Linked Life Data

21542625

Source:http://linkedlifedata.com/resource/pubmed/id/21542625

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2011-6-10
pubmed:abstractText
Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug-resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH(4) reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1? and 1?. In the solid state, the drug consists exclusively of the ?-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the ?/? equilibration. To this purpose, free energy activation barriers (?G(‡)) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of ?G(‡) on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1520-6904
pubmed:author
pubmed:issnType
Electronic
pubmed:day
17
pubmed:volume
76
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4831-40
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Stereolability of dihydroartemisinin, an antimalarial drug: a comprehensive kinetic investigation. Part 2.
pubmed:affiliation
Analytical Development, R&D Department, Sigma-Tau S.p.A., Via Pontina km 30.400, 00040 Pomezia, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't