RU2305103C1 - Uniformly tritium-labeled [3h]-14-hydroxydaunomycin of adriamycinone - Google Patents
Uniformly tritium-labeled [3h]-14-hydroxydaunomycin of adriamycinone Download PDFInfo
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- RU2305103C1 RU2305103C1 RU2006119312/04A RU2006119312A RU2305103C1 RU 2305103 C1 RU2305103 C1 RU 2305103C1 RU 2006119312/04 A RU2006119312/04 A RU 2006119312/04A RU 2006119312 A RU2006119312 A RU 2006119312A RU 2305103 C1 RU2305103 C1 RU 2305103C1
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- Prior art keywords
- tritium
- labeled
- uniformly
- adriamycinone
- hydroxydaunomycin
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- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 title claims abstract description 13
- 229910052722 tritium Inorganic materials 0.000 title claims abstract description 13
- IBZGBXXTIGCACK-CWKPULSASA-N Adriamycinone Chemical compound C1[C@@](O)(C(=O)CO)C[C@H](O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O IBZGBXXTIGCACK-CWKPULSASA-N 0.000 title abstract 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 14
- 229940009456 adriamycin Drugs 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AOZUYISQWWJMJC-UHFFFAOYSA-N acetic acid;methanol;hydrate Chemical compound O.OC.CC(O)=O AOZUYISQWWJMJC-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 2
- 229910003445 palladium oxide Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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Abstract
Description
Изобретение относится к области органической химии и может найти применение в аналитической химии, биоорганической химии, биохимии и прикладной медицине.The invention relates to the field of organic chemistry and can find application in analytical chemistry, bioorganic chemistry, biochemistry and applied medicine.
При изучении физиологически активных соединений необходимы их меченые аналоги.In the study of physiologically active compounds, their labeled analogues are necessary.
Известен 14-гидроксидауномицин адриамицинона формулы I:Known 14-hydroxidaunomycin adriamycin of the formula I:
Данное соединение необходимо для изучения карценогенеза: Seventh Annual Report on Carcinogens (PB95-109781, 1994) p. 86. The Merck Index 1999 N 3495) [1].This compound is necessary for the study of carcinogenesis: Seventh Annual Report on Carcinogens (PB95-109781, 1994) p. 86. The Merck Index 1999 N 3495) [1].
Однако его равномерномеченный тритием аналог не описан.However, its counterpart uniformly labeled with tritium is not described.
Известно, что замена атомов соединений на их меченые аналоги не приводит к изменению каких-либо свойств исходного соединения (Evans Е.А. Tritium and its compounds London Butterworths. 1974, p.48) [2].It is known that replacing the atoms of compounds with their labeled analogues does not lead to a change in any properties of the starting compound (Evans EA, Tritium and its compounds London Butterworths. 1974, p. 48) [2].
Техническим результатом, достигаемым настоящим изобретением, является расширение ассортимента меченых аналогов физиологически активных соединений.The technical result achieved by the present invention is to expand the range of labeled analogues of physiologically active compounds.
Достигается указанный технический результат получением равномерномеченного тритием 14-[3Н]-гидроксидауномицина адриамицинона формулы I.This technical result is achieved by obtaining uniformly labeled with tritium 14- [ 3 H] -hydroxidaunomycin adriamycin of formula I.
На чертеже представлен результат ВЭЖХ полученного равномерномеченного тритием 14-[3Н]-гидроксидауномицина адриамицинона на колонке Kromasil 100C18, 4.0×150 мм, 6.0 мкм, скорость элюента 1.0 мл/мин, в системе метанол-вода-уксусная кислота, 40:60:0.1, время удерживания 4.28 мин).The drawing shows the result of HPLC obtained uniformly labeled with tritium 14- [ 3 H] -hydroxidunomycin adriamycin on a column Kromasil 100C 18 , 4.0 × 150 mm, 6.0 μm, eluent speed 1.0 ml / min, in the system methanol-water-acetic acid, 40:60 : 0.1, retention time 4.28 min).
Ниже приведен пример реализации изобретения.The following is an example implementation of the invention.
