Poly(ethylene glycol) prodrugs of the CDK inhibitor, alsterpaullone (NSC 705701): synthesis and pharmacokinetic studies

Bioconjugate Chemistry
R B GreenwaldDaniel W Zaharevitz

Abstract

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.

References

May 25, 2002·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S F StinsonR W Nims
Feb 5, 2003·Advanced Drug Delivery Reviews·Richard B GreenwaldCharles D Conover

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Citations

Apr 1, 2005·Drug Discovery Today. Technologies·Tamara Minko
Apr 23, 2008·Expert Opinion on Drug Delivery·Sinéad M RyanDavid J Brayden
Apr 20, 2010·Chembiochem : a European Journal of Chemical Biology·Manuela Bartolini, Vincenza Andrisano
Feb 14, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jayant J KhandareTamara Minko
Nov 5, 2019·Cell Chemical Biology·Pieter H BosBrent R Stockwell
Aug 10, 2007·Molecular Pharmaceutics·Pooja ChandnaTamara Minko

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