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 [in Japanese] Organic Synthesis, Chemical Properties, and Biological Activities of Cyclic bis(3'-5')Diguanylic Acid (c-di-GMP) and Its Analogs [in Japanese]
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This paper describes efficient synthesis, chemical behaviors, and biological activities of cyclic bis (3'-5') diguanylic acid (<I>c</I>-di-GMP) and its analogs, including cyclic bis (3'-5') guanylic-inosinic acid (<I>c</I>-GpIp), cyclic bis (3'-5') guanylic-adenylic acid (<I>c</I>-GpAp), and bis (3'-5') diguanylic acid monophosphorothioate (<I>c</I>-GpGps). <I>c</I>-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, <I>c</I>-GpIp, <I>c</I>-GpAp, and <I>c</I>-GpGps were synthesized via strategies similar to that of Scheme 2. Studies on chemical behaviors of <I>c</I>-di-GMP indicated that these cyclic dinucleotides exist as the monomers in aprotic solvents such as DMSO. By contrast, it was shown that <I>c</I>-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 <I>c</I>-di-GMP, such as inhibition of biofilm formation of <I>Staphylococcus aureus</I>, inhibition of basal and growth factor stimulated human colon cancer cell prolifelation, and reduction of the viluence of biofilm-formed <I>Staphylococcus aureus</I> in a mouse model.
- J. Synth. Org. Chem. Jpn.
J. Synth. Org. Chem. Jpn. 64(4), 359-370, 2006-04-01
The Society of Synthetic Organic Chemistry, Japan