Research
Chemistry in the Service of Biology
and Medicine
Our research interests involve the use of synthetic and mechanistic organic chemistry to shed light on questions in biology and medicine. For example, one area of current interest is the mechanism by which the hormone insulin exerts its effect on target cells. It has been demonstrated that binding of insulin to the cell-surface insulin receptor results in (among other things) the release of a small inositol-containing phosphorylated oligosaccharide that serves to activate the cell.(1) Such a substance, believed to be a second messenger of insulin action because it appears to carry the insulin message from the surface of the cell into the interior, is of tremendous interest in the treatment of diabetes mellitus. However, the precise structure of this material and its chemical target within the cell have not yet been elucidated. We are engaged in a program of chemical synthesis of inositol-containing oligosaccharides 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 a molecule that is insulin-mimetic in an intact cell, though not as active as insulin itself.(2, 3) We are now engaged in the design and synthesis of more fully active molecules as well as in the preparation of molecules designed to probe the biochemical targets of these second messengers within the insulin-sensitive cell.(4, 5) This work has required that we develop synthetic methods for the efficient preparation of these complex molecules.(6, 7, 8) Another area of interest is the design of chemotherapeutic agents for cancer. We are approaching this problem from two distinct directions: the design of new agents which interfere specifically with cancer cell proliferation but do not affect normal normal cells, and the development of better strategies for delivering known antitumor agents more efficiently to cancer cells. The later approach involves chemically appending transportable groups to a moderately effective antitumor agent resulting in enhanced biological transport of the agent to the cancer cell and then facilitating its entry into the cell across the cell membrane.(9) The goal of this approach is to enhance profoundly the efficacy and selectivity of existing anti-cancer pharmaceuticals. A third area of
current research involves the design of new synthetic methods useful
for the preparation of modified oligonucleotides potentially valuable
as antisense therapeutics.(10,11) Our strategy is to design a
template-directed synthesis of such materials to greatly enhance the ease
of their synthesis. 1. Larner, J.;
Huang, L. C. Diabetes Rev. 1999, 7 (3), 217-231. 2. Plourde, R.;
d'Alarcao, M.; Saltiel, A. R. J. Org. Chem. 1992, 57 (9), 2606-2610. [Full Article PDF] 3. Plourde, R.;
d'Alarcao, M. Tetrahedron Lett. 1990, 31 (19), 2693-2696. [ Full Article PDF ] 4. Jaworek, C.
H.; Iacobucci, S.; Calias, P.; d'Alarcao, M. Carbohydr. Res. 2001, 331 (4), 375-391. [ Full Article PDF ] 5. Jaworek, C.
H.; Calias, P.; Iacobucci, S.; d'Alarcao, M. Tetrahedron Lett. 1999, 40 (4), 667-670. [Full Article PDF] 6. Kornienko,
A.; d'Alarcao, M. Tetrahedron Lett. 1997, 38 (37), 6497-6500. [Full Article PDF] 7. Kornienko,
A.; Turner, D. I.; Jaworek, C. H.; d'Alarcao, M. Tetrahedron:
Asymmetry 1998, 9 (16), 2783-2786. [Full Article PDF] 8. Kornienko,
A.; d'Alarcao, M. Tetrahedron: Asymmetry 1999, 10 (5), 827-829. [Full Article PDF] 9. Calias, P.;
Galanopoulos, T.; Maxwell, M.; Khayat, A.; Graves, D.; Antoniades, H. N.;
d'Alarcao, M. Carbohydr. Res. 1996, 292 83-90. [Full Article PDF] 10. Tamm, I.;
Dorken, B.; Hartmann, G. Lancet 2001, 358 (9280), 489-497. 11. Taylor, M. F. Drug Discov. Today 2001, 6 (15), S97-S101. |
Last Updated: 8/29/01