Tobramycin synthesis

Scheme 4.23. Synthesis of tobramycin analogs with side chains at 0-5.

Chloramphenicol (bacteriostatic interrupts protein synthesis at the ribosome) Macrolides (bacteriostatic interrupt protein synthesis at the SOS ribosome subunit) e.g., erythromycin, azithromycin, clarithromycin Lincomycins (bacteriostatic interrupt protein synthesis at the SOS subunit) Aminoglycosides (bactericidal interrupt protein synthesis at the 30S subunit) e.g., gentamicin, amikacin, kanamycin, neomycin, tobramycin Tetracyclines (bacteriostatic interrupt protein synthesis at the 30S subunit) e.g., tetracycline, doxycycline, minocycline... 

The remarkably successful clinical application of aminoglycoside antibiotics attracted the attention of many organic chemists. With his continuous interest in this field for more than 20 years, Sumio Umezawa accomplished the first total synthesis of many aminoglycosides, including paromamine,- neamine," trehalosamine, kanamycins A, B, and C, 2 butirosin B, tobramycin, " streptomycin, dihydrostreptomycin, and neomycins B and C. ... 

Dexamethasone is a steroid antibiotic combination. Tobramycin inhibits bacterial protein synthesis, causing death dexamethasone suppresses the inflammatory response. The combination is indicated in superficial bacterial ocular infection or risk of bacterial ocnlar infection inflammatory conditions of palpebral and bulbar conjunctiva, cornea, and anterior segments of globe where inherent risk of steroid use in certain infective conjunctivitis is accepted to obtain a diminution of edema and inflammation chronic anterior uveitis and comeal injury from chemical, radiation, or thermal bums, or penetration of foreign bodies, where risk of superficial ocular infection is high, or an expectation, or when potentially dangerous numbers of bacteria will be present in the eye. 

Higgens, Kastner Thompson, Presti Wick, Welles, Antimi-crob. Ag Chemother. 1967, 314-348. Review Stark er al. Folia Microbiol (Prague) 16, 205-217 (1971). Tobramycin is structurally similar to the kanamycins and the gentami-cins. Elucidation of structure Koch, Rhoades, Antimicrob. Ag. Chemother- 1970, 309. Synthesis Y. Takagi et at.. Bull Chem. Soc. Japan 49, 3649 (1976) M. Tanabe et al. Tetrahedron Letters 1977, 3607, Activity studies Black. Griffith Preston, Wick, ibid 314, 322 Meyers, Hirschman, J. Clin. Pharmacol 12, 313, 321 (1972). Toxicology Welles el al., Toxicol Appl Pharmacol. 22, 332 (1972) De Rosa et al, J. Int. Med. Res. 2, 100 (1974). 

The discovery of streptomycin by Waksman introduced the aminoglycoside class of antibiotics, having as a mechanism of action the inhibition of protein synthesis. Among the commonly used aminoglycosides are neomycin (used topically), gentamycin, tobramycin, and amikacin. Although the clinical appearance of... 

Aminoglycoside prototype bactericidal inhibitor of protein synthesis (30S) active against many aerobic gram-negative bacteria. Narrow therapeutic window dose reduction required in renal impairment. Tox renal dysfunction, ototoxicity once-daily dosing is effective (postantibiotic effect) and less toxic. Amikacin and tobramycin are similar. 

The synthetic challenge posed by the complex carbohydrate antibiotics was met by the total synthesis of the kanamycins in 1968, and, later, ribostamycin, butirosin B, and tobramycin were synthesized. The total synthesis of dihydrostreptomycin was accomplished by Umezawa and coworkers in 1973. 

Included among the modified components of aminoglycoside antibiotics reported during the past year were 3, 4, 5,6-tetradeoxy- and 5- and 6-deoxy-and 5,6-dideoxy-neamine removal of HO-6 from the 2-deoxystreptamine residue of neamine decreased the antimicrobial activity relative to that of the parent neamine, whereas removal of HO-5 enhanced the activity, especially against kanamycin-resistant strains. l,2, 3,6 -Tetra-JV-benzyloxycarbonyl-5,6-0-cyclo-hexylideneneamine has been synthesized and converted into nebramine derivatives for use in the synthesis of tobramycin and 4"-epi-tobramycin. 2, 4, 6 -Triacetyl-3,3 -0-carbonyl-3 -deoxydihydrostreptobiosamine, a precursor for the synthesis of 3"-deoxydihydrostreptomycin, has been synthesized from benzyl a-dihydrostreptobiosaminide. The synthesis involved chlorination of the key... 

Scheme 6.11 Synthesis of tobramycin- and neamine-based amphiphilic AGs.

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