В первую камеру реакционной двухкамерной ампулы помещали 60 мг окиси палладия и 60 мг 5% PdO/BaSO4, в другую - 15 мг 14-гидроксидауномицина адриамицинона, 16 мг борной кислоты и 300 мкл смеси диоксана с триэтиламином (9:1). Вторую камеру замораживали жидким азотом, ампулу вакуумировали до давления 0.1 Па и заполняли газообразным тритием до давления 333 гПа. Затем первую камеру нагревали до 70°С. Окись палладия восстанавливалась, тритиевая вода перемораживалась во вторую камеру. Реакционную ампулу, не прекращая охлаждения второй камеры жидким азотом, вакуумировали до давления 0.1 Па и заполняли аргоном. Затем вторую камеру, содержащую 14-гидроксидауномицин адриамицинона, борную кислоту, диоксан, триэтиламин и тритиевую воду, запаивали и помещали в термостат. Изотопный обмен проводили в течение 30 мин при 115°С. Затем ампулу вскрывали, содержимое фильтровали, осадок промывали хлороформом (5×1 мл). Фильтраты объединяли и упаривали. Лабильный тритий удаляли, несколько раз растворяя вещество в метаноле (5×2 мл) и упаривая последний. Радиоактивность реакционной смеси составила 25 мКи. Анализ методом ВЭЖХ показал, что 8% метки содержалась в равномерномеченном тритием [3H]-14-гидроксидауномицине адриамицинона. После двойной очистки методом ВЭЖХ на колонке Kromasil 100C18 (4.0×150 мм, 6.0 мкм, скорость элюента 1,0 мл/мин, в системе метанол-вода-уксусная кислота, 40:60:0.1, время удерживания 4.28. мин) выделено 1 мКи целевого меченого соединения с молярной радиоактивностью 72 мКи/ммоль и радиохимической чистотой 98%.60 mg of palladium oxide and 60 mg of 5% PdO / BaSO 4 were placed in the first chamber of the reaction two-chamber ampoule, 15 mg of 14-hydroxidaunomycin adriamycin, 16 mg of boric acid, and 300 μl of a mixture of dioxane and triethylamine (9: 1) were placed in another. The second chamber was frozen with liquid nitrogen, the ampoule was evacuated to a pressure of 0.1 Pa and filled with gaseous tritium to a pressure of 333 hPa. Then the first chamber was heated to 70 ° C. Palladium oxide was reduced, tritium water was frozen in the second chamber. The reaction ampoule, without stopping the cooling of the second chamber with liquid nitrogen, was evacuated to a pressure of 0.1 Pa and filled with argon. Then the second chamber, containing 14-hydroxidaunomycin adriamycin, boric acid, dioxane, triethylamine and tritium water, was sealed and placed in a thermostat. Isotope exchange was carried out for 30 min at 115 ° C. Then the ampoule was opened, the contents were filtered, the precipitate was washed with chloroform (5 × 1 ml). The filtrates were combined and evaporated. Labile tritium was removed by dissolving the substance several times in methanol (5 × 2 ml) and evaporating the latter. The radioactivity of the reaction mixture was 25 mCi. HPLC analysis showed that 8% of the label was contained in the uniformly labeled with tritium [ 3 H] -14-hydroxidaunomycin adriamycin. After double purification by HPLC on a Kromasil 100C 18 column (4.0 × 150 mm, 6.0 μm, eluent speed 1.0 ml / min, methanol-water-acetic acid, 40: 60: 0.1, retention time 4.28 min.) 1 mCi of the labeled target compound with a molar radioactivity of 72 mCi / mmol and a radiochemical purity of 98%.
Таким образом, получено новое меченное тритием физиологически активное соединение.Thus, a new physiologically active compound labeled with tritium was obtained.
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| RU2006119312/04A RU2305103C1 (en) | 2006-06-02 | 2006-06-02 | Uniformly tritium-labeled [3h]-14-hydroxydaunomycin of adriamycinone |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2360896C1 (en) * | 2008-03-19 | 2009-07-10 | Институт молекулярной генетики Российской Академии наук (ИМГ РАН) (Статус Государственного учреждения) | Uniformly marked with tritium tilosin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1590045A3 (en) * | 1986-06-12 | 1990-08-30 | Фармиталиа Карло Эрба С.П.А.(Фирма) | Method of producing glycoside |
| WO2001021219A2 (en) * | 1999-09-21 | 2001-03-29 | The Government Of The United States Of America, As Represented By The Secretary Of Health And Human Services | Imaging of drug accumulation as a guide to antitumor therapy |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1590045A3 (en) * | 1986-06-12 | 1990-08-30 | Фармиталиа Карло Эрба С.П.А.(Фирма) | Method of producing glycoside |
| WO2001021219A2 (en) * | 1999-09-21 | 2001-03-29 | The Government Of The United States Of America, As Represented By The Secretary Of Health And Human Services | Imaging of drug accumulation as a guide to antitumor therapy |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2360896C1 (en) * | 2008-03-19 | 2009-07-10 | Институт молекулярной генетики Российской Академии наук (ИМГ РАН) (Статус Государственного учреждения) | Uniformly marked with tritium tilosin |
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