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Design and synthesis of metabolically stabilized inhibitors of TNF-α production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18 . Structure–activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported.

Discovery of new chemical leads of inhibitors for TNF-α production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-α expression in the liver and spleen of mice. Structure–activity relationships (SARs) are also discussed and full details including the chemistry are reported.

To clarify the mechanisms of nitric oxide (NO)-induced cell death in human neuronal cells, we examined effects of NO donors such as sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on activities of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and poly(ADP-ribose) polymerase (PARP) in human neuroblastoma cell line, SH-SY5Y. SNP-induced [32P]ADP-ribosylation of 113-kDa and 37-kDa proteins in SH-SY5Y cells. Treatment with PARP inhibitors such as 3-aminobenzamide and 1,5-isoquinolinediol partially prevented SNAP-induced cell death of SH-SY5Y. In purified GAPDH (37-kDa protein), SNP- and SNAP-induced enhancement of [32P]ADP-ribosylation, and inhibition of GAPDH activity. These results suggest that NO-induced cell death in human neuroblastoma SH-SY5Y cells possibly involves in covalent modifications such as ADP-ribosylation in PARP and GAPDH.

Discovery of new chemical leads of inhibitors for TNF-alpha production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-alpha expression in the liver and spleen of mice. Structure-activity relationships (SARs) are also discussed and full details including the chemistry are reported.

2-(Acylamino)benzylphosphonic acid 6 derived from an artificial substrate of sphingomyelinase was found to show inhibitory activity of TNF-alpha production. Structural optimization was started with the chemical modification of 6. The discovery of another chemical leads 7, 8, 10 and 16 for the development of structurally new inhibitors of TNF-alpha production is reported.

In human neuroblastoma SH-SY5Y cells, S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO)-donor, caused cell death accompanying p53 expression, nucleosomal DNA fragmentation and cell death. In addition, SNAP-induced cell death and DNA fragmentation were enhanced by pretreatment for 4 days with N6,2'-O-dibutyryl cyclic AMP (diBu-cAMP) or staurosporine, while those were not changed by pretreatment with phorbol 12-myristate 13-acetate (PMA). Protein level of Bcl-2 was decreased by pretreatment with diBu-cAMP or staurosporine, and, on the contrary, the level was increased by pretreatment with PMA. However, these pretreatments did not change Bax protein level and SNAP-induced p53 expression. However, SNAP-treatment did not change protein levels of Bcl-2 and Bax. These results suggest that SNAP-induced p53-sensitive apoptosis is enhanced by Bcl-2 reduction, and that Bcl-2 and Bax may act downstream of p53 in SH-SY5Y cells.

Recent studies suggest that cortical neurons and glial cells undergo apoptosis in Alzheimer's disease (AD). Since the protein p53 is known to induce apoptosis, we assessed p53 in postmortem samples from normal human and AD brains using specific antibody. In AD brains, the amount of p53 in temporal cortex was significantly higher than in controls, and this p53-like immunoreactivity was observed in glial cells. These findings suggest that the p53 may be involved in the apoptosis of glial cells in AD brains, but apoptosis in neurons may occur through a p53-independent pathway.