(2R,3R,4S,5S,6R)-4-Amino-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2R,3R,6S)-3-amino-6-(aminomethyl)oxan-2-yl]oxy-2-hydroxy-cyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol

Description

Dibekacin was synthesized in 1967 by Umezawa et al. by the removal of the 3 - and 4 -hydroxyl groups of kanamycin B. Studies by the same workers on the mechanisms of bacterial resistance to kanamycin-group antibiotics preceded the discovery. Dibekacin shows excellent activity, as expected, against a variety of bacteria, including kanamycin-resistant strains. It shows higher activity than kanamycin against Pseudomonas aeruginosa, Proteus, and other pathogens.

Originator

Panimycin,Meiji Seika,Meiji Seika,1975

Uses

Dideoxykanamycin B is an antibacterial compound.

Definition

ChEBI: A kanamycin that is kanamycin B lacking the 3- and 4-hydroxy groups on the 2,6-diaminosugar ring.

Manufacturing Process

Penta-N-benzyloxycarbonyl-2"-O-benzylsulfonyl-3',4'-dideoxy-3'-enokanamycin B (61 mg) was dissolved in about 18 ml of liquid ammonia at - 50°C, followed by addition of about 120 mg of metal sodium. The mixture was gently stirred at -50°C for 1 hour, followed by addition of methanol to consume up the excess of the metal sodium. The reaction mixture was allowed to slowly raise up to ambient temperature while permitting the ammonia to evaporate. The residue so obtained was dissolved in water, and the aqueous solution was admixed with 4 ml of a cation-exchange resin, Dowex 50WX2 (H cycle) (a product of Dow Chemical Co., USA) under stirring. The admixture comprising the resin was placed on the top of a column of 3,5 ml of the same resin. Dowex 50WX2, and the whole resin column was well washed with water and then eluted using 1 M aqueous ammonia as the developing solvent. The eluate was collected in fractions, and such fractions which gave positive reaction with ninhydrin were combined together and concentrated to dryness, affording 3',4'-dideoxy-3'-eno-kanamycin B in the form of its monocarbonate. The yield was 23,8 mg (97%).
The product (12.1 mg) obtained in the above step was dissolved in 0.3 ml of water, to which was then added a catalytic quantity (about 5 mg) of platinum oxide. Hydrogenation was made with hydrogen gas at a pressure of 3.5 kg/cm2 for 1? hours. The reaction solution was filtered to remove the catalyst, and the filtrate was concentrated to dryness, giving the desired product 3',4'-dideoxykanamycin B in the form of its monocarbonate. The yield was 11.5 mg (95%). [α]D25 +110° (c 1, water). The overall yield of 3',4'- dideoxykanamycin B based on the starting kanamycin B was 57%.

Therapeutic Function

Antibacterial

Antimicrobial activity

3′,4′-Dideoxy kanamycin B. A semisynthetic aminoglycoside closely related to the natural compound tobramycin (3′-deoxy kanamycin B). Supplied as the sulfate.
It is active against staphylococci including methicillinresistant strains, a wide range of enterobacteria, Acinetobacter and Pseudomonas spp. It is also active against M. tuberculosis and the M. avium complex (MICs 4–16 mg/L). It exhibits the usual aminoglycoside properties of bactericidal activity at concentrations close to the MIC and bactericidal synergy with selected β-lactam antibiotics.
Absence of hydroxyl groups present in the parent kanamycin B renders dibekacin resistant to phosphorylation by APH(3′). It is also resistant to some forms of ANT(4′). However, the type of this enzyme, ANT(4′), found in some Gram-positive organisms modifies dibekacin at the 2″-hydroxyl group; nevertheless dibekacin has much greater activity than tobramycin against organisms that produce the enzyme.
A 1 mg/kg intravenous bolus dose achieves a peak plasma concentration of around 5 mg/L. The plasma half-life is 2.3 h. Protein binding is 3–12%. It is eliminated principally by the renal route, 75–80% of the dose appearing in the urine in the first 24 h. Elimination is inversely related to renal function. In patients maintained on chronic hemodialysis, the half-life rises to 54 h between dialyses and falls to 6–7 h on dialysis.
Toxic effects are those typical of aminoglycosides with a frequency similar to or less than those of gentamicin.
It is used for severe infections caused by susceptible microorganisms, especially those resistant to established aminoglycosides, but availability is limited.

Safety Profile

Poison by intraperitoneal, subcutaneous, intramuscular, and intravenous routes. Moderately toxic by ingestion. Experimental teratogenic and reproductive effects. An antibacterial agent. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Dibekacin is synthesized from kanamycin B by the application of the Tipson- Cohen deoxygenation method after selective Nand O-protections . A modified synthetic route via the 3_x0002_,4_x0002_-epoxy compound has given a high yield of more than 40 % on an industrial scale .