Synthesis and characterization of new and potent α-lipoic acid derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 5; pp. 1183 - 1190
• Main Authors: GRUZMAN, Arie, HIDMI, Adel, KATZHENDLER, Jehoshua, HAJ-YEHIE, Abdalla, SASSON, Shlomo
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.03.2004
• Subjects: Animals; Biological and medical sciences; Biological Transport - drug effects; Blood Glucose - drug effects; Cell Line; Diabetes Mellitus, Type 2 - drug therapy; Esters - chemical synthesis; Esters - pharmacokinetics; Esters - pharmacology; General and cellular metabolism. Vitamins; Glucose - metabolism; Kinetics; Medical sciences; Mice; Mice, Inbred C57BL; Muscle, Skeletal - metabolism; Pharmacology. Drug treatments; Rats; Streptozocin; Structure-Activity Relationship; Thioctic Acid - chemical synthesis; Thioctic Acid - pharmacokinetics; Thioctic Acid - pharmacology; Type 2 diabetes; Endocrinopathy; Five membered ring; Rat; Biological transport; Glucose; Ester; Organic disulfide; Hypoglycemic agent; Structure activity relation; Subcutaneous administration; Chemical synthesis; Acylate; Rodentia; Striated muscle; In vitro; In vivo; Vertebrata; Chemotherapy; Sulfur heterocycle; Experimental disease; Mammalia; Treatment; Mouse; Animal; Carboxamide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2003.11.025

alpha-Lipoic acid [5-[1,2]-dithiolan-3-yl-pentanoic acid (LA)] is a natural antioxidant and cofactor of several enzymes. It increases the glucose transport activity in skeletal muscles and adipocytes in a non-insulin dependent manner. Therefore, LA is widely used in Type 2 diabetic patients as an oral auxiliary drug. However, large doses of LA (0.8-1.8 gr/day p.o.) are required due to its unfavorable pharmacokinetic parameters. In order to improve these parameters, we synthesized ester and amide LA derivates. Two of these newly synthesized compounds, 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]dithiolan-3yl-pentanoylamino)-propyl]-amide (AN-7) and 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]-dithiolan-3yl-pentanoyloxy)-propyl ester (AN-8) augmented the rate glucose transport in myotubes in culture in the absence or presence of insulin. Their potency was 12-fold higher than that of the parent compound; their maximal stimulatory effect was 1.5-fold higher than that of LA. When tested in vivo in streptozotocin-diabetic C57/Black mice, AN-7 (10 mg/kg/day for 2 weeks, s.c.) reduced blood glucose level by 39% while a higher dose of LA (50 mg/kg/day for 2 weeks, s.c.) lowered it by 30%. These results indicate that AN-7 is more potent than LA in augmenting glucose transport in skeletal muscles and reducing blood glucose in diabetic animals.