We have been working to developing a new strategy for delivering known, effective,
medicinal agents to the interior of the cells where they are needed. The strategy
is based the observations that certain ionic inositol phosphate glycans (IPGs) are
actively transported across the cell membrane in some types of cell, probably through
an endocytosis mechanism. We have been engaged in a program to synthesize covalent
conjugates of medicinal agents or test molecules to IPGs to evaluate the ability of the
conjugates to enter cells. Since the IPGs are ionic carbohydrates and therefore highly
water soluble, we expect that the IPGs will confer two normally antithetical properties
on the conjugates: high water solubility and transportability across cell membranes.
Since intracellularly active drugs must be soluble in aqueous fluids such as blood to
reach the target cells, but must then cross a lipid membrane to enter the target cells,
we are hopeful that the drug-IPG conjugates will exhibit both of these favorable
Compounds 1 and 2 are representative of the strategy. In compound 1, an inositol phosphate
has been attached via a succinate linker to one of the hydroxyl groups of quercetin (in red),
an antioxidant flavonoid with known anti-tumor properties. Conjugate 1 was indeed found to have
dramatically increased water solubility compared with unconjugated quercetin, but was not
transported into cells. Compound 2, consists of a somewhat larger IPG disaccharide (in blue)
conjugated with a fluorescent dye (yellow). Compound 2 was also found not to be transported into
cells, suggesting that a more complete substructure of the natural IPGs may be necessary
to elicit transport.
We are currently exploring other, more complete synthetic IPG analogues as potential drug delivery agents.
P. Calias, T. Galanopoulos, M. Maxwell, A. Khayat, D. Graves, H. N. Antoniades, and M. d'Alarcao Carbohydr. Res. 1996, 292 83-90. Link to PDF
D. I. Turner, N. Chakraborty, and M. d'Alarcao, Bioorg. Med. Chem. Lett. 2005 15, 2023-25 Link to PDF.