Creation and efficient synthesis of nucleic acids and related compounds with valuable functionality and bioactivity

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(1) We developed a new strategy for the stereoselective preparation of dideoxyribonucleoside phosphorothioates with the (R) or the (S) configuration at the stereogenic phosphorus atom, and, based on this strategy, achieved the synthesis of oligodeoxyribonucleotides with stereochemically pure phosphate/phosphorothioate chimeric backbones, which are important compounds for antisense chemotherapy.(2) We developed new methods for the synthesis of c-di-GMP and its various analogs; these methods are capable of providing target compounds in large amounts, such as hundreds of milligrams to several grams. The synthesis allowed us to carry out extensive investigations of the biological activities of c-di-GMP and its analogs. As a result, we found that c-di-GMP appears to act as a second messenger in bacteria and shows a variety of important bioactivities. Among them, the particularly attractive one is the regulation of biofilm formation and infection to host cells by various bacteria; that is, inhibition of biofilm formation of S. aureus, P. aeruginosa and E. coli; reduction of infection of S. aureus to HeLa cells; reduction of the virulence of biofilm-forming S. aureus strains in a mouse model of mastitis infection in vivo; and activation of immune response. Further, it was disclosed that c-di-GMP inhibits basal and growth factor-stimulated human colon cancer cell proliferation.