Studies on construction of bioactive scaffolds: development of dual inhibitors for G-protein coupled receptor & casein kinase

Abstract

Part 1. Construction of intramolecular C-O and C-N bond1.1. Stereoselective C-O bond formation via palladium (II)-catalyzed C(sp$^3$)-H activation using chiral bidentate groupOxaspiro compound structure, which is often found in natural materials and pharmacologically active structures, is produced through palladium-catalyzed activation of sp3 hybridized-carbon-hydrogen bonds. At this time, a chiral bidentate directing group using pyridine and alkyl substituent enhanced the stereoselectivity of the intramolecular alkoxylation reaction. This could make it possible to synthesize from a simple ring structure to spiro compounds, nitrogen-containing heterocyclic compound and its derivatives.1.2. C-N bond formation via photocatalyzed oxidative C-H amidationThe generation of amidyl radical through concerted proton-coupled electron transfer (PCET) formed intramolecular carbon-nitrogen bonds. The triplet energy state of the photocatalyst, which is excited by visible light, caused isomerization of alkene, followed by proton loss and electron transfer by excited photocatalyst and base, resulting in homolytic cleavage of N-H bond and radical generation. Finally, through participation of oxygen as oxidant, we synthesized quinolinone and phenanthridinone, which are important scaffolds of bioactive natural compound and drug, and their derivatives.Part 2. Developing dual inhibitors for muscarinic acetylcholine receptor 3 and casein kinase 1Overexpression of the ERK1/2 signal causes proliferation and growth of cancer cell, and muscarinic acetylcholine receptors (mAChRs) are important factor as upstream factor in signal transduction. We have developed a dual inhibitor that could reduce the activation of ERK1/2 by suppressing mAChR3 as antagonist, also block casein kinase 1, which induced ERK1/2 as downstream signaling of mAChR3. Our dual inhibitors inhibit both extracellular receptor and internal kinase and has an inhibitory activity that lowers the side effect.