P57. IMMUNOMODULATORY PROPERTIES OF SELECTED NATURAL AND CHEMICALLY MODIFIED LIGNANS Juraj Harmatha 1, Eva Kmoníčková 2 and Zdeněk Zídek 2 1
Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Laboratory of Natural products. 166 10 - Prague 6, Czech Republic;
[email protected] 2 Institute of Experimental Medicine, Academy of Sciences, Lab. of Immunopharmacology; 142 20 - Prague 4, Czech Republic;
[email protected]
Our interest to study lignans originated from our wish to use their rich structural variability and their close biogenetic relation with other phenylpropanoids for solving certain problems in the taxonomy of the order Cupresales (Erdtman & Harmatha, 1979). Later on, our interest turned more towards their insect feeding regulatory activity (Nawrot & Harmatha, 1994, Harmatha & Nawrot, 2002) and insect antihormonal effect, especially their assumed antagonistic influence reflecting their binding affinity to the ligand-binding site of the ecdysteroid receptor (Harmatha & Dinan, 2003). Now we are interested to learn more on the immunomodulatory properties of lignans assessed in our well-established bioassay (Zídek et al., 2003). Effects of dibenzylbutane type lignans on immunobiological responses triggered by lipopolysaccharide and interferon- was tested under in vitro conditions using murine resident peritoneal macrophages. Namely, production of nitric oxide and secretion of cytokines and chemokines were investigated. The series of test agents encompassed lignan lactones (1, 3, 5, 8), hemiacetals (4), ethers (6) and alcohols (2, 7), comparing with the structurally related aryltetraline type lactone podophyllotoxin (3), all with methoxy- and/or methylenedioxysubstituents. HO H O
O O
CH3O
O O H
H
O
OCH3 OCH3
CH3O
1
CH3O
OCH3 OCH3
H O
O
O
OH OH
O
O
O H
R
H
O
O
O
OCH3 OCH3
HO
H
O
O
3
2
H O H
O
OH OH
O O H
H
H
O
O
O
4. R = H, OH 5. R = O
6
7
O
CH3O O RO
H
OCH3 OCH3 8. R = Glu
Relation between the molecular structure and immunobiological activity was investigated, and implication of the functional groups was assessed. Majority of the tested compounds represent natural substances. Yatein (1) was isolated from the heartwood of Libocedrus yateensis (Erdtman & Harmatha, 1979), (-)-cubebin (4) from seeds of Piper cubeba (Harmatha & Nawrot, 2002) and tracheloside (8) from the medicinal plant Leuzea carthamoides (Harmatha & Nawrot, 2002). Hinokinin (5) and the structural analogues 2, 6, 7 and were prepared from yatein or cubebin by simple chemical transformations (Harmatha et al., 1982, Harmatha & Nawrot, 2002). Podophyllotoxin (3) was obtained from commercially available sources. Natural lignan lactones possessing methoxy and/or methylenedioxy substituents showed a considerable high activity with a potency to be effective
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in assumed therapeutic exploitation. The highest activity was recorded for lignan lactones and diols. Similar activity was examined also in the case of structurally related phenylpropanoid monomers (containing identical substituents). The maximum activity has been achieved by the lignan lactone hinokinin (5), revealing a specific course of action. Selected data are shown in the figures.
Supression of NO production (24-h culture)
500
Supression of chemokine RANTES secretion (5-h culture) Control
400
(1) (2) (3) (4) (5) (6) (7) (8)
75 (1) yatein
pg/mL
NO (% of Control i.e. IFN+LPS)
100
(2) tetrahydroyatein (3) podophyllotoxin
50
300
200
(4) cubebin (5) hinokinin (6) deoxycubebin
25
IFN+LPS
yatein tetrahydroyatein podophyllotoxin cubebin hinokinin deoxycubebin dihydrocubebin trachelosid
100
(7) dihydrocubebin
(8)
(7)
(6)
(5)
(4)
1000
(3)
100 Compounds (µM)
(2)
10
(1)
1
IFN+LPS
0
0
Control
(8) trachelosid
Compounds 200 µM
References: Erdtman H., Harmatha J. (1979) Phenolic and terpenoid heartwood constituents of Libocedrus yateensis. Phytochemistry 18: 1495-1500. Harmatha J., Buděšínský M., Trka A. (1982) The structure of yatein. Determination of the positions and configurations of benzyl groups in lignans of the 2,3-dibenzoyl type. Collect. Czech. Chem. Commun. 47: 644-663. Harmatha J., Dinan L.: (2003) Biological activities of lignans and stilbenoids associated with plant-insect chemical interactions. Phytochemistry Reviews 2: 321-330. Harmatha J., Nawrot J.: (2002) Insect feeding deterrent activity of lignans and related phenylpropanoids with methylenedioxy (piperonyl) structure moiety. Ent. Exp. Appl. 104/1: 51-60. Nawrot J., Harmatha J. (1994) Natural products as antifeedants against stored products insects. Review article. Postharvest News and Information 5/2: 17N-21-N. Zídek Z., Potměšil P., Kmoníčková E., Holý A. (2003) Immunobiological activity of N-[2-(phosphonomethoxy) alkyl] derivatives of N6-substituted adenines, and 2,6-diaminopurines. Eur. J. Pharmacol. 475: 149-159. Supported by GAČR grants No. 203/04/0298, No. 305/03/1470, in part also by research projects AV0Z4055905 and AV0Z5008914.
Reprinted from: POLYPHENOLS COMMUNICATIONS 2004 XXII International Conference on Polyphenols 25-28 August 2004, Helsinki – Finland Editors: A. Hoikkala, O. Soidinsalo, K. Wähälä Printing: Gummerus Printing, Jyväskylä, Finland, 2004 ISBN 952-10-1977-8
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