JP6887195B1 - 新規有機ゲルマニウム化合物 - Google Patents
新規有機ゲルマニウム化合物 Download PDFInfo
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- -1 organogermanium compound Chemical class 0.000 title abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 5
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 7
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical group [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 28
- 239000000126 substance Substances 0.000 abstract description 6
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- 238000010586 diagram Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 34
- XEABSBMNTNXEJM-UHFFFAOYSA-N propagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 description 32
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 18
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
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- 239000011734 sodium Substances 0.000 description 7
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
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- 238000004090 dissolution Methods 0.000 description 4
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- 229910052732 germanium Inorganic materials 0.000 description 4
- CBFCDTFDPHXCNY-UHFFFAOYSA-N icosane Chemical compound CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
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- 239000002245 particle Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IQULGZQMMPRBLA-UHFFFAOYSA-N 2-carboxyethylgermanium Chemical compound OC(=O)CC[Ge] IQULGZQMMPRBLA-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
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- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MUDDKLJPADVVKF-UHFFFAOYSA-N trichlorogermane Chemical compound Cl[GeH](Cl)Cl MUDDKLJPADVVKF-UHFFFAOYSA-N 0.000 description 2
- LZIZCRNBBGNAJO-UHFFFAOYSA-N 2-carboxyethylgermanium;trihydrate Chemical compound O.O.O.OC(=O)CC[Ge] LZIZCRNBBGNAJO-UHFFFAOYSA-N 0.000 description 1
- JNBNHESIBOINSU-UHFFFAOYSA-N 3-germylpropanoic acid Chemical compound OC(=O)CC[GeH3] JNBNHESIBOINSU-UHFFFAOYSA-N 0.000 description 1
- NDXDBRPAQRIKCT-UHFFFAOYSA-N C(=O)(O)CC[Ge]O Chemical compound C(=O)(O)CC[Ge]O NDXDBRPAQRIKCT-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 235000012601 Euterpe oleracea Nutrition 0.000 description 1
- 244000207620 Euterpe oleracea Species 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 235000003650 acai Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
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- 238000013480 data collection Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- YOMFVLRTMZWACQ-UHFFFAOYSA-N ethyltrimethylammonium Chemical compound CC[N+](C)(C)C YOMFVLRTMZWACQ-UHFFFAOYSA-N 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002291 germanium compounds Chemical class 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000000082 organogermanium group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229950004871 repagermanium Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- SEACXNRNJAXIBM-UHFFFAOYSA-N triethyl(methyl)azanium Chemical compound CC[N+](C)(CC)CC SEACXNRNJAXIBM-UHFFFAOYSA-N 0.000 description 1
