6-Deoxy tetracycline

Brown BA, Wallace RJ, Onyi G. Activities of the glycylcydines N.N-dimethylglycylamido-minocydine and N,N-d i me thy Iglyc ylamido-6-d e methyl-6-deoxy tetracycline against Nocar-dia ipp. and tetracycline resistant isolates of rapidly growing Mycobacteria. Aniimictob Agents Chemother 1996 40 874-878. 

The 7-chloro-derivative, the first of the group to be isolated (1948) is known as chlortetracy-cline. The 5-hydroxy-derivative is oxytetracy-dine. More recently introduced tetracyclines are 6-demethyl-7-chlorotetracycline and 5-hydroxy-6-deoxy-6-methyienetetracycline. 

Fig. 1. Tetracycline (1) and its derivatives chlortetracycline (7-chlorotetracycline) (2) oxytetracycline (5-hydroxytetracycline) (3), demeclocycline (6-demethyl-7-chlorotetracycline) (4) methacycline (6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline) (5) doxycycline (6a-deoxy-5-hydroxytetracycline) (6) and minocycline (6-demethy1-6-deoxy-7-dimethy1 amino tetracycline) (7). Substituents at positions not specifically...

The 6- uoro isomers, 6-deoxy-6-demethyl-6a- uorotetracycline [24333-20-8] C2 H2 FN20y, and 6-deoxy-6-demethyl-6P- uorotetracycline [24333-21-9] C2 H2 FN202, have been prepared and showed relatively high in vitro and in vivo biological activities compared to the parent tetracyclines. 

The iacreased chemical stabiUty of the 6-deoxytetracyclines allows chemical modification with retention of biological activity electrophilic substitutions have been carried out at C-7 and C-9 under strongly acidic conditions (46—53). Reactions of 6-deoxy-6-demethyltetracycline [808-26-4] (16), C21H22N2O7, with electrophiles, such as nitrate ion (49), bromomium ion (46,47) (from N-bromosuccinimide), or N-hydroxymethylphthalimide (53), yielded 7-substituted tetracyclines. In the case of the nitration reaction, both the 7- and 9-nitro isomers (17, X = NO2, Y = H) and (17, X = H, Y = NO2) were obtained. 

Similar transformations have not as yet been successfully applied to the tetracyclines bearing a hydroxy group at Cs, and no mutant culture has been reported that biosynthesizes a 6-deoxy-5-oxytetracycline. However, other means have been found to avoid 5a,6-dehydration in this subfamily. Treatment of 3 with N-... 

Treatment of 14 with hydrogen and a catalyst converts it to a mixture of epimeric 6-deoxy-5-oxytetracyclines (15 and 16), each of which is active as an antibiotic. The more active isomer has the natural tetracycline configuration of the methyl group at Ce and is in clinical use as a 6-deoxyoxytetracycline (15). ... 

Doxycycline (6-deoxy-5-hydroxytetracycline, Vibramycin, III) is, chemically, the most stable tetracycline in current use but its outstanding property is its high lipid solubility these features combine to make it the most reliably and completely absorbed tetracycline derivative, with the longest half-life. 

Figure 5.27. Part of the 400 MHz H-NMR spectrum of 6-epidoxycycUne fie) hydrochloride in DMSO-dg plus D2O. The broad signal near the H-4a resonance is due to the NMe2 protons. Inset shows the H-SP and H-5a signals of tetracycline hydrochloride, typical of the 5-deoxy derivatives.

Structural susceptibilities and structure/activity studies have both inspired a large amount of semi-synthetic vrork to find more stable compounds without loss of antibacterial activity. The less active 6p methyl isomer of doxycycline (6) has been derived from oxytetracycline (3 R = OH) by catalytic reduction.. Treatment of (3) with N-chlorosuccinimide followed by hydrofluoric acid gave the chloro compound (X) which upon catalytic reduction afforded doxycycline (6), the 6a compound together with the less active 6p isomer (refs.250, 251) by saturation of the methylene group and removal of chlorine from (X). Reductive treatment of (X) with sodium hydrosulphite produced methacycline (5). The corresponding 5-deoxy analogues have likewise been derived by using tetracycline (3 R = H) in the same reaction sequences. 

Deoxy-7-demethyl-6a-fluorotetracycline and the corresponding 6p- isomer have been synthesised and exhibit high activities compared to the parent tetracyclines. Acquired resistance to tetracyclines has been an impediment to their clinical use and in this context semi-synthetic studies which have already been very extensive have resulted in the introduction of valuable compounds such as minocycline. 

The 6-deoxy-6-methylenetetracyclines and their corresponding mercaptan adducts possess typical characteristics tetracycline activity and illustrate further the level of modification feasible at C-6 with the possible retention of biologic activity. 

The gross structure of nogalamycin (527) has been reported. It contains nogalose (6-deoxy-3-C-methyl-2,3,4-tri-0-methyl-L-mannose) and a 3,6-dideoxy-3-di-methylaminohexose that is linked both glycosidically and through C-5 to ring A of the tetracycline system. 

Methylenetetracycline > tetracycline > 6-deoxy-5-oxytetracycline > 5-oxytetracycline > 6-methylene-5-oxytetracycline Ref. 

---