Oh

Figure 6.4. (Continued.)

C6' is permissible, at least up to one carbon, because branching at this position doesn't disrupt the pseudo-trans pairing to G1408 (41).

All active aminoglycoside compounds have a hydroxyl at C4', are C4'-deoxy, or are unsaturated at C4' (41); hydroxyl groups at C4' form a hydrogen bond to the phosphate of The methoxy derivative is not tolerated at C4' (41), presumably because of steric clash with the phosphate of A1493. An amino at the C4f position surprisingly abolishes activity. Because an amino at this position should make a productive salt bridge, the particular C4'- NH, derivative tested may be inactive for other reasons.

The 3' hydroxyl group in paromomycin forms a hydrogen bond to the phosphate of A1492. Phosphorylation at this position abolishes all activity and forms a mode of resistance (41, 62); however, 3'-deoxy and 3'-epi analogs are not substrates for such resistance enzymes, and they remain active against some bacteria resistant to aminoglycosides (41). Recognition that all 3'-deoxyderivatives lose a productive interaction that presumably lowers their affinities for 16S rRNA prompted the design of 3' ketokanamycin A, in an effort to preserve the hydroxyl phosphate hydrogen bond while eliminating the possibility of inac-tivation by phosphorylating enzymes (63).It is

mannose—0

5'" epi expected that the 3' keto derivative will exist in equilibrium with a hydrated variant (3'-gemdiol analog) and serve as a substrate for phosphorylation. However, the phosphory-lated product would undergo spontaneous : elimination of the phosphate moiety, thereby regenerating the 3' ketokanamycin A analog, which retains the same hydrogen bonding to A1492. Although the keto analog was substantially less active than kanamycin A against E. colit it was more active than kanamycin A against E. coli harboring the gene for APH(3')-Ia, a resistance gene which, when expressed, phosphorylates C3'-OH.

Only hydroxyl and amino groups are toler-pated at C2' because an intramolecular hydrogen bond must be satisfied between ring I and firing III of the 4,5 subclass and ring I and ring [lllofthe 4,6 subclass to stabilize the conformation of the antibiotics in the active state. In ¡lothsubclasses other substitutions at the C2' position would disrupt this hydrogen bond. lAdenylation of this site by resistance enzymes or conversion to the 2'-epi configuration aLboI-Jashes activity (41, 62).

Ring II structurally defines this class of an-[tftibiotics as the 2-deoxystreptamine aminogly-

Figure 6.4. (Continued.)

cosides and has given way to modification more frequently than the other rings (Fig. 6.4b). Conversion of kanamycin A to include 4-amino-2(S)-hydroxylbutyrylamide (AHBA) at CI yielded an aminoglycoside (amikacin) that was effective against many aminoglyco-side resistant bacteria with little reduction in activity against aminoglycoside sensitive bacteria (41).Success with amikacin prompted an exhaustive search for other CI derivatives with improved efficacy over parental aminoglycosides. Several important commercial aminoglycosides emerged from such efforts. It is impossible to catalogue all of the reported CI modifications, therefore only the most illustrative examples will be described here.

N-acylation of C1-NH2 is the most explored type of modification at this position. Although only a limited number of highly active derivatives were found, a large variety of modifications are tolerated at Cl-NH2 (41, 64, 65). Using AHBA as a basis of comparison for all iV-1 acyl modifications, clear structure-activity relationships of other acylated products are observed. Shortening or lengthening the carbon chain by more than one carbon unit drastically reduces activity, as does moving the hydroxyl

Therapeutic Agents Acting on RNA Targets

c—och2ch3

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