Organic synthesis, chemical properties, and biological activities of cyclic bis(3′-5′)diguanylic acid (c-di-GMP) and its analogs

被引:5
|
作者
Hyodo, M [1 ]
Hayakawa, Y [1 ]
Karaolis, DKR [1 ]
机构
[1] Nagoya Univ, Grad Sch Human Informat Informat Sci, CREST JST, Chikusa Ku, Nagoya, Aichi 4648601, Japan
关键词
c-di-GMP; nucleotide; biofilm; phosphoramidite; aggregation; cancer; MRSA;
D O I
10.5059/yukigoseikyokaishi.64.359
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
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, e-GpIp, c-GpAp, and e-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 disclosed 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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页码:359 / 370
页数:12
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