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

(1)我们发展了一种立体选择性地制备立体异构磷原子上具有（R）或（S）构型的双脱氧核苷硫代磷酸酯的新策略，并基于此策略合成了具有立体化学纯的磷酸/硫代磷酸酯嵌合骨架的寡脱氧核苷酸，这是一种重要的反义化疗化合物。(2)我们开发了用于合成c-di-GMP及其各种类似物的新方法;这些方法能够提供大量的目标化合物，例如数百毫克到几克。该合成使我们能够对c-di-GMP及其类似物的生物活性进行广泛的研究。因此，我们发现c-di-GMP似乎在细菌中充当第二信使，并显示出多种重要的生物活性。其中，对生物膜形成和各种细菌感染宿主细胞的调控，即抑制S. aureus、P. aeruginosa和E.大肠杆菌感染;金黄色葡萄球菌对HeLa细胞的毒力降低;金黄色葡萄球菌菌株在体内乳腺炎感染的小鼠模型中的作用;以及免疫应答的激活。此外，公开了c-di-GMP抑制基础和生长因子刺激的人结肠癌细胞增殖。

(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.