alpha-asarone and Weight-Gain

In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Binding Sites; Catalytic Domain; Cholesterol; Cholesterol, LDL; Crystallography, X-Ray; Enzyme Activation; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Inbred ICR; Molecular Conformation; Molecular Docking Simulation; Phenols; Protein Binding; Triglycerides; Weight Gain

A series of homologues of alpha-asarone (1), containing variable size and functionality on the side chain attached to the aromatic ring, has been subjected to a study of structure-activity relationship. For most of the prepared derivatives, either with a carbonyl (8a-8e), a hydroxy group (9a-9e), or with a conjugated double bond (10a-10d), significant effects on serum lipoprotein cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were displayed. The results showed an enhancement of the hypocholesterolemic activity as the length of the chain is decreased. Theoretical conformational and electrostatic potential analyses of I and olefins 10 suggest unfavorable steric interactions in the bulky superior side-chain homologues as the deactivating biological effect.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Cholesterol, Dietary; Crystallography, X-Ray; Diet; Eating; Hypolipidemic Agents; Male; Mice; Models, Molecular; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Weight Gain

The embryotoxicity and teratogenicity of alpha-asarone were investigated in mice. The drug was dissolved in corn oil, and administered daily, by gavage, on days 6 to 15 of gestation, at 0 (controls), 5, 15, 30 and 60 mg/kg. Fetuses were removed on day 18 by caesarean section and examined using routine teratological methods. A significant maternal toxicity was observed in dams given 60 mg/kg, as indicated by a reduced weight gain. An embryolethality was observed in 15, 30 and 60 mg/kg treated groups. In addition, the highest dose induced fetal malformations, mainly represented by hydrocephaly, extra-ribs, clubfeet and cleft lips.

Topics: Abnormalities, Drug-Induced; Allylbenzene Derivatives; Animals; Anisoles; Carcinogens; Female; Fetal Death; Gestational Age; Mice; Pregnancy; Weight Gain