(c) Halokanamycins. In an attempt to make more active antibiotics, Umemura and colleagues  synthesized halogenated derivatives of amikacin, including 6"-chloro-6"-deoxyamikacin (compound 202), 6"-iodo-6"-deoxyamikacin (compound 203), and some other analogs, including compounds 204 and 205. Among these, the 6"-chloro-3',6"-dideoxyamikacin showed the best activity, and the study concluded that substitution of the 6"-hydroxyl group of amikacin with chlorine enhances the antibacterial activity of the antibiotic against all bacteria except P. aeruginosa. On the other hand, it has been demonstrated that introduction of fluorine at the 6"-position of amikacin lowers the activity to some extent .
Several other derivatives including 5-fluoro-, 6"-fluoro-, and 5,6"-difluorokan-amycin A were prepared by Albert and coworkers . In another synthesis by these investigators, 4"-bromo-, 4"-fluoro-, and 4"-aminokanamycin A were prepared by double inversion substitution reaction using the 4"-0-triflate 206 as the key syn-
thetic intermediate. This intermediate was first treated with sodium nitrite in DMF to give the corresponding 4"-epi-hydroxy derivative 207, which was subjected to triflic anhydride to furnish the 4"-epi-O-triflate 208. This compound was then converted to the corresponding bromo, fluoro, and azido derivatives 209-211 (compounds 206-211) by another nucleophilic displacement, using tetrabutylammonium bromide and fluoride in acetonitrile or sodium azide in DMF. Antibacterial activity screening showed no dramatic changes in activity for these compounds compare to those of kanamycin A .
The same group has also synthesized a number of 4"-epi-kanamycin A analogs, including 4",6"-dideoxy-4",6"-difluoro-, 4",6"-dideoxy-4"-fluoro-, 6"-deoxy-6"-fluoro-,
and 6"-deoxy-4"-epi-kanamycin A, using a 4",6"-ditriflyl derivative as the key intermediate. These compounds showed comparable or better activity for some strains tested .
3'-Deoxy-3'-fluorokanamycins A and B have been synthesized and showed strong activities against both sensitive and resistant bacteria . The 3'-deoxy-3'-fluorokanamycin A (214), was prepared by condensation of the 3-fluoro-a-glucopyr-anosyl derivative 212 with the appropriately protected compound 213 in the presence of mercury(II) cyanide followed by deprotection and hydrogenolysis (compounds 212-214).
The same group also has described the syntheses of 6"-deoxy-6"-fluorokana-mycin A, 6"-deoxy-6"-fluoroamikacin, and 1-jV-[(^)- and (^S)-3-amino-2-fluoropro-panoyl] kanamycin A, using the DAST reagent for fluorination of the corresponding hydroxyl groups of kanamycin A and amikacin derivatives .
The 2',3'-dideoxy-2'-fluorokanamycin A 217 and its 1'-epimer have been prepared by coupling reaction of the fluoro sugar 215 and the pseudodisaccharide 216. The resulting analog 217 was only slightly less active than 3'-deoxykanamycin A, whereas the 1'-epimer was completely inactive  (compounds 215-217 ).
A series of halogenated analogs of kanamycins, including 3',4',6'-trideoxy-6'-fluorokanamycin C (218), 3',4'-dideoxy-6'-C-fluoromethyl kanamycin B , 6"-chloro-6"-deoxyamikacin (202) and some of its derivatives , as well as 3'-deoxy-3'-fluorokanamycin A (219) and its 3',4'-dideoxy-3'-fluoro analog 220  were also prepared by the same research group. Antibacterial activity results showed weak activity for 6'-fluoro, moderate activity for 6'-fluoromethyl, and good activity (better than the parent antibiotics) for 3'-fluoro derivatives.
Several other halogenated derivatives of kanamycins were synthesized by the Umezawa group. These include 3'-deoxy-3'-fluoro (219) and 3'-chloro-3'-deoxykan-amycin A (221) , 4'-deoxy-4'-fluorokanamycin A and B (222 and 223, respectively) , 5-deoxy-5-fluoro-(224), 5,3'-dideoxy-5-fluoro-(225), 5,3',4'-trideoxy-5-fluoro-(226), and 5,5-difluoro-(227) derivatives of kanamycin B . The antibacterial activity of the 3'-chloro analog 221 was one-sixth that of the 3'-fluoro derivative 219. Also the 4'-fluoro derivatives 222 and 223 were inactive against resistant bacteria producing phosphotransferase enzymes [APH(3')s], slightly less active than the parent compounds against common bacteria, but very active against the kind that produce [AAD(4')]. The 5-fluoro and 5,5-difluoro derivatives (com-
pounds 224-227) showed comparable or better activities and were markedly less toxic than the parent compounds (compounds 218-229 ).
3'-Deoxy-3'-fluoro (228) and 3',4'-dideoxy-3'-fluorokanamycin B (229) , 5-deoxy-5-fluoro (230), and 5-deoxy-5,5-difluoro (231) derivatives of netilmicin (1)
, as well as fluoroarbekacins (234-238) , were prepared by Umezawa's group. Both fluorinated derivatives of kanamycin B were active against resistant bacteria producing 3'-phosphotransferase enzymes . In the synthesis of fluorinated netilmicins (230 and 231), two other analogs, 5-epi-netilmicin (232) and 5-epi-6'-N-methylnetilmicin (233) were also prepared. Compounds 230 and 232 showed activity similar to that of netilmicin, 231 was slightly less active than netil-micin, but 233 showed markedly reduced activity. In terms of toxicity, the 5-fluoro derivative 230 showed half to one-third the acute toxicity of netilmicin . The fluorinated arbekacins (234-238 ) exhibited activity similar to that of arbekacin and were remarkably less toxic than the parent compound (compounds 230-238 ). These observations were suggestive of the fact that the presence of fluorine at the 5-position decreases the basicity of the 3-amino group and lowers the toxicity of the antibiotic
. A few other fluorinated kanamycins, including 5-deoxy-5-epi-fluoroamikacin, 5-deoxy-5-epi-fluoroarbekacin, and their related analogs, have been prepared to study the fluorination-toxicity relationship. In contrast to the low toxicities of the 5-fluoro derivatives , these epi-fluoro compounds showed acute toxicity values identical to those of arbekacin and amikacin . This indicates the importance of stereo-electronic effects of the fluoro group at position 5 of the 2-deoxystreptomine moiety in toxicity of aminoglycoside antibiotics.
The 3' -oxokanamycin A (239) has been recently synthesized. Compound 239, which adopts a hydrate chair conformation in aqueous solution, was shown to be an aminoglycoside antibiotic that can undergo a self and continuous phosphorylation-dephosphorylation process to generate the active antibiotic .
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