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5′‐Substituted Thalidomide Analogs as Modulators of TNF‐α
Author(s) -
Teubert Uwe,
Zwingenberger Kai,
Wnendt Stephan,
Eger Kurt
Publication year - 1998
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199801)331:1<7::aid-ardp7>3.0.co;2-n
Subject(s) - chemistry , sodium azide , phthalic anhydride , substituent , stereochemistry , acylation , chemical synthesis , thalidomide , organic chemistry , in vitro , biochemistry , immunology , multiple myeloma , biology , catalysis
The synthesis of 5′‐substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide ( 5 ) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8 . In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9 , 10 , and 11 . All final compounds were tested in vitro for their inhibitory activity on the release of TNF‐α, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5’ of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL‐2 in vitro .