Synthesis and immunological activity of water-soluble Thalidomide prodrugs

A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were...

Full description

Saved in:

Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 9; no. 5; pp. 1279 - 1291
Main Authors:	Hess, Sonja, Akermann, Michaela A., Wnendt, Stephan, Zwingenberger, Kai, Eger, Kurt
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-05-2001 Elsevier Science
Subjects:	Animals Binding Sites Biological and medical sciences Drug Stability Humans Hydrogen-Ion Concentration Hydrolysis Immunomodulators Interleukin-2 - antagonists & inhibitors Interleukin-2 - biosynthesis Kinetics Male Medical sciences Mice Permeability Pharmacology. Drug treatments Shwartzman Phenomenon - metabolism Solubility Thalidomide - chemical synthesis Thalidomide - chemistry Thalidomide - pharmacology Tumor Necrosis Factor-alpha - antagonists & inhibitors Water - chemistry Intraperitoneal administration Peptides Chemical stability Imide Mononuclear cell Aminoester Interleukin 2 Structure activity relation Water solubility Chemical synthesis Thalidomide Tumor necrosis factor α Human Rodentia Cytokine Prodrug In vitro Immunomodulator Water soluble compound In vivo Hydrolysis resistance α-Aminoacid Vertebrata Mammalia Mouse Animal Dipeptides Property structure relationship Kinetics Immunosuppressive agent Physicochemical properties
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxymethyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012 mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300 mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k′. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-α and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-α release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications. Graphic
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391
DOI:	10.1016/S0968-0896(00)00342-4