UZH-Logo

Maintenance Infos

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.

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.

Citations

11 citations in Web of Science®
9 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

6 downloads since deposited on 30 Oct 2008
0 downloads since 12 months
Detailed statistics

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:10.1002/hlca.200890167
Permanent URL: http://doi.org/10.5167/uzh-4411

Download

[img]
Filetype: PDF - Registered users only
Size: 1MB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations