US20170096439A1 - Inclusion compound of 3',5'-cyclicdiadenylic acid, and method for producing same - Google Patents

Inclusion compound of 3',5'-cyclicdiadenylic acid, and method for producing same Download PDF

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Publication number
US20170096439A1
US20170096439A1 US15/125,349 US201515125349A US2017096439A1 US 20170096439 A1 US20170096439 A1 US 20170096439A1 US 201515125349 A US201515125349 A US 201515125349A US 2017096439 A1 US2017096439 A1 US 2017096439A1
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inclusion compound
cyclic diadenylic
acid
diadenylic acid
cyclic
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Hisaki Tanaka
Kazuya Ishige
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Yamasa Corp
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Yamasa Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical

Definitions

  • the present invention is related to an inclusion compound of 3′,5′-cyclic diadenylic acid, which is deemed to be a useful substance as an adjuvant, and a manufacturing method thereof.
  • 3′,5′-Cyclic diadenylic acid is a substance discovered as a second messenger of bacteria. Recently, an application as a pharmaceutical is expected since, for example, said substance is reported to be capable of inducing type 1 interferon (Non-Patent Document 1).
  • Non-Patent Documents 2 and 3 As a manufacturing method of 3′,5′-cyclic diadenylic acid, a chemical synthesis method (Non-Patent Documents 2 and 3) and an enzymatic synthesis method (Non-Patent Documents 4 and 5), in which diguanylate cyclase from Genus Bacillus, Genus Streptococcus or the like is used, are known thus far, and it is provided in the form of a freeze-dried product.
  • Non-Patent Document 1 Science, 328, 1703-1705(2010)
  • Non-Patent Document 2 SYNTHESIS, 24, 4230-4236(2006)
  • Non-Patent Document 3 Nucleosides Nucleotides Nucleic Acids, 32, 1-16(2013)
  • Non-Patent Document 4 Molecular Cell, 30, 167-178(2008)
  • Non-Patent Document 5 Nagoya J. Med. Sci., 73, 49-57(2011)
  • 3′,5′-cyclic diadenylic acid is provided conventionally as a freeze-dried product, no preparation other than the freeze-dried product has been known.
  • a freeze-dried product requires a freeze dryer in the manufacturing process thereof, so that even if scaling up is intended for mass production, limitations inevitably exist.
  • an object of the present invention is to provide a completely novel preparation of 3′,5′-cyclic diadenylic acid that is different from a freeze-dried product, without using a special apparatus nor step.
  • the present inventors studied preparations of 3′,5′-cyclic diadenylic acid different from a freeze-dried product. As a result, it was newly found that by a extremely simple and easy method of adding acid to an aqueous solution of 3′,5′-cyclic diadenylic acid so as to lower pH to 1 to 3, an inclusion compound of 3′,5′-cyclic diadenylic acid can be manufactured that has physical properties completely different from those of a freeze-dried product.
  • the present invention provides an inclusion compound of 3′,5′-cyclic diadenylic acid that is completely different from the conventional freeze-dried product.
  • the inclusion compound of the present invention is a crystalline substance, and thus, easy to handle (for example, free from hygroscopicity, excellent in stability and solubility, and the like). Further, the manufacturing method of the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention does not need a special apparatus nor step for preparing, and is useful in producing 3′,5′-cyclic diadenylic acid in large amount.
  • FIG. 1 shows a photograph of an inclusion compound (amorphous) of 3′,5′-cyclic diadenylic acid.
  • FIG. 2 shows a photograph of a freeze-dried product of sodium salt of 3′,5′-cyclic diadenylic acid.
  • FIG. 3 shows a photograph of a freeze-dried product of ammonium salt of 3′,5′-cyclic diadenylic acid.
  • FIG. 4 shows a result of thermogravimetric measurement/differential thermal analysis of an inclusion compound (amorphous) of 3′,5′-cyclic diadenylic acid.
  • FIG. 5 shows a result of thermogravimetric measurement/differential thermal analysis of a freeze-dried product of sodium salt of 3′,5′-cyclic diadenylic acid.
  • FIG. 6 shows a result of thermogravimetric measurement/differential thermal analysis of a freeze-dried product of ammonium salt of 3′,5′-cyclic diadenylic acid.
  • FIG. 7 shows a nuclear magnetic resonance spectrum ( 1 H) of an inclusion compound of 3′,5′-cyclic diadenylic acid.
