dihydroisosteviol and isosteviol

Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (K

Topics: Animals; Diterpenes, Kaurane; Drug Discovery; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Partial Thromboplastin Time; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thrombin; Thrombosis

Isosteviol (1) has been reported to exhibit moderate vasorelaxant activity. In order to enhance the bioactivity of this compound, chemical modification of 1 to the dihydro analog, ent-16β-hydroxybeyeran-19-oic acid (2), was undertaken. Compound 2 was then converted to the corresponding acetate derivative, ent-16β-acetoxybeyeran-19-oic acid (3). Biotransformation of compounds 1-3 by the fungus Cunninghamella echinulata NRRL 1386 was investigated and the metabolites 4-9 were obtained. The substrates and their metabolites were subjected to in vitro rat aorta relaxant activity evaluation. The metabolite 4, ent-7α-hydroxy-16-ketobeyeran-19-oic acid, exhibited the most highly potent activity, with EC50 of 3.46 nM, whereas the parent compound 1 showed relatively low activity (EC50 57.41 nM). A 17-fold increase in vasorelaxant activity of the analog 4 relative to compound 1 is of particular significant. Compound 4 exerted vasorelaxant activity at particularly low concentration and the vasorelaxant profile reached maximum at relatively low concentration, especially when compared with acetylcholine, the positive control.

Topics: Animals; Aorta; Cunninghamella; Diterpenes, Kaurane; Dose-Response Relationship, Drug; Male; Molecular Conformation; Muscle, Smooth; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Vasodilator Agents

By means of functional interconversions in ring D of the tetracyclic diterpene isosteviol (ent-16-ketobeyeran-19-oic acid 1), various 15- and 16-substituted isosteviol derivatives were stereoselectively prepared. The cytotoxic activities in vitro of these new isosteviol derivatives were investigated, and some of them showed noteworthy activities against B16-F10 melanoma cells.

Topics: Animals; Cell Line, Tumor; Chemistry, Pharmaceutical; Computer Simulation; Crystallography, X-Ray; Diterpenes, Kaurane; Drug Design; Drug Screening Assays, Antitumor; Melanoma, Experimental; Mice; Models, Chemical; Molecular Structure; Stereoisomerism; Structure-Activity Relationship

Considerable interest has been attracted in isosteviol and its derivatives because of their large variety of pharmacological activities. In this project, a series of novel compounds containing hydroxyl, hydroxymethyl group and heteroatom-containing frameworks fused with isosteviol structure were synthesized and evaluated as alpha-glucosidase inhibitors, aimed at clarifying the structure-activity correlation. The results indicated that these isosteviol derivatives were capable of inhibiting in vitro alpha-glucosidase with moderate to good activities. Among them, indole derivative 15b exhibited the highest activities and thus may be exploitable as a lead compound for the development of potent alpha-glucosidase inhibitors.

Topics: Crystallography, X-Ray; Diterpenes, Kaurane; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Hydroxylation; Indoles; Models, Molecular; Molecular Structure; Stereoisomerism; Structure-Activity Relationship