Inositol Phosphates - Divergent Syntheses and Utilities as Molecular Probes
Our research interests over the years have covered a fairly wide range in the areas of natural products, mechanistic and synthetic bioorganic chemistry, and medicinal chemistry, and are still evolving in their targets and methodologies. In the natural products area, we have elucidated complex structures of antibiotic molecules, and carried out biosynthetic and biogenetic studies of steroids and terpenes, fatty acids and prostaglandins, polyketides and tetracyclines, peptides and ¥â-lactam antibiotics, glycopeptide antibiotics such as vancomycin and aridicins, and mRNA dependent peptide synthesis.
In the mechanistic and synthetic bioorganic chemistry area, we have investigated and proposed new possibilities for the molecular mechanisms of vitamin B12-dependent mutase and NADH-dependent alcohol dehydrogenase reactions.
In the medicinal chemistry field, we have explored a glycoside remodeling approach to bioactive macromolecules such as tissue plasminogen activator (tPA) in terms of biopotency, selectivity and phamacokinetic properties, in addition to design and syntheses of platelet activating factor (PAF) antagonists, quinolone antibacterials, and antifungal steroids.
More recently, we have focused our efforts on the bioorganic and medicinal chemistry aspects of intracellular signal transductions. The roles of myo-inositol-polyphosphates and related phospholipids in the intramolecular signal transduction events are well known, and the scope of these signaling processes is getting larger. Yet, a clear understanding of the molecular mechanisms has not been achieved. In order to help understand the molecular interactions between these signaling molecules and corresponding biomacromolecules such as receptors and metabolic enzymes, we have synthesized a complete set the 64 regioisomers of IPn in homochiral forms, and been using them to probe the structure-activity relationships in collaboration with other groups. We have also accomplished the first general synthesis of nine stereoisomers of inositol via conduritols, and these intermediates are expected to be very useful in studying the IPn-based signaling processes. Possibly in connection with related signaling pathways, we have been carrying out synthesis and biological studies of sphingosine-based phospholipids.
Another research focus is related to developing new structural and synthetic methodologies for the study of microheterogeneity of carbohydrates and understanding the biological roles of oligosaccharides in peptides and proteins.
We are also interested in understanding and exploring the medicinal chemistry implications of human genomic information such as single nucleotide polymorphism (SNP) and haplotypes.
Signal Transduction Using Phosphoinositide System
myo-Inositol Phosphates as 2nd Messengers and Their Metabolism