Linked Life Data

10377217

Source:http://linkedlifedata.com/resource/pubmed/id/10377217

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1999-7-8
pubmed:abstractText
A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2112-24
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10377217-Anti-Bacterial Agents, pubmed-meshheading:10377217-Anti-Infective Agents, pubmed-meshheading:10377217-Cell Line, pubmed-meshheading:10377217-Chlorophenols, pubmed-meshheading:10377217-Chromones, pubmed-meshheading:10377217-Cryptococcus neoformans, pubmed-meshheading:10377217-Crystallography, X-Ray, pubmed-meshheading:10377217-Drug Design, pubmed-meshheading:10377217-Enzyme Inhibitors, pubmed-meshheading:10377217-Gram-Positive Bacteria, pubmed-meshheading:10377217-Humans, pubmed-meshheading:10377217-Lactobacillus casei, pubmed-meshheading:10377217-Models, Molecular, pubmed-meshheading:10377217-Phenolphthalein, pubmed-meshheading:10377217-Pneumocystis, pubmed-meshheading:10377217-Species Specificity, pubmed-meshheading:10377217-Structure-Activity Relationship, pubmed-meshheading:10377217-Thymidylate Synthase
pubmed:year
1999
pubmed:articleTitle
Phthalein derivatives as a new tool for selectivity in thymidylate synthase inhibition.
pubmed:affiliation
Dipartimento Scienze Farmaceutiche and Dipartimento Scienze Chimiche, Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't