Shorong-Shii Liou

γ‐Pyrone Compounds as Potential Anti‐cancer Drugs

Abstract— The γ‐pyrones, artomunoxanthotrione epoxide, cyclocommunol, cyclomulberrin, and cyclocommunin exhibited potent inhibition of human PLC/PRF/5 and KB cells in‐vitro. Dihydroisocycloartomunin showed significant and potent inhibition of human PLC/PRF/5 and KB cells in‐vitro, respectively. Cyclomorusin, dihydrocycloartomunin and artomunoxanthone showed significant inhibition of KB cells in‐vitro. Based on the above finding and the reported antileukaemic activity of xanthone psorospermin, a series of natural γ‐pyrones was prepared and the inhibition of human PLC/PRF/5 and KB cells in‐vitro was measured. Structure‐activity analysis indicated the epoxide group substituted at 3‐hydroxyl and 2,6‐; 3,6‐; and 3,5‐dihydroxyl xanthone enhanced the anti‐tumour activity. The epoxide group substituted at the 6‐hydroxyl group of 1,6‐dihydroxyxanthone did not show anti‐tumour activity.

Corni fructus as the major herb of Die-Huang-Wan for lowering plasma glucose in Wistar rats

Die‐Huang‐Wan is a mixture of six herbs used to lower plasma glucose by increasing insulin secretion in normal rats. Die‐Huang‐Wan contains the herbs dioscorea (Dioscoreae rhizoma), cornus (Corni fructus), alisma (Rhizoma alismatis), holelen (Poria), rehmannia (Rehmanniae radix) and tree peony bark (Moutan radicis cortex). The present study was designed to clarify the major herb contributing to the plasma glucose‐lowering action of Die‐Huang‐Wan in rats. A decrease in plasma glucose was not observed in Wistar rats treated with the cornus‐deleted formula of Die‐Huang‐Wan; however, the action was retained in the other herb‐deleted formulas containing cornus. In normal rats, the decrease in plasma glucose and increase in plasma insulin concentrations were dependent on the dose of cornus and were similar to those produced by Die‐Huang‐Wan. Treatment of Wistar rats with each of the other five herbs separately did not result in a decrease in plasma glucose. Moreover, the increase in plasma insulin or reduction in plasma glucose resulting from cornus treatment was blocked by atropine or 4‐diphenylacetoxy‐N‐methylpiperidine methiodide mustard, indicating mediation of muscarinic M3 receptors similar to that caused by Die‐Huang‐Wan. These results suggest that cornus is the major contributor to the plasma glucose‐lowering action in Die‐Huang‐Wan in normal rats.

Xanthonolol: a calcium channel and beta-adrenoceptor blocker with vasodilating properties.

1. Xanthonolol (0.1-5.0 mg/kg, i.v.) reduced the blood pressure, heart rate, and L-isoproterenol (0.05 microgram/kg, i.v.)-induced tachycardia in rats. 2. In the isolated guinea-pig right atrium, xanthonolol (10(-6)-3 x 10(-4) M) produced long-lasting negative, inhibited L-isoproterenol-induced positive chronotropic effects, prevented the rate-increasing effects of increased extracellular Ca2+ (3.0-9.0 mM), and inhibited Ca2+ (3.0-9.0 mM)-induced heart rate-increase. 3. In the isolated guinea-pig thoracic aorta, the contractions induced by CaCl2 (0.1-5.0 mM) were inhibited by xanthonolol (10(-6)-10(-4) M). 4. Xanthonolol is suggested to have a calcium channel and beta adrenergic blocking effect with vasodilating properties.

Synthesis and anticancer evaluation of certain γ-aryloxymethyl-α-methylene-γ-phenyl-γ-butyrolactones

Certain gamma-aryloxymethyl-alpha-methylene-gamma-phenyl- gamma-butyrolactones were synthesized and evaluated for their anticancer activity. These compounds demonstrated a strong growth inhibitory activity against leukemia cell lines but are relatively inactive against non-small cell lung cancers and CNS cancers. The anticancer potency for aryl portion is in an order of quinoline > 8-hydroxyquinoline > 2-methylquinoline >> naphthalene >> benzene.

Synthesis and Cytotoxic Evaluation of Potential Bis-Intercalators: Tetramethylenebis(oxy)- and Hexamethylenebis(oxy)-Linked Assemblies Consisting of Flavone, Xanthone, Anthraquinone, and Dibenzofuran

In a search for potential inhibitors of solid-tumor growth, certain alkanediylbis(oxy)-linked assemblies were synthesized and evaluated for their cytotoxicity as bis-intercalators. Symmetrical assemblies 1b–12b were synthesized from their respective Aryl-OH and either dibromobutane or dibromohexane, while unsymmetrical ones 13–15 were prepared from Aryl1-OH and either Aryl2-O-(CH2)4Br or Aryl2-O-(CH2)6Br. These bis-intercalators were inactive against the growth of leukemia cells. However, some of them were active against the growth of certain solid tumors such as HOP-62, HOP-92 (non-small-cell lung cancer), SF-265, SNB-75, U251 (CNS cancer), A498 (renal cancer), and HS578T (breast cancer). Among them, [hexane-1,6-diylbis(oxy)bis(4,1-phenylene)]bis[4H-1-benzopyran] (6b) was especially active against the growth of all CNS cancer cell lines and also the growth of A498, HOP-62, and HOP-92 with GI50 values of 17.0, 20.0, and 21.8 μM, respectively.

Synthesis and Antiplatelet Effects of ω-Aminoalkoxylxanthones

A series of ω‐aminoalkoxylxanthones were synthesized and tested in‐vitro for their ability to inhibit aggregation of rabbit washed platelets and human platelet‐rich plasma (PRP) induced by various inducers. Nine of these compounds showed more potent antiplatelet effects than natural norathyriol tetraacetate on collagen‐induced aggregation. The various ω‐aminoalkoxyl side chains of the synthesized compounds modified the antiplatelet effects. All the compounds tested in human PRP showed significant inhibition of secondary aggregation induced by adrenaline, suggesting that the antiplatelet effects of these compounds is mainly due to an inhibitory effect on thromboxane formation. These compounds at high concentration also cause vasorelaxing action in rat thoracic aorta.

Synthesis, antiplatelet and vasorelaxing effects of monooxygenated flavones and flavonoxypropanolamines

A series of flavones and flavonoxypropanolamines were synthesized and tested in‐vitro for their ability to inhibit aggregation of washed rabbit platelets and human platelet‐rich plasma (PRP), and for vasoconstriction of rat thoracic aorta. The various substituted positions of the hydroxyl group in flavone ring B and the various oxypropanolamine side chains substituted at position C‐2′ of flavone modified the antiplatelet effects. All the compounds tested in human PRP showed significant inhibition of secondary aggregation induced by adrenaline (epinephrine), suggesting that the antiplatelet effect of these compounds is mainly due to an inhibitory effect on thromboxane formation. Compounds 11 and 12 also had potent vasorelaxant effects in rat thoracic aorta. Phenylephrine‐ and high‐K+‐induced 45Ca2+ influx in aorta were both inhibited by the selected compound 11. This result indicates that the inhibitory effect of 11 on the contractile response caused by high‐K+ medium and noradrenaline (norepinephrine) in rat thoracic aorta is mainly due to inhibition of Ca2+ influx through both voltage‐dependent and receptor‐operated Ca2+ channels.