AMG = aminoglycoside

Compounds 260-265

Laboratories, impurities of bulk amikacin were identified as 1,6'- and 1,3"-di-N-[(S)-4-amino-2-hydroxybutyryl] kanamycin A [140].

In an attempt to probe structure-toxicity relationships of aminoglycoside antibiotics via fluorination, the fluoroacyl derivatives 1-N-[(2S,4S)- and (25,4^)-5-amino-4-fluoro-2-hydroxypentanoyl]dibekacin (266 and 267, respectively) were synthesized. These fluorinated analogs showed antibacterial activity almost similar to that of amikacin, but they were less toxic. Toxicities of these compounds were compared with those of arbekacin analogs 268-270 , and the investigators concluded that the observed decrease in toxicity is a function of the chain length rather than of the introduction of fluorine [31]. The fluorinated derivatives 266 and 267 showed toxicities analogous to 269, but lower than arbekacin 260 (compounds 266-270 ).

The 3"-N-acetylation of arbekacin 260 and amikacin 2, the first example of 3"-N-acetylation of aminoglycoside antibiotics by enzymatic modification, was reported in 1988. Subjection of kanamycin group antibiotics to an aminoglycoside 3-N-ace-

Acetylation Aminoglycosides

tyltransferase, AAC(3)-X, resulted in formation of 3"-N-acetyl derivatives of arbekacin and amikacin, but 3-N-acetyldibekacin was formed in the case of dibekacin 194, which lacks the (S)-4-amino-2-hydroxybutyryl moiety in its structure, showing the importance of this side chain in the enzymatic modification of kanamycins. Interestingly, 3"-N-acetylarbekacin showed antibacterial activity as high as that of 2'-N-acetylarbekacin, whereas the 3"-N-acetylamikacin exhibited no substantial activity. These results illuminate a novel aspect of arbekacin chemistry, distinct from the other aminoglycoside antibiotics [141].

(e) N-Hydroxy and C-Hydroxymethylkanamycins. Tsuchiya et al. prepared [142] 6'-N-hydroxykanamycin A and 6'-N-hydroxydibekacin by reduction of the corresponding 6'-aldoximes with sodium cyanoborohydride. However, these compounds showed very weak antibacterial activity. In other reports and in extensive work by van Schepdael et al. [143,144] the 6"-triisopropylbenzenesulfonyl ester derivative of kanamycin B (compound 271) was used to prepare a series of 6"-substituted kana-mycin B analogs. In these compounds, the 6"-hydroxyl group was replaced with Cl, N3, NH2, NHMe, NMe2, alkylamido, thioalkyl, alkoxy, and a few other substituents [143]. Likewise, a number of analogs having the 1-position modified by the hydroxy-methyl group axial to the 1-amino group were prepared [144]. These include the 6"-chloro, 6"-amino, and 6"-acetamido derivatives 280, 281, and 282, respectively. To introduce the hydoxymethyl function at position 1, the Cbz-protected derivative 272 was deprotected by hydrogenolysis, and the resultant free amino group was oxidized to a nitro group with m-chloroperbenzoic acid to afford compound 273. This intermediate was subjected to paraformaldehyde in the presence of triethylamine to furnish the hydroxymethyl analog 274, which after hydrogenolysis in the presence of Raney nickel was converted to the amino derivative 275. Amino group protection followed by nucleophilic displacement at the 6"-position with lithium chloride or azide in anhydrous DMF afforded the chloro and azido derivative 276 and 277, respectively. Reduction of the azide function with triphenylphosphine in anhydrous pyridine followed by treatment with aqueous ammonia gave the amino derivative

278, which after acetylation with acetic anhydride afforded the acetamido analog

279. Removal of the protecting groups in 276, 277, and 279 with trifluoroacetic acid resulted in the formation of the title compounds 280, 281, and 282 (compounds 271282). However, these new antibiotics showed activity comparable to that of kanamycin B and were only slightly less toxic than the parent compound [145].

(f) Amino Kanamycins. 2"-Amino-2"-deoxyarbekacin (283), together with five related analogs (284-288 ) were synthesized by reductive amination from their corresponding 2"-oxo derivatives. For example, oxidation of the 2"-hydroxyl group of 289 by the Pfitzner-Moffatt procedure, followed by reductive amination, gave exclusively an equatorial 2"-amino group, which after protection with the Boc group afforded compound 290. Treatment of the Cbz-deprotected derivative 291 with N-hydroxysuccinimide ester of (S)-2-hydroxy-4-( p-methoxybenzyloxycarbonyl-amino)butyric acid in THF mainly gave the 1-N-acylated derivative, which after deprotection furnished the title compound 283 (compounds 283-291). All the new antibiotics showed good antibacterial activities against staphylococci and gram-negative bacteria with improved anti-MRSA activity. Among these analogs, compounds 283 and 286 exhibited excellent anti-MRSA activity and were less toxic than the parent antibiotic [30,146].

Compounds 271-282

A series of 2"-amino-2"-deoxy and 2"-acylamido-2"-deoxy derivatives of 5-deoxy-5-epi-fluorodibekacin (compounds 292-298 ) were also prepared via an oxi-dation-methoxyimination-reduction sequence to introduce the 2"-NH2 group. All the new compounds except 292 showed only limited or no antibacterial activity, and the epi-amino derivative 293 exhibited much lower activity than 292 [147] (compounds 292-298 ).

In another synthesis, Wang et al. [73] prepared 6"-amino-6"-deoxykanamycin A, together with 6"-amino-6"-deoxytobramycin and 5"-amino-5"-deoxyneomycin B, by nucleophilic displacement of an azido group with a tosyl group in the O-tosylated derivatives. These amino-aminoglycosides were tested for their binding ability to RNA and showed improved binding ability, being much stronger RNA binders than their corresponding parent counterparts.

(g) Deamino Kanamycins. A series of neamine and kanamycin A derivatives involving amino group deletions have been synthesized to investigate the importance of electrostatic interactions for both substrate recognition and enzymatic modification by resistant enzymes. The three deaminated kanamycin A analogs compounds 299301, together with those of neamine (see Section IV.A.1: compounds 74-77 ) were

Compounds 283-291

tested against resistant organisms harboring APH(3')-Ia and APH(3')-IIa, and the same organisms without the resistance enzymes. The resulting data showed virtually unmodified products in the face of these enzymes, indicating the importance of electrostatic interactions for enzymatic modification [24].

(h) Other Kanamycin Derivatives. Cyclic carbamate derivatives of kanamycin A have been prepared [148], and in another report regiospecific methylation and ster-eospecific 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 compound 303 (part structure).

Metal acetates were used for selective protection of the amino groups in the preparation of 2'-deamino-2'-nitrokanamycin B together with 2'-nitroneamine analog


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