Cytokine modulators

Hogaboam, C.M., Snider, D.P. and Collins, S.M. (1997) Cytokine modulation of T-lymphocyte activation by intestinal smooth muscle cells. Gastroenterology 112, 1986-1995. 

Alexander, J., Samples, J., and Acott, T., Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression, Curr. Eye Res., 17, 276, 1998. 

Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007 120 150-155. 

Smith SR, Denhardt G, Terminelli C (2002) A role for histamine in cytokine modulation by the adenosine A3 receptor agonist 2-C1-IB-MECA. Eur J Pharmacol 457 57-69 Tilley SL, Wagoner VA, Salvatore CA, Jacobson M, Koller BH (2000) Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells. J Clin Invest 105 361-367... 

Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 1994 152 4149-4156. 

Lotan M, Solomon A, Ben-Bassat S, Schwar tz M (1994) Cytokines modulate die inflammatory response and change permissiveness to neuT orial adhesion in mjur ed mammalian ceritr al nervous system. Exp Neurol 126 284-290. 

More than 100 NSAIDs are marketed or at an advanced stage of development worldwide. Their use is constantly expanding and the search for more efficacious and better-tolerated compounds is still being pursued, and has received renewed impulse with studies on selective inhibitors of cyclo-oxygenase type 2 (COX-2), nitric oxide-releasing NSAIDs, peroxidase inhibitors, enantiomers of already known NSAIDs, NSAIDs associated with zwitterionic phospholipids, and cytokine-modulating antirheumatic drugs. 

Breedveld F. Tenidap a novel cytokine-modulating antirheumatic dmg for the treatment of rheumatoid arthritis. Scand J Rheumatol Suppl 1994 100 31 4. 

Wylie G, Appelboom T, Bolten W, Breedveld FC, Feely J, Teeming MR, Le Loet X, Manthorpe R, Marcolongo R, Smolen J. A comparative study of tenidap, a cytokine-modulating anti-rheumatic drug, and diclofenac in rheumatoid arthritis a 24-week analysis of a 1-year clinical trial. Br J Rheumatol 1995 34(6) 554-63. 

Several non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to interfere with the natriuretic effects of thiazides (SED-11, 423). A similar interaction is seen with tenidap, an antiarthritic cytokine modulating drug (46). The salt-retaining properties of the NSAIDs probably play the central role in this interaction. 

Bilyk, N. and Holt, P.G. (1994). Cytokines modulate the immunosuppressive phenotype of pulmonary alveolar macrophages via regulation of nitric oxide production (submitted). 

The enantioselective total synthesis of the cytokine modulator (-)-cytoxazone using a syn-stereoselective aldol addition and a Curtius rearrangement as key steps was described by J.A. Marco et al. The key intermediate acid was treated with DPPA and triethylamine in toluene at reflux. This step furnished the oxazolidinone directly and in good yield through an in situ capture of the isocyanate group by the free secondary alcohol functionality. Removal of the protecting group led to the formation of the natural product. 

Cytoxazone is a novel cytokine modulator. The total synthesis of this natural product and its enantiomer was accomplished by S. Sugiyama. The 3-amino-1,2-propanediol moiety was synthesized by a Petasis boronic acid-Mannich reaction between DL-glyceraldehyde, (R)-1-(1-naphthyl)ethylamine and 4-methoxyphenylboronic acid to provide a 1 1 mixture of the diastereomeric products. The diastereomers could be separated at a later stage in the synthesis and transformed into (-)- and (+)-cytoxazone. 

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