tetracyclines in dairy products widely used methods FIPLC, immunoaffinity chromatography, kinetic spectrophotometry, which are expensive and complicated. 

The production of tetracycline by catalytic dechlorination is described in U.S. Patent 2,699,054 as follows Pure chlortetracycline (4.8 grams) was suspended in 100 ml of methanol and sufficient anhydrous dioxane was added to completely dissolve the product. To the solution was added 0.5 gram of 5% palladium-on-charcoal catalyst. The mixture was placed in a conventional hydrogenation apparatus and subjected to a pressure of 50 psi of hydrogen while being agitated. 

An additional 50 ml of methanol was added to the flask and then 22.2 grams (0.05 mol) of tetracycline, neutral form, was added portionwise intermittently with another 50 ml of methanol. A clear solution was maintained throughout the addition of the tetracycline. After addition of all of the tetracycline, the solution was a deep orange color and the temperature in the reaction flask was 35 C. 

One alternative strategy is to use metabolic inhibitors. Although this approach has not been used with the P-lactams, it is worthwhile bearing in mind as a possibility. It has been used in the production of tetracyclines. 

Fig. 29. Effect of the extent of crosslinking of sulfonated cation exchangers (quantity of cross-linking agent) on diffusion coefficient of tetracycline in sorbent grains 1) SDMDMA, 2) SHMDMA, i) SEDMA, 4) Dowex-50W...

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