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

File Download
  • No File Attached
Links for fulltext
(May Require Subscription)
Supplementary
  • Basic View
  • Metadata View
  • XML View
TitleAntitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino- 4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase i inhibitors and cytotoxic agents
AuthorsYe, D4
Shi, Q4
Leung, CH2
Kim, SW2
Park, SY2
Gullen, EA2
Jiang, ZL2
Zhu, H1
MorrisNatschke, SL4
Cheng, YC2
Lee, KH3 4
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
CitationBioorganic And Medicinal Chemistry, 2012, v. 20 n. 14, p. 4489-4494 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.bmc.2012.05.030
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.
ISSN0968-0896
2011 Impact Factor: 2.921
2011 SCImago Journal Rankings: 0.194
DOIhttp://dx.doi.org/10.1016/j.bmc.2012.05.030
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorYe, D
dc.contributor.authorShi, Q
dc.contributor.authorLeung, CH
dc.contributor.authorKim, SW
dc.contributor.authorPark, SY
dc.contributor.authorGullen, EA
dc.contributor.authorJiang, ZL
dc.contributor.authorZhu, H
dc.contributor.authorMorrisNatschke, SL
dc.contributor.authorCheng, YC
dc.contributor.authorLee, KH
dc.date.accessioned2012-10-08T03:23:56Z
dc.date.available2012-10-08T03:23:56Z
dc.date.issued2012
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.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationBioorganic And Medicinal Chemistry, 2012, v. 20 n. 14, p. 4489-4494 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.bmc.2012.05.030
dc.identifier.citeulike10698222
dc.identifier.doihttp://dx.doi.org/10.1016/j.bmc.2012.05.030
dc.identifier.epage4494
dc.identifier.issn0968-0896
2011 Impact Factor: 2.921
2011 SCImago Journal Rankings: 0.194
dc.identifier.issue14
dc.identifier.scopuseid_2-s2.0-84863212686
dc.identifier.spage4489
dc.identifier.urihttp://hdl.handle.net/10722/168646
dc.identifier.volume20
dc.languageeng
dc.publisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/bmc
dc.publisher.placeUnited Kingdom
dc.relation.ispartofBioorganic and Medicinal Chemistry
dc.relation.referencesReferences in Scopus
dc.subjectCamptothecin (Cpt)
dc.subjectConjugates
dc.subjectCytotoxicity
dc.subjectEpipodophyllotoxin
dc.subjectEtoposide (Vp-16)
dc.subjectTopoisomerase
dc.titleAntitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino- 4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase i inhibitors and cytotoxic agents
dc.typeArticle
Author Affiliations
  1. Rutgers University-Camden campus
  2. Yale University
  3. China Medical University Hospital Taichung
  4. The University of North Carolina at Chapel Hill