O

NHMe -Me

NHMe -Me

Combimicins 189 R1 = NH2 or OH, R2 = H or Me, R3 = CH2OH Gentamicin C1a 190 R1 = NH2, R2 = R3 = H

Compounds 191-194

below to get the unsaturated derivative 196 (compounds 195-197 ). Reduction of the double bond followed by deprotection afforded the product. However, the resulting compound showed weak antibacterial activity [101].

1-epi-Kanamycin A together with 1- and 3-epi-tobramycin have been synthesized by either catalytic hydrogenation over Raney nickel or electrochemical reduction of their corresponding 1- or 3-hydroxyimino derivatives. 1-epi-Kanamycin A showed lower activity than kanamycin A against most bacteria tested, but it was more active against P. aeruginosa. 1-epi-Tobramycin was slightly less active than the parent antibiotic, whereas the 3-epi derivative showed marked decrease in activity against most sensitive and resistant bacteria [102].

1-epi-Kanamycin A (200) and its 1-V-acylamino derivative 201 were prepared by Takahashi et al. [103] to investigate the effect of C1 epimerization on antibiotic activity of kanamycin A. In this synthesis, oxidation of the kanamycin derivative 198 with hydrogen peroxide in the presence of sodium tungstate afforded the 1-hydroxyimino derivative 199, which after deprotection and reduction with hydrogen-Raney nickel in aqueous ammonia furnished 1-epi-kanamycin A (200). This compound was converted to the 1-jV-[(S)-4-amino-2-hydroxybutyryl] analog by regiospecific acylation in the presence of zinc acetate. Antibacterial activity results revealed that epimerization of the amino group at position 1 greatly reduces the original activity of the antibiotic (compounds 198-201).

Several other kanamycin A analogs, including 4"-epi-kanamycin A together with 4",5"-unsaturated, and 3",4"-cyclic urethane by products [104], 4"-deoxy-4",5"-didehydro, and 4"-deoxy-5"-epi-kanamycin A [105], as well as a number of 4"-epi-analogs (OH, F, N3) of amikacin [106] have also been prepared, all of which are much less active than the parent antibiotics.

NHBoc

NHBoc 1) (PhSe)2-NaBH4

0 0

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