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

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

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
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants from Found of Alex Grass Center for Drug Design and Synthesis at the Hebrew University and The Yedidut Foundation Mexico. S. S., A.H.Y. and J.K. are a members of the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem. A.G. received a fellowship award from the Diabetes Research Center of the Hebrew University of Jerusalem.

Funding

This work was supported by grants from Found of Alex Grass Center for Drug Design and Synthesis at the Hebrew University and The Yedidut Foundation Mexico. S. S., A.H.Y. and J.K. are a members of the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem. A.G. received a fellowship award from the Diabetes Research Center of the Hebrew University of Jerusalem.

FundersFunder number
Diabetes Research Center of the Hebrew University of Jerusalem
Hebrew University of Jerusalem

    Keywords

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

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