- 230000014567 type I interferon production Effects 0.000 description 1
- 238000001132 ultrasonic dispersion Methods 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/30—Germanium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
晶系:triclinic
空間群:P -1
格子定数:a=11.8879(7)、b=20.6589(12)、c=22.5198(13)、α=63.5610(10)、β=76.4800(10)、γ=81.3480(10)
単位格子体積:V=4808.14
1)合成
2 LビーカーにGe-132(500 g, モノマー換算で2.95 mol)を秤量し、蒸留水1 Lを加えて懸濁した。テフロン(登録商標)容器に95%水酸化ナトリウム(124 g, 2.95 mol)を秤量し、蒸留水500 mLを加えて溶解した。先のGe-132水懸濁液に水酸化ナトリウム水溶液を撹拌下で数回に分けて添加して中和し、Ge-132を溶解した。2 Lナスフラスコに中和溶液を移し、減圧下で加熱して約1 Lになるまで濃縮した。濃縮液を5 L容器に移し替え、3 Lのエタノールを添加し、十分に撹拌した後に室温下で24時間静置した。析出した結晶を吸引ろ過及びろ集して風乾し、さらにグラスチューブオーブンで105℃、8時間以上減圧下で加熱して乾燥させ、白色結晶として目的の化合物を収率95%で得た。得られた結晶のサイズは8 μm×2 μm、結晶形状は板状であった。
1)で得られた結晶をメタノールに溶解して飽和メタノール溶液を調製した。これを密栓せずに室温下で静置してメタノールを徐々に蒸発させることで、1 mm以上に成長した板状の結晶を得た。結晶を回収し、単結晶X線構造解析装置(SMART APEX II ULTRA、Bruker社)を用いて、以下の条件でX線回折強度の測定を行った。
検出器: Bruker APEXII CCD area detector
光源の種類:Bruker TXS fine-focus rotating anode
使用波長:Mo 0.71073 Å
管電流:24 mA
管電圧:50 kv
スキャン幅:0.5°
露光時間:3 s
解析ソフト及び手法:
data_collection 'APEX2 '
cell_refinement 'APEX2 (Bruker AXS, 2006)'
data_reduction 'SAINT (Bruker AXS, 2004)'
structure_solution 'SHELXS-97 (Sheldrick, 1997)'
structure_refinement 'SHELXL-97 (Sheldrick, 1997)'
molecular_graphics 'XSHEL (Bruker AXS,2002)'
publication_material 'XCIF (Bruker AXS, 2001)'
晶系:triclinic
空間群:P -1
格子定数:a=11.8879(7)、b=20.6589(12)、c=22.5198(13)、α=63.5610(10)、β=76.4800(10)、γ=81.3480(10)
単位格子体積:V=4808.14
1)で得られたTHGPオクタマー100 mgに精製水又はメタノールを少量ずつ加えて室温下で30分間撹拌する作業を繰り返し、目視によりTHGPオクタマーが完全に溶解したと認められる液量を測定した。測定した液量からTHGPオクタマーの溶解度(溶質量(g)/総質量(g)×100%)を算出した。また、完全溶解したときの溶液のpHを測定した。
精製水10 mLにGe-132及びTHGPオクタマー100 mgをそれぞれ加えて、室温下、300 rpmの速度で撹拌し、目視で完全に溶解したと認められるまでに要する時間を測定した。
レーザー回折式粒度分布測定装置(HRA、マイクロトラック社製)を用い、エタノールを分散媒として、1分間の超音波分散後、THGPオクタマーの粒度分布を測定した。測定条件は以下のとおりである。
測定範囲:0.06〜1400 μm
使用光源:炭酸ガスレーザー×3個
検出器:散乱光検出器
臭化カリウム(KBr)とTHGPオクタマー又はGe-132との混合物を錠剤化したものについて、赤外分光光度計(FTIR-8100M、島津製作所社製)を用いて赤外分光分析を行った。分析条件は以下のとおりである。
測定手法:KBr錠剤法
測定範囲:400〜4600 cm-1
分解能:4 cm-1
ミラースピード:2.8 mm/sec
積算回数:40回
THGPオクタマーのメタノール溶液を質量分析計(TOF-MS、QToF Ultima、Waters社)に供し、質量分析を行った。分析条件は以下のとおりである。
イオン化モード:ESI+
移動相:メタノール
THGPオクタマーを重水及び重メタノールにそれぞれ溶解した溶液について、核磁気共鳴装置(Gemini 2000、アジレント・テクノロジー社)を用いて1H NMRスペクトルを測定した。比較対照としてGe-132を重水に溶解後、重水酸化ナトリウム溶液で中和した溶液を調製し、同様に測定した。測定条件は25℃、積算回数16回、300 MHzとし、残存するHODのシグナルを4.80 ppmにオフセットした。
重水にTHGPオクタマーとアデノシンとを溶解して得た混合溶液(混合モル比1:1、pH7.0〜7.5、100 mM)について、30℃、積算回数16回、300 MHzの測定条件のもと、1H NMRスペクトルを測定した。残存するHODのシグナルを4.80 ppmにオフセットした。比較対照としてGe-132とアデノシンの混合溶液についても同様に測定した。
重水で調製した10 mMリン酸緩衝液(pH7.4)にTHGPオクタマーとNaHS(H2Sのナトリウム塩)とを溶解して得た混合溶液(混合モル比1:1、pH7.0〜7.5、20 mM)について、25℃、積算回数16回、300 MHzの測定条件のもと、1H NMRスペクトルを測定した。残存するHODのシグナルを4.80 ppmにオフセットした。比較対照としてGe-132とNaHSの混合溶液についても同様に測定した。
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