5′-Substituted Thalidomide Analogs as Modulators of TNF-α

Abstract

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.

Mono- and Dihydroxylated Metabolites of Thalidomide: Synthesis and TNF-.ALPHA. Production-Inhibitory Activity

“…Interestingly, cis-5Ј-acetoxythalidomide was reported to be more crystallizable than trans-5Ј-acetoxythalidomide. 14) Therefore, the crystallizability may depend on the nature of the 5Ј-hydroxyl substituent. Finally, removal of the TBDMS group of 21 with tetra-nbutylammonium fluoride (TBAF) at 0°C gave the desired cis-5Ј-OH-Thal (cis-2f) stereoselectively.…”

“…Hydroxylation is reported to occur mainly at the 5-position in the phthaloyl moiety and the 5Ј-position in the glutarimide moiety, 10) although the 4-position of the phthaloyl moiety and the nitrogen atom of the imide ring can also be hydroxylated (Fig. 1).10) 5-OH-Thal (2a), N-OH-Thal (2c) [11][12][13] and cis-5Ј-OHThal (cis-2f) [14][15][16] have been well-characterized and their methods of preparation have been reported in detail. For 4-OH-Thal (2b), trans-5Ј-OH-Thal (trans-2f), and the dihydroxylated metabolites, 5,N-di-OH-Thal (2d), 4,N-di-OHThal (2e), and 5,5Ј-di-OH-Thal (2g), neither spectroscopic data nor any detailed description of their synthesis is available in the literature, to our knowledge.…”

“…Thalidomide (1) is metabolically labile, and many metabolites have been identified or proposed, [10][11][12][13][14][15][16][17] including seven hydroxylated metabolites, 2a-g (Fig. 1).…”

Investigation of the stereoselectivein vitro biotransformation of thalidomide using a dual cyclodextrin system in capillary electrophoresis

“…The mixture of diastereomeric 5¢-acetoxy-TD pairs was hydrolyzed as described previously [18]. The compound was heated with p-toluenesulfonic acid in anhydrous methanol to give a mixture of both diastereomers of 5¢-OH-TD, which was confirmed by mass-spectral analysis.…”

Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms

“…Usually, these phthalimide analogs are compounds with different and complex modifications of the phthalimide ring and many of them also contain the glutaramide ring, similarly to thalidomide, the best known phthalimide analog (Chaulet et al, 2011;de Almeida et al, 2007;Mazzoccoli et al, 2012;Miyachi et al, 1997aMiyachi et al, , 1997bStewart et al, 2007Stewart et al, , 2010Teubert et al,1998).…”