Synthetic Organic Chemistry Laboratory

Outline

Our laboratory focuses on the following research based on synthetic organic chemistry: (1) development of new reactions and methodologies for the efficient synthesis of bioactive molecules, (2) design and synthesis of molecules with unique biological activities, (3) biological research using unique molecules as biological probes. Our research interests range from transition metal-catalyzed enantioselective reactions to design and synthesis of intracellular signal transduction modulators and their application to cell biology research. Design and synthesis of selective inhibitors of protein kinases and phosphatases, which are involved in the signal transduction of cell proliferation, aiming at clarification of the functions of their target enzymes are of particular interest. Clarification of unknown molecular mechanisms of cell death (necrosis) by using our original cell death control molecules is also currently underway. We are also working on the synthesis of ganglioside analogs and several other natural products with interesting biological activities.

Recent Research Topic

Elucidation of intracellular signal transduction mechanisms based on synthetic organic chemistry

Fig. 1 Synthetic Target Molecules Having Unique Biological Activities

Extracellular signals are received on cell surfaces and transmitted in the cell to the nucleus causing cell responses such as proliferation and differentiation. To clarify the complex intracellular signal transduction mechanisms, it is necessary to elucidate the role of each protein involved in these processes. For this purpose, we are trying to develop selective inhibitors of these proteins. Protein phosphorylation is a major mechanism of regulation of signaling proteins, and we are focusing on development of selective inhibitors of protein kinases and phosphatases. So far, we have succeeded in developing a selective inhibitor of protein kinase C (PKC), which plays a critical role in cell proliferation, and selective inhibitors of calcineurin, which is a phosphatase regulating immune T cell activation, and Cdc25, a key phosphatase for cell cycle progression. We are currently performing cell biology research using these inhibitors as biological probes. Furthermore, we are working on the total synthesis of histone methyltransferase inhibitors, chaetocin derivatives, and derivatives of the complex natural product physalin. We have also synthesized non-hydrolyzable fluorinated C-sialoside-type glycolipid mimics to study functions of gangliosides.

We are also interested in the molecular mechanism of cell death. Cell death is divided into two categories, apoptosis and necrosis, based on phenotype. In apoptosis shrinkage and fragmentation of cells are observed. On the other hand, cell swelling and rupture of the plasma membrane are characteristic of necrosis. Apoptosis is active cell death caused by using specific machinery and observed under physiological conditions such as development. Molecular mechanisms of apoptosis are well studied and clarified. In contrast, necrosis was believed to be accidental and passive cell death and to have no control mechanism. However, we successfully developed novel cell death inhibitors, IM derivatives, which selectively inhibit necrosis. Furthermore, IM derivatives were found to be effective in the rat heart and brain stroke models. These facts strongly indicate the unknown molecular mechanism of necrosis with which IM derivatives interact may be involved in such diseases, and found that their target protein exists in mitochondria. We are now pursuing elucidation of this unknown molecular mechanism of necrosis.

In addition, we are developing methodologies for facilitating chemical biology research with particular focus on live cell imaging by Raman microscopy.

Fig. 2

Gangliosides are hydrolyzed by an enzyme NEU3 at plasma membrane. CF2-linked ganglioside analogs are not hydrolyzed by NEU3.

Fig. 3 Novel cell death inhibitor Indolylmaleimide (IM) derivatives

IM derivatives inhibit oxidative-stress-induced necrosis but not apoptosis induced by anticancer drugs or physiological death ligand.