  • FIG. 8 shows a nuclear magnetic resonance spectrum ( 13 C) of an inclusion compound of 3′,5′-cyclic diadenylic acid.
  • FIG. 9 shows a nuclear magnetic resonance spectrum ( 31 P) of an inclusion compound of 3′,5′-cyclic diadenylic acid.
  • FIG. 10 shows an infrared absorption spectrum of an inclusion compound of 3′,5′-cyclic diadenylic acid.
  • FIG. 11 shows an infrared absorption spectrum of a freeze-dried product of sodium salt of 3′,5′-cyclic diadenylic acid.
  • FIG. 12 shows an infrared absorption spectrum of a freeze-dried product of ammonium salt of 3′,5′-cyclic diadenylic acid.
  • FIG. 13 shows a photograph of an inclusion compound (crystalline) of 3′,5′-cyclic diadenylic acid.
  • FIG. 14 shows a result of thermogravimetric measurement/differential thermal analysis of an inclusion compound (crystalline) of 3′,5′-cyclic diadenylic acid.
  • FIG. 15 shows an X-ray diffraction spectrum of an inclusion compound (crystalline) of 3′,5′-cyclic diadenylic acid.
  • the present invention provides an inclusion compound of 3′,5′-cyclic diadenylic acid represented by the following structural formula.
  • the inclusion compound referred to in this invention means a solid material in a state where a solvent plays an auxiliary role in solidification, such that the compound and the solvent form a complex by weak interactions, and the configuration of inclusion and the structure of solidification are not limited.
  • the inclusion compound in the present invention since water is used as the solvent, the inclusion compound in the present invention means an inclusion compound with water. Note that the inclusion compound of the present invention encompasses a crystalline substance and an amorphous substance.
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention can be obtained by adding acid to an aqueous solution of 3′,5′-cyclic diadenylic acid so as to lower pH to 1 to 3.
  • 3′,5′-Cyclic diadenylic acid used to obtain the inclusion compound of the present invention may be synthesized by a known method such as the enzymatic synthesis method and the chemical synthesis method, and one synthesized by the enzymatic synthesis method is preferable. Enzymatic synthesis may be performed following the known method and, for example, the method described in Patent Documents 4 and 5 may be used. After the reaction, 3′,5′-cyclic diadenylic acid generated in a reaction solution can be isolated and purified by the usual chromatography method using activated carbon, an ion-exchange resin or the like.
  • acid may be added to an aqueous solution of 3′,5′-cyclic diadenylic acid so as to lower pH to 1 to 3, preferably to 1.5 to 2.0.
  • the acid used may be any one that can regulate pH into the range mentioned above, and specifically, inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid can be exemplified. Note that in order to prevent amorphism or rapid precipitation from being caused by adding acid rapidly, slow addition is preferable.
  • the inclusion compound may be obtained again by performing said process repeatedly several times on the filtrate of said inclusion compound.
  • a method may be employed which comprises (1) a step of adding acid to an aqueous solution of 3′,5′-cyclic diadenylic acid so as to lower pH to 1 to 3, (2) a step of heating said aqueous solution of 3′,5′-cyclic diadenylic acid to 50 to 70° C., and (3) a step of cooling said aqueous solution of 3′,5′-cyclic diadenylic acid until the solution reaches 1 to 10° C. Further, steps (1) and (2) or steps (2) and (3) may be performed simultaneously.
  • a method may be employed which consists of (1) a step of adding acid to a diluted aqueous solution of 3′,5′-cyclic diadenylic acid so as to lower pH to 1 to 3, (2) a step of heating said aqueous solution of 3′,5′-cyclic diadenylic acid with adjusted pH to 50 to 70° C., and (3) a step of cooling said aqueous solution of 3′,5′-cyclic diadenylic acid until the solution reaches 1 to 10° C.
  • cooling in step (3) is performed slowly. Specifically, cooling with a temperature gradient of ⁇ 3 to ⁇ 11° C./hr is preferable.
  • the inclusion compound of 3′,5′-cyclic diadenylic acid obtained by the manufacturing method described above may be collected by filtration and then dried at a room temperature (25° C.) to 70° C. for 1 to 10 hours, to be a product.
  • the inclusion compound of the present invention can be obtained as a crystalline substance by drying at a low temperature ranging from a room temperature (25° C.) to 40° C., and as an amorphous substance by drying under a high temperature condition ranging from 40 to 70° C.
