RU2624439C1 - 5-oxo-pro-arg-pro labeled by tritium on all amino acid residues - Google Patents
5-oxo-pro-arg-pro labeled by tritium on all amino acid residues Download PDFInfo
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- RU2624439C1 RU2624439C1 RU2016119012A RU2016119012A RU2624439C1 RU 2624439 C1 RU2624439 C1 RU 2624439C1 RU 2016119012 A RU2016119012 A RU 2016119012A RU 2016119012 A RU2016119012 A RU 2016119012A RU 2624439 C1 RU2624439 C1 RU 2624439C1
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- 229910052722 tritium Inorganic materials 0.000 title claims abstract description 22
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 title claims abstract description 21
- 108010055361 5-oxoprolyl-arginyl-proline Proteins 0.000 title claims abstract description 14
- 125000000539 amino acid group Chemical group 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910013684 LiClO 4 Inorganic materials 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 230000005574 cross-species transmission Effects 0.000 description 1
- 150000001975 deuterium Chemical class 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- 210000001362 glutamatergic neuron Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/008—Peptides; Proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0825—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Glp-amino acid; Derivatives thereof
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- Peptides Or Proteins (AREA)
Abstract
Description
Изобретение относится к области органической химии и может найти применение в аналитической химии и биологических исследованиях.The invention relates to the field of organic chemistry and may find application in analytical chemistry and biological research.
При изучении физиологически активных соединений необходимы их меченые аналоги.When studying physiologically active compounds, their labeled analogues are necessary.
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) [1].It is known that the replacement of 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) [1].
Кроме того, показано, что реакции дейтерия и трития с веществами, нанесенными на поверхность катализатора, происходят с близкими скоростями и одинаковой селективностью, а отношение скоростей этих реакций приближается к единице (Золотарев Ю.А., Дадаян А.К., Кост Н.В., Воеводина М.Э., Соколов О.Ю., Козик B.C., Шрам С.И., Азев В.Н., Бочаров Э.В., Богачук А.П., Липкин В.М., Мясоедов Н.Ф. Количественный анализ пептида HLDF-6-амида и его метаболитов в тканях лабораторных животных с использованием их меченных тритием и дейтерием производных // Биоорганическая химия, 2015, том 41, №6, с. 644-656 и Zolotarev Yu. A., Dadayan А.К., Borisov Yu. A., Kozik V.S., Nazimov I.V., Ziganshin R.H., Bocharov E.V., Chizhov A.O., Myasoedov N.F. New Development in the Solid-State Isotope Exchange with Spillover Hydrogen in Organic Compounds // J. Phys. Chem. C. 2013. V. 117. P. 16878-16884) [2, 3].In addition, it was shown that the reactions of deuterium and tritium with substances deposited on the catalyst surface occur with similar rates and the same selectivity, and the ratio of the rates of these reactions approaches unity (Zolotarev Yu.A., Dadayan A.K., Kost N. V., Voevodina M.E., Sokolov O.Yu., Kozik BC, Scar S.I., Azev V.N., Bocharov E.V., Bogachuk A.P., Lipkin V.M., Myasoedov N .F. Quantitative analysis of the peptide HLDF-6-amide and its metabolites in the tissues of laboratory animals using their labeled with tritium and deuterium derivatives // Bioorganic chemistry I, 2015, Volume 41, No. 6, pp. 644-656 and Zolotarev Yu. A., Dadayan A.K., Borisov Yu. A., Kozik VS, Nazimov IV, Ziganshin RH, Bocharov EV, Chizhov AO, Myasoedov NF New Development in the Solid-State Isotope Exchange with Spillover Hydrogen in Organic Compounds // J. Phys. Chem. C. 2013. V. 117. P. 16878-16884) [2, 3].
Также в работе [1] показано, что в биологических исследованиях принципиально важную роль играет распределение трития в молекулах меченых препаратов. В работе подчеркивается, что при исследовании метаболизма лекарственных препаратов стабильность положения трития является одним из наиболее важных условий биологического эксперимента. Для каждого конкретного исследования требуется определенное распределение трития в молекулах меченых препаратов. Химически устойчивый связанный атом трития может стать подвижным при взаимодействии тритийсодержащего соединения с энзимом. В результате этого атом трития может быть потерян, несмотря на полную сохранность углеродного скелета молекулы. Если же тритий находится в другом фрагменте молекулы вещества или в молекулах вещества их несколько, то вероятность получения более достоверных данных значительно повышается. При этом важно не только распределение трития, но даже и его стереохимическая конформация. Например, показано, что конверсия холестерина-4-14С-7а-3Н в холевую кислоту в организме крысы in vivo ведет к потере, по меньшей мере, 93% трития из положения 7. Однако при использовании холестерина-4-14С-7β-3Н весь тритий оставался в холевой кислоте.It was also shown in [1] that in biological studies, the distribution of tritium in the molecules of labeled preparations plays a crucial role. The work emphasizes that in the study of drug metabolism, the stability of the position of tritium is one of the most important conditions of a biological experiment. For each specific study, a certain distribution of tritium in the molecules of the labeled preparations is required. A chemically stable bound tritium atom can become mobile upon the interaction of a tritium-containing compound with an enzyme. As a result, the tritium atom can be lost, despite the complete safety of the carbon skeleton of the molecule. If tritium is in another fragment of the molecule of the substance or there are several of them in the molecules of the substance, then the probability of obtaining more reliable data is significantly increased. It is important not only the distribution of tritium, but even its stereochemical conformation. For example, it is shown that the conversion of cholesterol-4- 14 C-3 H 7a- cholic acid in the body in vivo rat leads to a loss of at least 93% of the tritium position 7. However, the use of cholesterol-14 C 4- 7β- 3 N all tritium remained in cholic acid.
