Linked Life Data

1967653

Source:http://linkedlifedata.com/resource/pubmed/id/1967653

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1990-3-9
pubmed:abstractText
Dihydroorotase (DHO) catalyzes the conversion of carbamyl aspartate (CA) to dihydroorotate (DO) in the de novo pyrimidine biosynthetic pathway. Few effective inhibitors of DHO have been reported, and thus blockade of this reaction has not been widely pursued as a strategy for development of antitumor agents. Utilizing two mechanism-based strategies, we have designed and prepared potential DHO inhibitor analogues of CA. One strategy replaced the gamma-carboxyl moiety of CA with a boronic acid. This substitution yields compounds which form stable charged tetrahedral intermediates and mimic the enzyme-substrate transition state. Preparation of the boronic acid analogues of CA and its carboxylic acid esters focused on a Curtius rearrangement as a key step following a malonic ester synthesis. This was followed by carbamoylation of the free amine under nonaqueous neutral conditions with Si(NCO)4. The ethyl ester was a competitive inhibitor of DHO with an apparent Ki of 5.07 microM, while the nonesterified analogue and the methyl ester were not effective inhibitors. None of the compounds were cytotoxic against L1210 cells in culture. An active-site-directed sulfhydryl-containing zinc chelator was also prepared. This analogue irreversibly inhibited the enzyme, but it also was ineffective in L1210 growth inhibition.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
819-23
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1990
pubmed:articleTitle
Analogues of carbamyl aspartate as inhibitors of dihydroorotase: preparation of boronic acid transition-state analogues and a zinc chelator carbamylhomocysteine.
pubmed:affiliation
Department of Oncology, Mayo Clinic & Foundation, Rochester, Minnesota 55905.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't