  • the inclusion compound of the present invention is obtained as a crystalline substance by drying at a low temperature of a room temperature (25° C.) or higher and lower than 40° C., and as an amorphous substance by drying under a high temperature condition of 40° C. or higher and 70° C. or lower. Further, the inclusion compound obtained may be washed as appropriate with ethanol or the like after collecting by filtration and before drying. A method of drying under reduced pressure may be utilized as appropriate in drying.
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention obtained by the method described above has purity of 97% or more, preferably 99% or more, when purity test is performed by the high performance liquid chromatography method, as well as the following physical properties. Note that among the physical properties below, those not specifically limited are common to both the crystalline substance and the amorphous substance.
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention has water content of 3.5 to 17% as measured by a thermogravimetric measurement/differential thermal analysis (TG/DTA) apparatus, though it varies according to the extent of drying. That is, in the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention, 1 to 7 molecules of water, more specifically, 1.1 to 6.1 molecules of water bond or attach to one molecule of 3′,5′-cyclic diadenylic acid.
  • TG/DTA thermogravimetric measurement/differential thermal analysis
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention When analyzed by a thermogravimetric measurement/differential thermal analysis (TG/DTA) apparatus (temperature elevation rate of 5° C./min), the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention has an endothermic peak around 193° C. when the inclusion compound is a crystalline substance and around 220° C. when the inclusion compound is an amorphous substance.
  • TG/DTA thermogravimetric measurement/differential thermal analysis
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention is needle-shaped.
  • the inclusion compound (amorphous) of 3′,5′-cyclic diadenylic acid of the present invention has characteristic peaks around 3087, 1686, 1604, 1504, 1473, 1415, 1328 and 1213 (cm -1 ) when an infrared absorption spectrum is measured.
  • an error range less than 2 (cm ⁇ 1 ) is sometimes included in measuring an infrared absorption spectrum, so that not only inclusion compounds whose peak positions in an infrared absorption spectrum coincide exactly with the values noted above but also inclusion compounds whose peak positions coincide within the error range less than 2 cm ⁇ 1 are included in the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention.
  • characteristic peaks are observed at 3087 ⁇ 1.9, 1686 ⁇ 1.9, 1604 ⁇ 1.9, 1504 ⁇ 1.9, 1473 ⁇ 1.9, 1415 ⁇ 1.9, 1328 ⁇ 1.9 and 1213 ⁇ 1.9 (cm ⁇ 1 ).
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention is a crystalline substance
  • the inclusion compound of the present invention has characteristic peaks in X-ray powder analysis.
  • characteristic peaks are observed, as shown in Example below, around 9.2, 10.2, 10.9, 11.1, 13.7, 15.2, 19.0, 20.6, 22.4, 23.1, 24.3, 26.6 and 26.8(°) in diffraction angle (2 ⁇ ), especially around 9.2, 15.2, 19.0, 20.6 and 26.8(°) in diffraction angle (2 ⁇ ).
  • characteristic peaks are observed at 9.2 ⁇ 0.45, 10.2 ⁇ 0.50, 10.9 ⁇ 0.54, 11.1 ⁇ 0.55, 13.7 ⁇ 0.68, 15.2 ⁇ 0.75, 19.0 ⁇ 0.94, 20.6 ⁇ 1.02, 22.4 ⁇ 1.11, 23.1 ⁇ 1.15, 24.3 ⁇ 1.21, 26.6 ⁇ 1.32 and 26.8 ⁇ 1.33(°) in diffraction angle (2 ⁇ ), especially at 9.2 ⁇ 0.45, 15.2 ⁇ 0.75, 19.0 ⁇ 0.94, 20.6 ⁇ 1.02 and 26.8 ⁇ 1.33(°) in diffraction angle (2 ⁇ ).
  • the inclusion compound is an amorphous substance, no apparent peaks are observed in X-ray powder diffraction.
  • 3′,5′-Cyclic diadenylic acid was synthesized and purified according to a known method.
  • said solution was warmed to 60° C. using a programmable incubator. Thereafter, the solution was cooled with a temperature gradient of ⁇ 4° C./hr until the temperature of the solution reached 4° C. Precipitates were collected by a glass filter (17G3) to obtain white solids. Said white solids were dried at 60° C. for 6 hours and 2.169 g of inclusion compound (amorphous) was obtained.
  • the solution in which 3′,5′-cyclic diadenylic acid was dissolved was further diluted with water to 35 mL, and then, freeze-dried by a freeze dryer, thereby a freeze-dried product of sodium salt or ammonium salt of 3′,5′-cyclic diadenylic acid was obtained.
