Kanamycin derivatives

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... 

Dideoxy-2 -fluorokanamycin A (Ref. 170), a kanamycin derivative in which the OH-2 or NH2-2 of kanamycin A and B, respectively, is replaced by a fluorine atom, was prepared by condensation of 6-azido-4-0-benzoyl-2,3,6-trideoxy-2-fluoro-a-D-n77ohexopyranosyl bromide, derived from 179 (see Section 11,2), with the pseudodisaccharide component of kanamycin. The compound showed mediocre antibacterial activity however, on attachment of an (5)-4-amino-2-hydroxybutanoyl residue, as in amikacin, to the NHj-l group, the derivative showed considerably enhanced activity. ... 

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). 

Metal-chelating method has also been commonly employed for the regios-elective incorporation of AHB at N-1 of kanamycin class aminoglycoside (Scheme 4.20). Other kanamycin derivatives have been prepared in similar fashion (Figure 4.10). ... 

The trend of antibacterial activity of these kanamycin derivatives with N-1 AHB (amikacin analogs) is similar to amikacin regardless of the presence of 3 -deoxygenation (Table 4.10). The design of amikacin is, however, less effective against AAC(6 ). One interesting finding is the difference between 3, ... 

Qi) Other Kanamycin Derivatives. Cyclic carbamate derivatives of kanamycin A have been prepared [148], and in another report regiospecific methylation and stereospecific hydrogenation were used to synthesize three kanamycin B analogs with the general formula of compound 302 [149], The same group [150] has also reported conversion of the neosamine ring of kanamycin B to the bicyclo-oxazoctene unit compoimd 303 (part structure). 

The reduction of the described l-N-[(S)-to-amino-2-hydroxyacyl]-kanamycin derivatives by treatment with diborane leads to the corresponding l-N-[(S)-activity similar to that of amikacin ... 

Kanamycin derivatives with a changed configuration in C-2"-position such as 2"-manno-kanamycin A, 6"-amlno-6-deoxy-2"-manno-kanamycin (161) and 6"-deoxy-6"-hydrazino-2"-maimo-kanamycin A (162) have a decreased activity compared with the parent compounds. 

When the A-tosylaziridine 11 was opened with fluoride (KHFj, DMF, 150°C) initially the 2-fluoride 12 was produced, but over time the thermodynamic product 13 formed, presumably by reversal back to 11. This reaction was also utilized in the synthesis of fluorinated kanamycin derivatives." These and other syntheses of 4 -deoxy-4 -fluorokanamycins A and B are covered in Chapter 19. The synthesis of a fluorinated analogue of the acceptor of bovine (l- 4)-P-D-galactosyl transferase is mentioned in Chapter 3, and the conformational analysis of some deoxyfluoro sugars by H-n.m.r. spectroscopy is detailed in Chapter 21. The use of e.i. and c.i. mass spectrometry to determine the location of a fluorine atom in deoxyfluoro glucosides is outlined in Chapter 22. 

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