| Mechanism of hydrolysis of a novel indolocarbazole topoisomerase I inhibitor. | |
| | |
MedLine Citation:
|
PMID: 20025967 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The degradation kinetics and reaction product profile of the antitumor agent 1 in aqueous solution was studied. Hydrolysis of the pendant imide ring of 1 is the primary mode of thermal degradation in aqueous solution, and the pH rate profile of 1 has a V-shape indicating that hydrolysis of the imide ring can be catalyzed by either acid or base. Hydrolysis of 1 to the anhydride derivative 3 or the dicarboxylic acid derivative 4 is stepwise and the intermediates 2a and 2b formed by initial hydrolytic attack have been observed under alkaline conditions. An overall mechanism for the hydrolysis of 1 in aqueous solution has been proposed. Extrapolating Arrhenius behavior to the hydrolysis reaction of 1 in aqueous solution maintained at a pH value of 4 suggests an aqueous buffered formulation has sufficient thermal stability to be considered a robust room temperature drug product. |
| | |
Authors:
|
David Breslin; Yuichi Sato; Shyam B Karki |
Related Documents
:
|
17448557 - A novel variant of thermotoga neapolitana beta-glucosidase b is an efficient catalyst f... 19401257 - Environmental occurrence and degradation of the herbicide n-chloridazon. 19088977 - Heterogeneous photocatalyst materials for water splitting. 16856757 - Photodegradation kinetics of some thiols and thiones in aqueous suspension of zinc oxide. 20047287 - Salt effect on the aggregation behavior of 1-decyl-3-methylimidazolium bromide in aqueo... 8254697 - In vitro cyanide release of four prussian blue salts used for the treatment of cesium c... |
Publication Detail:
|
Type: Journal Article Date: 2009-12-16 |
Journal Detail:
|
Title: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences Volume: 39 ISSN: 1879-0720 ISO Abbreviation: Eur J Pharm Sci Publication Date: 2010 Mar |
Date Detail:
|
Created Date: 2010-03-08 Completed Date: 2010-07-26 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9317982 Medline TA: Eur J Pharm Sci Country: Netherlands |
Other Details:
|
Languages: eng Pagination: 291-7 Citation Subset: IM |
Copyright Information:
|
Copyright 2009 Elsevier B.V. All rights reserved. |
Affiliation:
|
Pharmaceutical Research and Development, Merck Research Laboratories, West Point, PA 19486, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Carbazoles
/
chemistry,
pharmacology* DNA Topoisomerases, Type I / chemistry, pharmacology* Electrophoresis, Capillary Enzyme Inhibitors / chemistry, pharmacology* Hydrogen-Ion Concentration Hydrolysis Kinetics |
| Chemical | |
Reg. No./Substance:
|
0/Carbazoles; 0/Enzyme Inhibitors; EC 5.99.1.2/DNA Topoisomerases, Type I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Physiologically based mechanistic modelling to predict complex drug-drug interactions involving simu...
Next Document: Cytotoxicity study of ordered mesoporous silica MCM-41 and SBA-15 microparticles on Caco-2 cells.