  • FIG. 1 A representative photograph of the inclusion compound of 3′,5′-cyclic diadenylic acid is shown in FIG. 1 . As seen from FIG. 1 , it was revealed that the inclusion compound of 3′,5′-cyclic diadenylic acid is needle-shaped.
  • freeze-dried products of sodium salt of 3′,5′-cyclic diadenylic acid and ammonium salt of 3′,5′-cyclic diadenylic acid had, as shown in FIGS. 2 and 3 , completely different shapes from that of the inclusion compound.
  • thermogravimetric measurement/differential thermal analysis (TG/DTA) apparatus temperature elevation rate of 5° C./min
  • water content of the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention was 8.7 to 9.5% for the inclusion compound before redrying, 3.5 to 3.6% for the inclusion compound after redrying at 100° C. under reduced pressure, 10.3% for the inclusion compound after redrying and subsequent storing at a room temperature and at a humidity of 40 to 50% overnight, 15.0% for the inclusion compound after redrying and subsequent storing at a temperature of 30° C. and at a humidity of 70% overnight, and 17.0% for the inclusion compound after vacuum dried at 20° C. for 2 hours.
  • TG/DTA thermogravimetric measurement/differential thermal analysis
  • thermogravimetric measurement was performed similarly on the freeze-dried product of sodium salt of 3′,5′-cyclic diadenylic acid and on the freeze-dried product of ammonium salt of 3′,5′-cyclic diadenylic acid, the freeze-dried product of sodium salt contained 16 to 17% of water and the freeze-dried product of ammonium salt contained 13 to 15% of water as their measured values before redrying.
  • thermogravimetric measurement/differential thermal analysis (TG/DTA) apparatus temperature elevation rate of 5° C./min
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention showed a characteristic endothermic peak around 220° C. ( FIG. 4 ).
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention showed peaks around 8.37, 7.96, 6.08, 4.98-5.02, 4.86, 4.51-4.55 and 4.17 (ppm).
  • 31 P a peak was observed around ⁇ 0.91 (ppm).
  • Infrared absorption spectrum was measured on each of the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention, and the freeze-dried product of sodium salt of 3′,5′-cyclic diadenylic acid and the freeze-dried product of ammonium salt of 3′,5′-cyclic diadenylic acid using a Fourier transform infrared spectrophotometer, Spectrum One (product of PerkinElmer Co., Ltd.) by the ATR (Attenuated Total Reflectance) method.
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention had characteristic peaks around 3087, 1686, 1604, 1504, 1473, 1415, 1328 and 1213 (cm ⁇ 1 ).
  • 3′,5′-Cyclic diadenylic acid was synthesized enzymatically by a known method, and purification was performed.
  • 2 N hydrochloric acid was added with stirring so as to adjust pH to 1.8. As a result, white solids precipitated in the aqueous solution.
  • said solution was warmed to 50° C. using a programmable incubator. Thereafter, the solution was cooled with a temperature gradient of ⁇ 3° C./hr until the temperature of the solution reached 4° C. causing solids to precipitate. Precipitates were collected by a glass filter (17G3) to obtain white solids. Said white solids were vacuum dried at a room temperature and the inclusion compound of 3′,5′-cyclic diadenylic acid was obtained.
  • 3′,5′-Cyclic diadenylic acid was synthesized enzymatically by a known method, and purification was performed.
  • said solution was warmed to 50° C. using a programmable incubator, and 2 N hydrochloric acid was added with stirring so as to adjust pH to 1.8.
  • FIG. 13 A photograph of the inclusion compound (crystalline) of 3′,5′-cyclic diadenylic acid prepared in Example 3 above is shown in FIG. 13 . As seen from FIG. 13 , the inclusion compound (crystalline) of 3′,5′-cyclic diadenylic acid was needle-shaped.
  • thermogravimetric measurement/differential thermal analysis (TG/DTA) apparatus temperature elevation rate of 5° C./min
  • TG/DTA thermogravimetric measurement/differential thermal analysis
  • thermogravimetric measurement/differential thermal analysis (TG/DTA) apparatus temperature elevation rate of 5° C./min
  • water content of the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention was 17.0% after removing water by vacuum drying under the condition of a temperature of 20° C. for 2 hours.
  • the inclusion compound of 3′,5′-cyclic diadenylic acid of the present invention showed characteristic peaks around 9.2, 10.2, 10.9, 11.1, 13.7, 15.2, 19.0, 20.6, 22.4, 23.1, 24.3, 26.6 and 26.8(°) in diffraction angle (2 ⁇ ).

