Inositol Glycans and Diabetes

Binding of insulin to the cell-surface insulin receptor of insulin-sensitive cells results in the release of small inositol-containing phosphorylated oligosaccharide (IPGs) to the extracellular medium. Isolated IPGs have been found to be competent to activate insulin-sensitive cell in a manner similar to insulin, even without insulin.1,2 These observations have lead to the hypothesis that IPGs are second messengers of insulin action. Since the IPGs are active in a post-receptor fashion, they are of interest for their potential in the treatment of type II diabetes mellitus. However, neither the precise structures of these materials, nor their chemical target within the cell, has yet been fully elucidated.

synthetic IGs

We are engaged in a program of chemical synthesis of IPGs with the goals of establishing the structures of the natural second messengers, locating the intracellular targets of these molecules, and developing substances useful in the treatment and study of diabetes mellitus. Early studies lead to the synthesis of molecule 1 that is insulin-mimetic in an intact cell, though not as active as insulin itself.3,4 Larger molecules (such as 2 and 3) have also been prepared and evaluated for activity, with mixed results.5,6 More recently we have succeeded in the design and synthesis of more fully active molecules7,15 as well as in the preparation of molecules designed to probe the biochemical targets of these second messengers within the insulin-sensitive cell.8 This work has required that we develop synthetic methods for the efficient preparation of these complex molecules.9-13

inositol synthesis

These studies, together with those from other labs, have led to a good understanding of the relationship between IPG structure and insulin-like activity as well as a deeper understanding of the signaling mechanisms.8,14

(1)   Varela-Nieto, I.; Leon, Y.; Caro, H. N. Comp. Biochem. Physiol., B: Comp. Biochem. 1996, 115, 223-41.

(2)   Larner, J.; Huang, L. C. Diabetes Rev. 1999, 7, 217-231.

(3)   Plourde, R.; d'Alarcao, M. Tetrahedron Lett. 1990, 31, 2693-2696. [pdf]

(4)   Plourde, R.; d'Alarcao, M.; Saltiel, A. R. J. Org. Chem. 1992, 57, 2606-2610. [pdf]

(5)   Jaworek, C. H.; Calias, P.; Iacobucci, S.; d'Alarcao, M. Tetrahedron Lett. 1999, 40, 667-70. [pdf]

(6)   Jaworek, C. H.; Iacobucci, S.; Calias, P.; d'Alarcao, M. Carbohydr. Res. 2001, 331, 375-91. [pdf]

(7)   Chakraborty, N.; d'Alarcao, M. Bioorg. Med. Chem. Lett. 2005, 13, 6732-6741. [pdf]

(8)   Turner, D. I.; Chakraborty, N.; d'Alarcao, M. Bioorg. Med. Chem. Lett. 2005, 15, 2023-25. [pdf]

(9)   Kornienko, A.; d'Alarcao, M. Tetrahedron Lett. 1997, 38, 6497-6500. [pdf]

(10) Kornienko, A.; d'Alarcao, M. Tetrahedron: Asymmetry 1999, 10, 827-829. [pdf]

(11) Kornienko, A.; Turner, D. I.; Jaworek, C. H.; d'Alarcao, M. Tetrahedron: Asymmetry 1998, 9, 2783-2786. [pdf]

(12) Luchetti, G.; Ding, K.; d'Alarcao, M.; Kornienko, A. Synthesis 2008, 3142-47. [pdf]

(13) Luchetti, G.; Ding, K.; Kornienko, A.; d'Alarcao, M. Synthesis2008, 3148-54. [pdf]

(14) Goel, M.; Azev, V. N.; d'Alarcao, M. Future Med. Chem. 2009, 1, 95-118. [pdf]

(15) Suzuki, S., Suzuki, C., Hinokio, Y., Ishigaki, Y. Katagiri, H., Kanzaki, M., Azev, V. N., Chakraborty, N., and d’Alarcao, M. PLoS ONE  2014, 9 (6), e100466. [html]