Poly(ethylene glycol) Prodrugs of the CDK Inhibitor, Alsterpaullone (NSC 705701):  Synthesis and Pharmacokinetic Studies

Two methods were devised to conjugate PEG to alsterpaullone (NSC 705701) via the N of the indole ring portion of the molecule. In the first approach, activation of the indole was accomplished by reaction with p-nitrophenyl chloroformate to produce a reactive carbamate that was then condensed with a...

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Bibliographic Details
Published in:Bioconjugate chemistry 2004-09, Vol.15 (5), p.1076-1083
Main Authors: Greenwald, Richard B, Zhao, Hong, Xia, Jing, Wu, Dechun, Nervi, Stephen, Stinson, Sherman F, Majerova, Eva, Bramhall, Chris, Zaharevitz, Daniel W
Format: Article
Language:English
Subjects:
Animals
Benzazepines - blood
Benzazepines - chemical synthesis
Benzazepines - pharmacokinetics
Biochemistry
Chemical bonds
Chemical synthesis
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclin-Dependent Kinases - metabolism
Indoles - blood
Indoles - chemical synthesis
Indoles - pharmacokinetics
Male
Mice
Pharmacology
Polyethylene glycol
Polyethylene Glycols - chemical synthesis
Polyethylene Glycols - pharmacokinetics
Prodrugs - chemical synthesis
Prodrugs - pharmacokinetics
Protein Kinase Inhibitors - blood
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacokinetics
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Summary:Two methods were devised to conjugate PEG to alsterpaullone (NSC 705701) via the N of the indole ring portion of the molecule. In the first approach, activation of the indole was accomplished by reaction with p-nitrophenyl chloroformate to produce a reactive carbamate that was then condensed with a mono blocked diamine to form a urea bond followed by deblocking and conjugation to PEG. The second route used the anion of the indole and produced a carbamate bond. Both compounds were highly water soluble, were stable in buffer, and released alsterpaullone in vitro and in vivo. Studies were conducted in mice to investigate the influence of PEGylation on the plasma pharmacokinetics of alsterpaullone. The total plasma clearance rate was decreased up to 32-fold, and the biological halflife lengthened up to 8-fold when alsterpaullone was injected i.v. as a PEG-conjugate and compared to injection of the unconjugated compound. The most pronounced effect on the pharmacokinetics of alsterpaullone was produced by a 40-kDa PEG urea-linked conjugate. When the 40- and 20-kDa urea-linked conjugates were administered by i.p. injection, high relative bioavailability (46% and 99%, respectively) of alsterpaullone was observed.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc049906a