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Article: Antitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino- 4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase i inhibitors and cytotoxic agents

TitleAntitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino- 4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase i inhibitors and cytotoxic agents
Authors
KeywordsCamptothecin (Cpt)
Conjugates
Cytotoxicity
Epipodophyllotoxin
Etoposide (Vp-16)
Topoisomerase
Issue Date2012
PublisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/bmc
Citation
Bioorganic And Medicinal Chemistry, 2012, v. 20 n. 14, p. 4489-4494 How to Cite?
AbstractTwo conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino- 4′-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties. © 2012 Elsevier Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/168646
ISSN
2014 Impact Factor: 2.793
2014 SCImago Journal Rankings: 0.874
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYe, Den_US
dc.contributor.authorShi, Qen_US
dc.contributor.authorLeung, CHen_US
dc.contributor.authorKim, SWen_US
dc.contributor.authorPark, SYen_US
dc.contributor.authorGullen, EAen_US
dc.contributor.authorJiang, ZLen_US
dc.contributor.authorZhu, Hen_US
dc.contributor.authorMorrisNatschke, SLen_US
dc.contributor.authorCheng, YCen_US
dc.contributor.authorLee, KHen_US
dc.date.accessioned2012-10-08T03:23:56Z-
dc.date.available2012-10-08T03:23:56Z-
dc.date.issued2012en_US
dc.identifier.citationBioorganic And Medicinal Chemistry, 2012, v. 20 n. 14, p. 4489-4494en_US
dc.identifier.issn0968-0896en_US
dc.identifier.urihttp://hdl.handle.net/10722/168646-
dc.description.abstractTwo conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino- 4′-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties. © 2012 Elsevier Ltd. All rights reserved.en_US
dc.languageengen_US
dc.publisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/bmcen_US
dc.relation.ispartofBioorganic and Medicinal Chemistryen_US
dc.subjectCamptothecin (Cpt)en_US
dc.subjectConjugatesen_US
dc.subjectCytotoxicityen_US
dc.subjectEpipodophyllotoxinen_US
dc.subjectEtoposide (Vp-16)en_US
dc.subjectTopoisomeraseen_US
dc.titleAntitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino- 4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase i inhibitors and cytotoxic agentsen_US
dc.typeArticleen_US
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_US
dc.identifier.authorityLeung, CH=rp00730en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.bmc.2012.05.030en_US
dc.identifier.pmid22698783-
dc.identifier.scopuseid_2-s2.0-84863212686en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84863212686&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume20en_US
dc.identifier.issue14en_US
dc.identifier.spage4489en_US
dc.identifier.epage4494en_US
dc.identifier.isiWOS:000305952500036-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridYe, D=55246166500en_US
dc.identifier.scopusauthoridShi, Q=7402698456en_US
dc.identifier.scopusauthoridLeung, CH=7402612570en_US
dc.identifier.scopusauthoridKim, SW=26653073900en_US
dc.identifier.scopusauthoridPark, SY=55043947900en_US
dc.identifier.scopusauthoridGullen, EA=6602138704en_US
dc.identifier.scopusauthoridJiang, ZL=55245704000en_US
dc.identifier.scopusauthoridZhu, H=55246427000en_US
dc.identifier.scopusauthoridMorrisNatschke, SL=6603758276en_US
dc.identifier.scopusauthoridCheng, YC=36041844200en_US
dc.identifier.scopusauthoridLee, KH=35450969800en_US
dc.identifier.citeulike10698222-

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