環状ビス(3′‐5′)ジグアニル酸(c‐di‐GMP)および類縁体の有機合成,化学的性質,および生物活性

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タイトル別名
  • Organic Synthesis, Chemical Properties, and Biological Activities of Cyclic bis(3'-5')Diguanylic Acid (c-di-GMP) and Its Analogs
  • カンジョウ ビス 3 5 ジグアニルサン c di GMP オヨビ ルイエンタイ ノ ユウキ ゴウセイ カガクテキ セイシツ オヨビ セイブツ カッセイ

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This paper describes efficient synthesis, chemical behaviors, and biological activities of cyclic bis (3'-5') diguanylic acid (c-di-GMP) and its analogs, including cyclic bis (3'-5') guanylic-inosinic acid (c-GpIp), cyclic bis (3'-5') guanylic-adenylic acid (c-GpAp), and bis (3'-5') diguanylic acid monophosphorothioate (c-GpGps). c-di-GMP was synthesized via two methods shown in Scheme 1 and Scheme 2. Between the two methods, that shown in Scheme 2 is more effective, particularly, for large-scale (gram-scale) synthesis to obtain the target compound in a high yield. While, c-GpIp, c-GpAp, and c-GpGps were synthesized via strategies similar to that of Scheme 2. Studies on chemical behaviors of c-di-GMP indicated that these cyclic dinucleotides exist as the monomers in aprotic solvents such as DMSO. By contrast, it was shown that c-di-GMP smoothly aggregates to form a mixture of many compounds in water, in < 0.9% sodium chloride solutions, in < 100 mM phosphate buffer solutions, and in < 100 mM ammonium acetate buffer solutions. All aggregated compounds smoothly revert to a single compound (probably an aggeregate) by dissolving in a 0.9% sodium chloride solution (a physiological salt solution), a > 100 mM phosphate buffer solution, or a > 100 mM ammonium acetate buffer solution. Biological investigation dis-closed some novel activities of c-di-GMP, such as inhibition of biofilm formation of Staphylococcus aureus, inhibition of basal and growth factor stimulated human colon cancer cell prolifelation, and reduction of the viluence of biofilm-formed Staphylococcus aureus in a mouse model.

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