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Synthesis and evaluation of paromomycin derivates modified at C(4')


Pathak, Rashmi; Perez-Fernandez, Déborah; Nandurdikar, Rahul; Kalapala, Sarath K; Böttger, Erik C; Vasella, Andrea (2008). Synthesis and evaluation of paromomycin derivates modified at C(4'). Helvetica Chimica Acta, 91(8):1533-1552.

Abstract

The 2-amino-2-deoxy--D-glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4-diamino-2,4-dideoxy--D-glucopyranosyl, 2,4-diamino-2,4-dideoxy--D-galactopyranosyl, 2-amino-2-deoxy--D-galactopyranosyl, or 3,4,5-trideoxy-4-aza--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--D-erythro-heptoseptanosides 25 and 26, respectively. Standard azide reduction and debenzylation yielded 9 (2,4-diamino-2,4-dideoxy--D-galactopyranosyl ring I), 13 (2-amino-2-deoxy--D-galactopyranosyl ring I), 17 (2,4-diamino-2,4-dideoxy--D-glucopyranosyl ring I), and 27 and 28 (3,4,5-trideoxy-4-aza--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.

Abstract

The 2-amino-2-deoxy--D-glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4-diamino-2,4-dideoxy--D-glucopyranosyl, 2,4-diamino-2,4-dideoxy--D-galactopyranosyl, 2-amino-2-deoxy--D-galactopyranosyl, or 3,4,5-trideoxy-4-aza--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--D-erythro-heptoseptanosides 25 and 26, respectively. Standard azide reduction and debenzylation yielded 9 (2,4-diamino-2,4-dideoxy--D-galactopyranosyl ring I), 13 (2-amino-2-deoxy--D-galactopyranosyl ring I), 17 (2,4-diamino-2,4-dideoxy--D-glucopyranosyl ring I), and 27 and 28 (3,4,5-trideoxy-4-aza--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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:27 August 2008
Deposited On:30 Oct 2008 08:25
Last Modified:05 Apr 2016 12:30
Publisher:Verlag Helvetica Chimica Acta
ISSN:0018-019X
Publisher DOI:https://doi.org/10.1002/hlca.200890167

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