Kanamycins synthesis

The next problem for H. Umezawa was to use his findings to design new kanamycin derivatives effective against resistant bacteria. The synthetic work was undertaken in cooperation with his brother. Prof Sumio Umezawa of Keio University, and one of the writers (T. Tsuchiya). The first useful derivatives active against resistant bacteria, namely, 3, 4 -dideoxy-kanamycin B (dibekacin) and 3 -deoxykanamycin A, were prepared in 1971. These were also found active against Pseudomonas known to have intrinsic resistance. These results supported the truth of H. Umezawa s theory. In the synthesis of dibekacin, the Tipson-Cohen method for introducing unsaturation, developed by one of the writers (D. Horton, 1966) for pyranoside... 

Figure 4.2. General strategies for the synthesis of neomycin and kanamycin classes of aminoglycosides.

Scheme 4,9. Synthesis of kanamycin derivatives via direct modification.

Seeberger and co-workers have reported synthesis of interesting C2-symmetrical kanamycin derivatives, such as 65, from glycosylation of diazido-2,5-dideoxystreptamine, 61 (Scheme 4.11). 

Scheme 4.19. Synthesis of 3, 4 -dideoxy kanamycin B analog and pyranmycin.

The synthesis of kanamycin and neomycin class aminoglycosides with N-... 

Scheme 4.20. Synthesis of kanamycin class of aminoglycosides with N-1 AHB.

Scheme 4.22. Synthesis of pyranmycin and kanamycin B analogs with AHB group at N-1.

Mobashery and co-workers also reported the synthesis and inhibitory apph-cation of 2 -N02 derivatives of neamine and kanamycin (Scheme 4.28). Using the metal-chelating method, the 2 -NH2 was selectively unmasked and then oxidized into 2 -N02, which will increase the acidity of 2 -H. Upon phosphorylation at the 3 -0H, elimination of phosphate will lead to the formation of a nitroalkene intermediate, 198, that can function as a Michael acceptor and... 

New concepts in the strategy of the synthesis of drugs rarely appear, such as from the observation that microorganisms often get resistance from enqrmes that inactivate the drug through phosphorylation. To avoid the problem, the aminoglycoside antibiotic kanamycin A was modified in a way that it was re-obtained whenever it was modified by the microorganism resistance enzymes (Haddad 1999). 

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... 

T. Tsuchiya and S. Umezawa, Studies of antibiotics and related substances. XXI. The synthesis of deoxy and chlorodeoxy derivatives of kanamycin, Bull. Chem. Soc. Jpn. 38 1181 (1965). 

Many of the same chromatographic and spectroscopic techniques were applied to the isolation and identification of natural products such as carbohydrates and glyco-lipids. The discovery, isolation, computational analysis, synthesis, and structure-activity relationship studies of antibiotics such as the aminoglycosides kanamycin and neamine are of particular note (Fig. 1.14) [157, 158],... 

A. Van Schepdael, R. Busson, H. J. Vanderhaeghe, P. J. Claes, L. Verbist, M. P. Mingeot-Leclercq, R. Brasseur, and P. M. Tulkens,/. Med. Chem., 34,1483 (1991). New Derivatives of Kanamycin B Obtained by Combined Modifications in Positions 1 and 6". Synthesis, Microbiological Properties, and In Vitro and Computer-Aided Toxicological Evaluation. 

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