1073243-60-3Relevant articles and documents
Synthesis and evaluation of paromomycin derivatives modified at C(4′)
Pathak, Rashmi,Perez-Fernandez, Deborah,Nandurdikar, Rahul,Kalapala, Sarath K.,Boettger, Erik C.,Vasella, Andrea
experimental part, p. 1533 - 1552 (2009/02/07)
The 2-amino-2-deoxy-α-D-glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4-diamino-2,4-dideoxy-α-D-glucopyranosyl, 2,4-diamino-2,4-dideoxy-α-D-galactopyranosyl, 2-amino-2-deoxy-α-D- galactopyranosyl, or 3,4,5-trideoxy-4-aza-α-D-erythro-heptoseptanosyl moiety to investigate the effect of the substituent at C(4′) on the interaction with ribosomal RNA. The triflate 6 was prepared from the key intermediate pentaazido 3′,6′-dibenzyl ether 5, and the hexosulose 10 was obtained by oxidation of 5 with Dess - Martin's periodinane. Stereoselective reduction of 10 with NaBH4 gave the alcohol 11 that was transformed into the triflate 12. The epimeric hexaazides 7 and 13 were obtained by treating the triflates 6 and 12, respectively, with tetrabutylammonium azide. Periodate cleavage of glycol 2 yielded the dialdehyde 24 that was reductively aminated with aniline and benzylamine to give the 3,4,5-trideoxy-4-aza-α-D-erythro-heptoseptanosides 25 and 26, respectively. Standard azide reduction and debenzylation yielded 9 (2,4-diamino-2,4-dideoxy-α-D-galactopyranosyl ring I), 13 (2-amino-2-deoxy-α-D-galactopyranosyl ring I), 17 (2,4-diamino-2,4- dideoxy-α-D-glucopyranosyl ring I), and 27 and 28 (3,4,5-trideoxy-4-aza- α-D-erythro-heptoseptanosyl ring I). The derivatives 9 and 13 possessing a D-galacto-configured ring I were less active than the corresponding D-gluco-analogues 17 and paromomycin (1), respectively. The C(4′)- aminodeoxy derivative 17 (D-gluco ring I) and the known 4′- deoxyparomomycin (23), prepared by a new route, displayed slightly lower antibacterial activities than paromomycin (1). Cell-wall permeability is not responsible for the unexpectedly low activity for 17, as shown by cell-free translation assays. The results evidence that the orientation of the substituent at C(4′) is more important than its nature for drug binding and activity.
