23297-34-9Relevant articles and documents
Synthesis and immunological activity of water-soluble thalidomide prodrugs
Hess, Sonja,Akermann, Michaela A.,Wnendt, Stephan,Zwingenberger, Kai,Eger, Kurt
, p. 1279 - 1291 (2007/10/03)
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.
A systematic entropy relationship for the general-base catalysis of the deprotonation of a carbon acid. A quantitative probe of transition-state solvation
Bunting, John W.,Stefanidis, Dimitrios
, p. 779 - 786 (2007/10/02)
The general-base-catalyzed deprotonation of a carbon acid, the l-methyl-4-(phenylacetyl)pyridinium cation (pKa = 9.02 at 25 °C), has been investigated for 32 general-base catalysts (25 amines and seven phenoxide ions) in aqueous solution. Amines give a generally scattered Bronsted plot; ring-substituted benzylamines have ?= 0.52, and ring-substituted phenoxides have ?= 0.60, with the phenoxides being more reactive than amines of similar basicity. The temperature dependences of the general-base-catalyzed deprotonation of this carbon acid have been measured over the range 15-45 °C for 12 base catalysts (eight primary, secondary, and tertiary amines; 4-(dimethylamino)pyridine; two phenoxide ions; hydroxide ion). The entropies of activation for these deprotonations show a clean curvilinear dependence upon the entropies of protonation of these base species, with the hydroxide ion being the only significant deviant from this relationship. This observation quantitatively establishes the importance of solvation effects as the major source of deviations that are commonly observed in Bronsted relationships for general-base-catalyzed processes.
