Inhibition of Trypsin and Chymotrypsin by Anti-Inflammatory Triterpenoids from Compositae Flowers

Abstract

Taraxastane, oleanane, ursane, lupane, taraxane, cycloartane, dammarane and tirucallane triterpenoids isolated from flowers of Compositae plants have been previously reported to exhibit anti-inflammatory effects and are variously competitive and non-competitive inhibitors of the serine proteases trypsin and chymotrypsin. The general features of those triterpenoids found to be protease inhibitors are having a hydroxy group and an appropriate side chain in the region of the molecule distal to the 3-hydroxy group. However, fatty acid esterification of the triterpenoid 3-hydroxy group can have a marked effect on inhibitor effectiveness. This suggests a possible means of rapid alteration of the plant defensive complement in vivo and of the bioactivity of these anti-inflammatory compounds.

Abbreviations

BAPNA:N _α-benzoyl-DL-arginine-p-nitroanilide

BYPNA:N-benzoyl-L-tyrosine-p-nitroanilide

PKA:cyclic AMP-dependent protein kinase

TLCK:N-α-p-tosyl-L-lysinylchloromethyl ketone (1-chloro-3-tosylamido-7-amino-L-2-heptanone)

TPCK:N-tosyl-L-phenylalanylchloromethyl ketone (L-(1-tosyl-amido-2-phenyl)ethylchloromethyl ketone).

Compositae - triterpenoids - protease inhibitors - trypsin - chymotrypsin

References

• 1 Spence A P, Mason E B. Human Anatomy and Physiology. Benjamin/Cummings London, U.K; 1979: 465-87
• 2 Aderem A, Underhill D M. Mechanism of phagocytosis in macrophages.  Annu. Rev. Immunol.. 1999;  17 593-623
• 3 Luscinskas F W, Gimbrone M A. Endothelial-dependent mechanisms in chronic inflammtory leukocyte recruitment.  Annu. Rev Med.. 1996;  47 679-705
• 4 Momboul J -V, Vanhoutte P M. Kinins and endothelial control of vascular smooth muscle.  Annu. Rev. Pharmacol.. 1995;  35 679-705
• 5 Locati M, Murphy P M. Chemokines and chemokine receptors: biology and clinical relevance in inflammation and AIDS.  Annu. Rev. Med.. 1999;  50 425-40
• 6 Schindler C, Darnell J E. Transcriptional responses to polypeptide ligands : the JAK- STAT pathway.  Annu. Rev. Biochem.. 1995;  64 621-651
• 7 Tracey K J, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target.  Annu. Rev. Med.. 1994;  45 491-503
• 8 Wallach D, Varfolomeev E E, Malinin N L, Golstev Y V, Kovalenko A VC, Boldin  M P. Tumor necrosis factor receptor and Fas signalling mechanisms.  Annu. Rev. Immunol.. 1999;  17 331-67
• 9 Balsinde J, Bolboa M A, Insel P A, Denis E E. Regulation and inhibition of phospholipase A₂ .  Annu. Rev. Pharmacol. Toxicol.. 1999;  39 175-89
• 10 Bohlin L. Structure-activity studies of natural products with anti-inflammatory/immunomodulatory effects. In: Hostettmann K, Marston M, Maillard M, Hamburger M. eds Phytochemistry of Plants Used in Traditional Medicine Clarendon, Oxford, U.K; 1995: 138-63
• 11 Cronstein B N, Weissman G. Targets for anti-inflammatory drugs.  Annu. Rev. Pharmacol.. 1995;  35 449-62
• 12 Geis G S. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect?.  Rheumatol. 26, Suppl.. 1999;  56 31-36
• 13 Komaroff A L. Harvard Medical School Family Health Guide. Simon and Schuster 1999 (Ed.) New York, NY, U.S.A;
• 14 Parnham M J. Antirheumatic agents and leukocyte recruitment.  Biochem. Pharmacol.. 1999;  58 209-15
• 15 Szekanecz Z, Szegedi G, Koch A E. Angiogenesis in rheumatoid arthritis: pathogenic and clinical significance.  J. Investig. Med.. 1998;  46 27-41
• 16 Thorn G W, Adams R D, Braunwald E, Isselbacher K J, Petersdorf R G. Harrison’s Principles of Internal Medicine. 1997, (8th edition) McGraw-Hill New York, NY, U.S.A;
• 17 Cockerill G W, Gamble J R, Vadas M A. Angiogenesis: models and modulatators.  Int. Rev. Cytol.. 1995;  159 113-60
• 18 Paper D H. Natural products as angiogenesis inhibitors.  Planta Medica. 1998;  64 686-95
• 19 Ying Q L, Rinehart A R, Simon S R, Cheronis J C. Inhibition of human leukocyte elastase by ursolic acid. Evidence for a binding site for pentacyclic triterpenes.  Biochem. J.. 1991;  277 521-6
• 20 Wang B H, Polya G M. Selective inhibition of cyclic AMP-dependent protein kinase by amphiphilic triterpenoids and related compounds.  Phytochemistry. 1996;  41 55-63
• 21 Hasmeda M, Kweifio-Okai G, Macrides T, Polya G M. Selective inhibition of eukaryote protein kinases by anti-inflammatory triterpenoids.  Planta Medica. 1998;  65 14-8
• 22 Rajic A, Kweifio-Okai G, Macrides T, Sandeman R M, Chandler D S, Polya G M. Inhibition of serine proteases by anti-inflammatory triterpenoids.  Planta Medica. 2000;  66 206-10
• 23 Yasukawa K, Akihisa T . Anti-inflammatory and antitumor-promoting activities of sterols, triterpene alcohols and their derivatives.  Recent. Res. Devel. in Oil Chem.. 1997;  1 115-25
• 24 Akihisa T, Yasukawa K, Oinuma H, Kasahara Y, Yamanouchi S, Takido M, Kumaki K, Tamura T. Triterpene alcohols from the flowers of Compositae and their anti-inflammatory effects.  Phytochemistry. 1996;  43 1255-60
• 25 Yasukawa K, Akihisa T, Oinuma H, Kasahara Y, Kimura Y, Yamanouchi S, Kumaki K, Tamura T, Takido M. Inhibitory effect of di- and trihydroxy triterpenes from the flowers of Compositae on 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice.  Biol Pharm. Bull.. 1996;  19 1329-31