Linked Life Data

15339176

Source:http://linkedlifedata.com/resource/pubmed/id/15339176

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
35
pubmed:dateCreated
2004-9-1
pubmed:abstractText
We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0002-7863
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
126
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
10913-22
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Discovery of (E)-9,10-dehydroepothilones through chemical synthesis: on the emergence of 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B as a promising anticancer drug candidate.
pubmed:affiliation
Contribution from the Laboratory for Bioorganic Chemistry, Preclinical Pharmacology Core Facility, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't