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

(1)提出了一种立体选择性合成具有(R)或(S)构型的二脱氧核糖核苷硫代酸酯的新策略，并在此基础上合成了具有立体纯磷酸/硫代酸嵌合骨架的寡脱氧核糖核苷，这是反义化疗的重要化合物。(2)开发了c-二- gmp及其各种类似物的合成新方法；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似乎是细菌中的第二信使，并显示出多种重要的生物活性。其中，特别吸引人的是各种细菌对生物膜形成和宿主细胞感染的调节；即抑制金黄色葡萄球菌、铜绿假单胞菌和大肠杆菌的生物膜形成；减少金黄色葡萄球菌对HeLa细胞的感染；降低生物膜形成金黄色葡萄球菌菌株在乳腺炎感染小鼠模型中的毒力；以及免疫反应的激活。此外，还发现c-di-GMP可抑制基础因子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.