Synthetic Studies on Bioactive Substances: From Research on Water-soluble Compounds to the Field of Lipophilic Ligands

Abstract

This is a personal review of my chemistry research on retirement from Teikyo University. Under the guidance of Prof. Masaji Ohno of the Faculty of Pharmaceutical Sciences, The University of Tokyo, my research career started with the synthesis of water-soluble basic natural compounds, including the first artificial bleomycin showing potent molecular-oxygen activation effects and DNA binding abilities. While studying abroad at Eidgenössische Technische Hochschule (ETH) under the guidance of Prof. Albert Eschenmoser, I studied the formation of ribose under prebiotic conditions. The condensation reaction between formaldehyde and glycolaldehyde phosphate produced ribose in far greater yield than the formose reaction. In the School of Pharmacy, Showa University, I conducted research in nucleic acid chemistry to synthesize, for example, anomeric spiro-nucleosides using radical chemistry and oligonucleotides that interacted with the κB motif. After moving to Teikyo University in 1999, I engaged in studies on the synthesis of vitamin D derivatives, included in fat-soluble vitamins, with selective biological activities without calcemic side-effects, and discovered, for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D3 (MART-10), which exhibits potent anticancer activity in vivo, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (AH-1), which shows greater bone-forming effects than natural active vitamin D3 in vivo, and the A-ring-converted vitamin D derivative KK-052, which is an in vivo selective inhibitor of sterol regulatory-element binding protein (SREBP), a master transcription factor of lipogenesis, independent of the vitamin D canonical activity through a vitamin D receptor.