Cell Type-/Inducer-Specific Bidirectional Regulation by Thalidomide and Phenylphthalimides of Tumor Necrosis Factor-Alpha Production and Its Enantio-Dependence

Stereoselective Synthesis of (R)‐3‐Methylthalidomide by Piperidin‐2‐one Ring Assembly Approach

“…It has also been reported that regulation of TNF‐ α production by thalidomide analogs is specific to cell type and the inducer. It is well known that only ( S )‐3‐methylthalidomide increases TNF‐α production in the 12‐ O ‐tetradecanoylphorbol 13 acetate/human leukemia HL‐60 assay system, while the ( R )‐isomer is more active than the ( S )‐isomer of 3‐methylthalidomides in the okadaic acid/HL‐60 assay system …”

“…The methodology for the stereoselective synthesis of 3‐methylthalidomide enantiomers is not yet explored and the major limitation associated with previously reported methods is the formation of a racemic mixture which requires chiral purification to obtain the particular enantiomer of 3‐methylthalidomide . The biological activity including teratogenicity of 3‐methylthalidomide derivatives are reported to exhibit enantiodependent bidirectional regulatory effects on TNF‐ α production . Therefore, efforts were made to develop stereoselective synthesis of nonracemizable 4‐trifluoromethyl substituted and 2‐oxetano thalidomides (Fig.…”

Interaction of a Biological Response Modifier with Proteins

“…PPARα has a large Y-shaped ligand-binding pocket of approximately 1300 to 1400Å 3 [40]. Based on the structures of FA (44) and KCL (45), as well as the shape of the ligand-binding pocket of PPARα and the potential usefulness of the 3,3-diphenylmethane skeleton as a scaffold for PPARα ligands, the 3,3-diphenylpentane derivative DPPK-01 (46) and a diphenylcyclohexane derivative, DPHK-01 (47), have been designed, both of which possess a butyric acid moiety (Fig. 8-11).…”

“…8-11). The butyric acid moiety was chosen to mimic the carboxylic acid side chain of KCL (45), and a cyclohexyl moiety was adopted to provide a rigid Y-shape of the molecule, as the carbonyl group of FA (44) does. In the transcriptional activation reporter gene assay, DPHK-01 (47) shows more potent agonistic activity for transcriptional activation of PPARα than does FA (44).…”

“…Studies on structural development of thalidomide (48) have resulted in very potent bidirectional TNF-α production regulators [e.g., PP-33 (49) and FPP-33 (50)] and complete separation of the bidirectionality [pure inhibitors (e.g., R-FPTP (51) and R-FPTN (52)] and pure enhancers [e.g., S-FP13P (53)] (Fig. 8-13) [1][2][3]7,8,44,45]. Some of the TNF-α production regulators prolong the life span of mice with cachexia induced by lipopolysaccharide injection and show more potent anti-angiogenic activity than that of thalidomide (48) at a much lower dose than thalidomide (48) [2].…”