Triterpenes and Phytosterols as Human Leucocyte Elastase Inhibitors

Abstract

Ten triterpenes and phytosterols β-amyrin, lupeol, lupeol acetate, ursolic acid, friedelin, canophyllol, 29-hydroxy-friedelan-3-one, β-sitosterol, 3-O-β-D-glucopyranosyl-β-sitosterol, 3-O-(6′-O-palmitoyl)-β-D-glucopyranosyl-β-sitosterol, were evaluated as potential inhibitors of human leucocyte elastase (HLE). In this series, lupeol, ursolic acid and canophyllol showed marked HLE inhibitory activity with IC₅₀ values at 1.9 μM, 4.4 μM, and 2.5 μM, respectively. It appeared that HLE inhibition depended on the presence and the orientation of two reactive groups in the tested molecules, distant from 10 - 12 Å, reacting with Arg-217 in S₄-S₅ subsites of the extended substrate-binding domain of HLE, and S₃, respectively.

References

• 1 Muñoz V, Sauvain M, Bourdy G, Callapa J, Bergeron S, Rojas I, Bravo J A, Balderrama L, Ortiz B, Gimenez A, Deharo E. A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. Part I. Evaluation of the antimalarial activity of plants used by the Chacobo Indians.  J. Ethnopharmacol.. 2000;  69 127-37
• 2 Mitaine-Offer A C, Sauvain M, Petermann C, Zèches-Hanrot M. Constituents of the trunk bark of Maquira coriacea .  Fitoterapia.. 2001;  72 841-3
• 3 Mitaine-Offer A C, Sauvain M, Deharo E, Muñoz V, Zèches-Hanrot M. A new diterpene from Tanaecium jaroba .  Planta Med,. 2002;  68 568-9
• 4 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
• 5 Yasukawa K, Takido M, Matsumoto T, Takeuchi M, Nagawa S. Sterol and triterpene derivatives from plants inhibit the effects of a tumor promoter, and sitosterol and betulinic acid inhibit tumor formation in mouse skin two-stage carcinogenesis.  Oncology. 1991;  48 72-6
• 6 Yasukawa K, Akihisa T, Yoshida Z Y, Takido M. Inhibitory effect of euphol, a triterpene alcohol from the roots of Euphorbia kansui, on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin.  J Pharm Pharmacol. 2000;  52 119-24
• 7 Fernández M A, De Las Heras B, García M D, Saénz M T, Villar A. New insights into the mechanism of action of the anti-inflammatory triterpene lupeol.  J Pharm Pharmacol. 2001;  53 1533-9
• 8 Navarro A, De Las Heras B, Villar A. Anti-inflammatory and immunomodulating properties of a sterol fraction from Sideritis foetens Clem.  Biol Pharm Bull. 2001;  24 470-3
• 9 Shimizu M, Tomoo T. Anti-inflammatory constituents of topically applied crude drugs. V. Constituents and anti-inflammatory effect of aoki, Aucuba japonica Thunb.  Biol Pharm Bull. 1994;  17 665-7
• 10 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 Med. 2000;  66 206-10
• 11 Rajic A, Akihisa T, Ukiya M, Yasukawa K, Sandeman R M, Chandler D S, Polya G M. Inhibition of trypsin and chymotrypsin by anti-inflammatory triterpenoids from Compositae flowers.  Planta Med. 2001;  67 599-604
• 12 Liu J. Pharmacology of oleanolic acid and ursolic acid.  J Ethnopharmacol. 1995;  49 57-68
• 13 Subbaramaiah K, Michaluart P, Sporn M B, Dannenberg A J. Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells.  Cancer Res. 2000;  60 2399-404
• 14 Ying Q L, Rinehart A R, Simon S R, Cheronis J C. Inhibition of human leucocyte elastase by ursolic acid.  Biochem J. 1991;  277 521-6
• 15 Safayhi H, Rall B, Sailer E R, Ammon H PT. Inhibition by boswellic acids of human leukocyte elastase.  J Pharmacol Exp Ther. 1997;  281 460-3
• 16 Bode W, Meyer E J r, Powers J C. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors.  Biochemistry. 1989;  28 1951-63
• 17 Powers J C. Synthetic elastase inhibitors: prospects for use in the treatment of emphysema.  Am Rev Resp Dis. 1983;  127 S54-8
• 18 Cook L, Ternai B. Similar binding sites for unsaturated fatty acids and alkyl 2-pyrone inhibitors of human sputum elastase.  Biol Chem Hoppe-Seyler. 1988;  369 627-31
• 19 Bieth J, Spiess B, Wermuth C G. The synthesis and analytical use of a highly sensitive and convenient substrate of elastase.  Biochem Med. 1974;  11 350-7
• 20 Ashe B M, Zimmerman M. Specific inhibition of human granulocyte elastase by cis-unsaturated fatty acids and activation by the corresponding alcohols.  Biochem Biophys Res Commun. 1977;  75 194-9
• 21 Hornebeck W, Moczar E, Szecsi J, Robert L. Fatty acid peptide derivatives as model compounds to protect elastin against degradation by elastases.  Biochem Pharmacol. 1985;  34 3315-21