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

Arie Gruzman, Adel Hidmi, Jehoshua Katzhendler*, Abdalla Haj-Yehie, Shlomo Sasson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

α-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 po) 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, sc) reduced blood glucose level by 39% while a higher dose of LA (50 mg/kg/day for 2 weeks, sc) 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.

Original languageEnglish
Pages (from-to)1183-1190
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number5
DOIs
StatePublished - 1 Mar 2004

Keywords

  • Antihyperglycemic drugs
  • Glucose transport
  • α-Lipoic acid, Prodrug

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