Linked Life Data

12852757

Source:http://linkedlifedata.com/resource/pubmed/id/12852757

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2003-7-10
pubmed:abstractText
The indenoisoquinolines are a novel class of topoisomerase I (top1) inhibitors that are cytotoxic in cancer cell cultures and are therefore under development as potential anticancer agents. As inhibitors of the DNA religation reaction occurring after DNA cleavage by the enzyme, they are classified as top1 poisons, similar to the camptothecins. Two strategies were employed in order to further develop the structure-activity relationships of the indenoisoquinolines and enhance their therapeutic potential. The first strategy involved the synthesis of indenoisoquinoline-camptothecin hybrid molecules to take advantage of a proposed structural analogy between the indenoisoquinolines and camptothecin. The desired hybrids were synthesized by reaction of halogenated phthalides with a dihydropyrroloquinoline. The second strategy involved the attachment of various alkenyl substituents to the C-11 position of the indenoisoquinolines, which were assumed to project into the DNA minor groove. The required C-11-substituted indenoisoquinolines were synthesized by McMurry reactions of 11-ketoindenoisoquinolines with aldehydes, and the geometries of the resulting alkenes were established by nuclear Overhauser effect difference NMR spectroscopy. All of the new indenoisoquinolines were examined for cytotoxicity in human cancer cell cultures as well as for activity vs top1. Although the indenoisoquinoline-camptothecin hybrid molecules proved to be less cytotoxic and displayed less activity against top1, an analogue incorporating a 3'-aminoalkenyl substituent at the C-11 position of the indenoisoquinoline system was significantly more potent than the prototype indenoisoquinoline in both assays. These results indicate that C-11 aminoalkyl substituents that are assumed to project into the minor groove enhance the cytotoxicity and top1 inhibitory activity of the parent indenoisoquinoline system.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3275-82
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids.
pubmed:affiliation
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.