Dr. Jungkyun Im has obtained his Ph.D. degree in 2010 from Pohang university of science and technology in the field of bioorganic medicinal chemistry. During the Ph.D. course he has synthesized glycodendrimer, molecular transporter, stereoisomers of kinase inhibitor, and etc. In particular, to overcome the problems in the drug delivery across biological barriers, he prepared a series of novel molecular transporters based on carbohydrate as a scaffold. The G8 (containing eight guanidine units) sorbitol-based molecular transporter was found to be highly effective in cellular uptake as well as crossing the BBB. Employing the G8 sorbitol-based molecular transporter, he has prepared AZT(the first drug approved by FDA for the treatment of AIDS), and 5-Fu(the drug approved for the treatment of solid tumors) conjugates to examine their delivery to the mouse brain.
The blood brain barrier (BBB) is composed of densely packed endothelial cells which surrounds the vessels of the brain. Endothelial cells of brain capillaries are tightly joined through tight junctions. Thus most molecules in blood plasma such as chemicals as well as pathogens are excluded from the brain. Due to this unique barrier property, brain can be effectively protected from common infectious and inflammatory processes. On the other hand, when the brain is in trouble by a certain disease, the BBB becomes the major hurdle for drug delivery to the brain. In addition, many kinds of efflux pumps are present in the endothelial cells in the brain. For these reasons, the development of CNS (central nervous drug) drugs with the BBB permeability is the major issue in pharmaceutical research. Employing the G8 sorbitol-based molecular transporter, we have prepared AZT and 5-FU conjugates to examine their delivery to the mouse brain. The transporter has two selectively protected-primary hydroxyl groups. One hydroxyl group was conjugated to the drug of interest, while the other was used to attach a fluorophore via suitable linkers. For AZT and 5-FU conjugation, we utilized the succinate ester linker, which can be enzymatically cleaved to release the drug after successful delivery to tissues.
Din-Chi Chiu has received his BS from Department of Material Science and Engineering, National Chiao Tung University. Motivated by the passion on organic synthesis and drug discovery, he’s currently majoring chemistry in National Taiwan University and conducting research about development of new anti-influenza agent as his master study.
Influenza, an acute respiratory disease, remains to impact public health greatly. One of the envelope protein called Neuraminidase (NA) acts as a critical role in replication cycle of influenza virus, and its inhibitors such as oseltamivir and peramivir have been widely used for clinical treatment of influenza infections. Despite NA’s high conservation, certain mutations such as H274Y and R292K have been observed, thus leading to suppression of drug effectiveness. Referring to the co-crystal structure of NA and peramivir or oseltamivir, the drop of drug activity can be attributed to those unfavorable interactions between the hydrophobic substituents, 3-pentyl or 3-pentoxyl, on NA inhibitors and amino acid residues of NA. Consequently, peramivir derivatives bearing hydrophilic side chain were designed and synthesized in order to overcome drug resistance. (Fig.1) Gratifying, a pioneering method with complete consumption of the dipolariphile was developed by using reduced amount of nitrile oxide 1,3-dipole to conduct the 1,3- dipolar cycloaddition reaction. Aside from discovery of an alternative synthetic route, alleviated drug resistance is observed on analogs with various hydrophilic substituents, and improvement of inhibitory effects toward mutant viruses can be expected.