O

R4 OH OH

Compounds 299-301

302 R1 = Me, R2 = H or R1 = H, R2 = Me Compounds 302 and 303

(see Section IV.A.1: compound 73). These compounds are the first mechanism-based inactivators for bacterial 3'-phosphotransfer enzymes [APH(3')s] [27].

Synthesis of kanamycin A analogs having 6-amino-3-oxo-2,3,4,6-tetradeoxy-d-and L-glycero-hexopyranose in their structures (e.g., 306) were described by Ku-wahara and Tsuchiya [151]. To make compound 306, the 1-thioglycoside 304 was condensed with appropriately protected disaccharide 305, using V-iodosuccinimide (NIS) in a slightly acidic solution (compounds 304-306 ). This compound was only slightly active against common bacterial strains, and the other isomers were devoid of antibacterial activity.

Synthesis of 2"-modified dibekacin and arbekacin derivatives including 5-deoxy-5,2"-di-ep;-5-fluorodibekacin 310 and their 2"-oxo analogs (compounds 311 and 312, as hydrated ketones) also was reported by the same group [152]. To make compound 310, the intermediate 307 was fluorinated by DAST at position 5 of the 2-deoxystreptamine moiety and converted to fluoro derivative 308 after deacetylation of the acetyl group at the 2"-position by 1.0 M methanolic sodium methoxide. Tri-flylation of the 2"-hydroxyl group followed by treatment of the resulting triflate with sodium acetate in DMF afforded the 2",3"-cyclic carbamate 309 with inversion of configuration at 2"-position. Sequential removal of the protecting groups led to the formation of the title compound 310. The oxo compound 311 was prepared from the intermediate 308 by pyridinium dichromate (PDC) oxidation, followed by deprotec-tion with trifluoroacetic acid. The same synthetic route was also employed to prepare the 2"-oxoarbekacin 312 (compounds 307-312 ). The 2"-oxo derivatives 311 and 312 were collected as the hydrated form after removal of the protecting groups and upon treatment with water. All three analogs were less active than the parent antibiotics, indicating that the equatorial 2"-hydroxyl group is essential for antibacterial activity.

In a study of ribozyme inhibitory effect, Wang and Tor [153] prepared cova-lently linked dimeric aminoglycosides derived from kanamycin A, tobramycin, and neomycin B. The resulting symmetrical or asymmetrical dimeric aminoglycosides showed enhanced affinity in binding to RNA in comparison with their monomeric counterparts. In another investigation, Sreedhara and Cowan [154] prepared a variety of metallokanamycin A compounds and tested them for their ability to cleave DNA at physiological pH. Only a mixture of Cu2+ and kanamycin A was found to be efficient in effecting the rapid degradation of plasmid DNA at 1 mM concentration.

To improve the antibacterial activity of arbekacin, addition salts of this antibiotic with ( — )-cw-1,2-epoxypropylsulfonic acid (compound 313) were prepared by making a hemisalt of 313 with (+)-a-phenylethylamine, followed by treatment with

NHBoc

NHBoc

NHBoc O^V^A .NHBoc

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