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PCT/JP2015/057386 WO2015137469A1 (ja) 2014-03-14 2015-03-12 ３'，５'－サイクリックジアデニル酸の包接化合物、およびその製造法

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US10787479B2 (en) 2014-03-03 2020-09-29 Yamasa Corporation Crystalline 3′,5′-cyclic diguanylic acid
US10836783B2 (en) 2014-03-14 2020-11-17 Yamasa Corporation Inclusion compound of 3′ ,5′-cyclic diadenylic acid and manufacturing method thereof
US11485754B2 (en) 2018-11-01 2022-11-01 Yamasa Corporation Cyclic-di-AMP sodium salt crystal

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EP1645561A1 (en) 2003-07-15 2006-04-12 Mitsui Chemicals, Inc. Method of synthesizing cyclic bisdinucleoside
EP1782826A1 (en) * 2005-11-08 2007-05-09 GBF Gesellschaft für Biotechnologische Forschung mbH PQS and c-diGMP and its conjugates as adjuvants and their uses in pharmaceutical compositions
WO2010101526A1 (en) * 2009-03-02 2010-09-10 Nanyang Technological University A diguanylate cyclase, method of producing the same and its use in the manufacture of cyclic-di-gmp and analogues thereof
CN102199183B (zh) 2010-03-26 2013-12-18 北京大学 环二鸟苷酸及其类似物和制备方法
US9061048B2 (en) * 2010-12-15 2015-06-23 The Regents Of The University Of California Cyclic di-AMP induction of type I interferon
WO2013129427A1 (ja) 2012-02-29 2013-09-06 ヤマサ醤油株式会社 cyclic di-GMPの実践的酵素合成法
US20170101432A1 (en) 2014-03-03 2017-04-13 Yamasa Corporation Crystalline 3',5'-cyclic diguanylic acid
CN110256507B (zh) 2014-03-14 2022-06-21 雅玛山酱油株式会社 3′,5′-环二腺苷酸包合物及其制造方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10787479B2 (en) 2014-03-03 2020-09-29 Yamasa Corporation Crystalline 3′,5′-cyclic diguanylic acid
US10836783B2 (en) 2014-03-14 2020-11-17 Yamasa Corporation Inclusion compound of 3′ ,5′-cyclic diadenylic acid and manufacturing method thereof
US11485754B2 (en) 2018-11-01 2022-11-01 Yamasa Corporation Cyclic-di-AMP sodium salt crystal

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EP3118207A4 (en) 2017-01-18
KR20160119236A (ko) 2016-10-12
CN106061989A (zh) 2016-10-26
US20190382426A1 (en) 2019-12-19
CA2942283A1 (en) 2015-09-17
CN110256507B (zh) 2022-06-21
EP3118207B1 (en) 2020-08-05
US10836783B2 (en) 2020-11-17
WO2015137469A1 (ja) 2015-09-17
CA2942283C (en) 2020-07-28
EP3118207A1 (en) 2017-01-18
CN110256507A (zh) 2019-09-20
JP6321135B2 (ja) 2018-05-09
KR102008279B1 (ko) 2019-08-07

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