ABSTRACT
Tuberiferin, 6-epi-tuberifelin, dehydrobrachylaenolide and two series of eudesmanolides, eudesmane-12,6 α-lactones and eudesmane-12,6ß-lactones, were synthesized for the studies of the structure-activity relationships to explore novel anti-inflammatory, anti-cancer and crop disease prevention agents. The anti-inflammatory activities were tested by the inhibitory on the induction of inter-cellular adhesion molecule (ICAM-1), the permeation of leucocyte into inflammatory air pouch of murine, the killing function of cytotoxic T-lymphocytes (CTL), production of IL-1; The anti-cancer activities were established on the cytotoxic activities to six kinds of cell lines (P388, CCRF-CEM, VA-13, HepG2, QG-56, and WI-38). Results showed that Dehydrobrachylaenolide (an exo-endo cross conjugated dienone and α-methylene γ-lactone) was the most effective compound inhibiting ICAM-1 (IC50 3.0 µM) and the cell line VA-13 (IC50 0.45 µM); Compound 20 with an α-bromo-ketone moiety embraced the most potent inhibitory activity towards the permeation of leucocyte into inflammatory air pouches of murine in vivo (inhibitory ratio 54% at 10 mg); Compound 25 with an α-bromo-ketone and α-methylene trans-γ-lactone) showed the most significant inhibitory activity on the killing function of CTL (IC50 18 µM), as well as the cell lines of CCRF-CEM (IC50 1.1 µM) and P388 (IC50 1.21 µM) ; Tuberiferin (an α,ß-unsaturated ketone and α- methylene γ-lactone) was on the top effective inhibitory on the production of IL-1; Compounds 19 with an α-bromo-ketone and α-methylene cis-γ-lactone exhibited the most potent inhibitory of QG-56 (IC50 12.5 µM); Compound 29 with an α-bromo-α,ß-unsaturated ketone and α-methylene γ-lactone) showed significant inhibitory for HepG2 (IC50 1.23 µM) , though potently inhibited WI 38 (IC50 0.31 µM) as well. A conclusion may be reached that the α-Methylene γ-lactone moiety, exo-endo cross conjugated dienone moiety, and α-bromo-ketone withα-methylene moiety might be essential for eudesmanolides in the expression of their anti-inflammatory, anti-tumour biological activities. Similarly, the above mentioned key moieties are also responsible for the preventive activity of crop disease controlling.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Sesquiterpenes/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Intercellular Adhesion Molecule-1/genetics , Molecular Structure , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Structure-Activity Relationship , T-Lymphocytes, Cytotoxic/drug effectsABSTRACT
A reliable method was developed for the synthesis of cis-fused alpha-methylene gamma-lactones via alpha-methyl gamma-lactones. Bromination of alpha-methyl gamma-lactones with LDA/CBr(4) or TMSOTf/PTAB and successive dehydrobromination with DBU or TBAF of the resulting alpha-bromo-alpha-methyl gamma-lactones gave the desired alpha-methylene gamma-lactones in high yield. This method was successfully applied to the synthesis of biologically active compounds. alpha-Methylene gamma-lactone derivatives 1c, 2c, 4c, and 17 showed cell growth inhibitory activity to P388 lymphocytic leukemia. They also showed significant activities to crop diseases. Thus, alpha-methylene gamma-lactone 1c showed preventive activity in controlling scab of apple caused by Venturia inaequalis. alpha-Methylene gamma-lactones 2c, 4c, 17, and 18 also showed significant preventive activities in controlling damping off of cucumber caused by Pythium aphanidermatum.
Subject(s)
Antifungal Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Bromides/chemistry , Combinatorial Chemistry Techniques , Lactones/chemical synthesis , Animals , Antifungal Agents/analysis , Antifungal Agents/pharmacology , Antineoplastic Agents/analysis , Antineoplastic Agents/pharmacology , Cucumis sativus , Drug Screening Assays, Antitumor , Lactones/analysis , Lactones/pharmacology , Leukemia P388 , Mice , Molecular Structure , Oryza , Plant Diseases , Pythium/drug effects , Rhizoctonia/drug effects , Stereoisomerism , TriticumABSTRACT
Methodology for synthesis of exo-endo cross-conjugated dienones with trans- and cis-decalin systems has been reported. Bromination of the silyl enol ether of alpha'-methyl alpha,beta-unsaturated ketones with PTAB and successive dehydrobromination of the resulting alpha'-bromo-alpha'-methyl alpha,beta-unsaturated ketones under three conditions (DBU/PhH; TBAF/THF; Li(2)CO(3), LiBr/DMF) gave the desired exo-endo cross-conjugated dienones in good yield. This method was applied to the syntheses of dehydrobrachylaenolide (1), isodehydrochamaecynone (5c), and trans-isodehydrochamaecynone (11) starting from tuberiferine (7), chamaecynone (5a), and trans-chamaecynone (9). Eudesmanolides possessing an alpha-methylene gamma-lactone moiety, i.e., 1, 7, and 13, exhibited significant inhibitory activity toward the induction of the intercellular adhesion molecule-1 (ICAM-1). Compound 1 showed greater activity than 7 and 13. All compounds possessing an ethynyl group, 5d, 9, 11, and 14, showed the same degree of termiticidal activity, and the exo-endo cross-conjugated dienone structure in 11 had no influence on the activity.