Известен 5-oxo-Pro-Arg-Pro формулы:Known 5-oxo-Pro-Arg-Pro formulas:
5-oxo-Pro-Arg-Pro - универсальный анксиолитик, проявляет гипогликемический эффект в организме животных, даже на фоне такой патологии, как метаболический синдром, снижает агрегацию тромбоцитов, восстанавливает нормальные значения показателей общего холестерина, липидного профиля даже при одновременном употреблении в пищу продуктов, приводящих к повышению уровня холестерина крови. Установлены антикоагулянтно-фибринолитические и антитромбоцитарные эффекты этого пептида, а также, что 5-oxo-Pro-Arg-Pro активен в отношении глутаматергических нейронов и будет вызывать биологические эффекты, связанные с изменением функциональной активности глутаматергической системы мозга (Глазова Н.Ю., Левицкая Н.Г., Андреева Л.А., Каменский А.А., Мясоедов Н.Ф. // Докл. АН физиология. 1999. Т 367. №1, С. 137-140 [4]).5-oxo-Pro-Arg-Pro is a universal anxiolytic, exhibits a hypoglycemic effect in animals, even against the background of a pathology such as metabolic syndrome, reduces platelet aggregation, restores normal values of total cholesterol, lipid profile even while eating food leading to increased blood cholesterol. The anticoagulant-fibrinolytic and antiplatelet effects of this peptide were established, as well as that 5-oxo-Pro-Arg-Pro is active against glutamatergic neurons and will cause biological effects associated with a change in the functional activity of the glutamatergic system of the brain (Glazova N.Yu., Levitskaya N.G., Andreeva L.A., Kamensky A.A., Myasoedov N.F. // Report of the Academy of Sciences of Physiology. 1999. T 367. No. 1, P. 137-140 [4]).
Однако его аналог, меченный тритием по всем аминокислотным остаткам, не описан.However, its analogue, labeled with tritium for all amino acid residues, is not described.
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 меченного тритием по всем аминокислотным остаткам 5-oxo-Pro-Arg-Pro формулыThis technical result is achieved by obtaining tritium-labeled 5-oxo-Pro-Arg-Pro formula for all amino acid residues
Ниже приведен пример реализации изобретения.The following is an example implementation of the invention.
Пример I.Example I.
Раствором 5 мг 5-oxo-Pro-Arg-Pro в 30 мкл воды пропитывали 50 мг 5% Pd/BaSO4 и лиофилизировали.A solution of 5 mg of 5-oxo-Pro-Arg-Pro in 30 μl of water was impregnated with 50 mg of 5% Pd / BaSO 4 and lyophilized.
В ампулу помещали 40 мг смеси, вакуумировали и заполняли газообразным тритием до давления 400 гПа. Реакцию вели при 190°С в течение 10 мин. Затем ампулу вакуумировали, катализатор удаляли на фильтре, вещество экстрагировали метанолом (5×2 мл). Экстракты упаривали, остаток растворяли в метаноле (3×1 мл) и вновь упаривали для удаления лабильного трития. Конечный метанольный раствор содержал 450 мКи пептида.40 mg of the mixture was placed in an ampoule, evacuated, and filled with gaseous tritium to a pressure of 400 hPa. The reaction was carried out at 190 ° C for 10 min. Then the ampoule was evacuated, the catalyst was removed on the filter, the substance was extracted with methanol (5 × 2 ml). The extracts were evaporated, the residue was dissolved in methanol (3 × 1 ml) and again evaporated to remove labile tritium. The final methanol solution contained 450 mCi of peptide.
Меченный тритием 5-oxo-Pro-Arg-Pro очищали препаративной высокоэффективной жидкостной хроматографией. После очистки радиохимическая чистота меченого 5-oxo-Pro-Arg-Pro - не менее 97-98%, выход - 75%, молярная радиоактивность - 60 Ки/ммоль (табл.).Tritium-labeled 5-oxo-Pro-Arg-Pro was purified by preparative high performance liquid chromatography. After purification, the radiochemical purity of the labeled 5-oxo-Pro-Arg-Pro is not less than 97-98%, the yield is 75%, the molar radioactivity is 60 Ci / mmol (table).
Анализ реакционных смесей проводили на хроматографе Милихром-А02, длины волн (нм): 200, 210, 220, 230, 240, с использованием колонки ProntoSIL-120-5-C18 AQ DB-2003 (2×75 мм, размер частиц 5 мкм), в градиенте метанол-буфер (0.2 М LiClO4+0.005 М HClO4, рН 2.24) в течение 12 мин при температуре 35°С. Анализ 5-oxo-Pro-Arg-Pro проводили, увеличивая концентрацию метанола с 1 до 30%. Скорость подачи элюента - 0.2 мл/мин, время удерживания 5-оксо-Pro-Arg-Pro - 8.11 мин.Analysis of the reaction mixtures was performed on a Milichrom-A02 chromatograph, wavelength (nm): 200, 210, 220, 230, 240, using a ProntoSIL-120-5-C 18 AQ DB-2003 column (2 × 75 mm, particle size 5 μm), in a gradient methanol-buffer (0.2 M LiClO 4 +0.005 M HClO 4 , pH 2.24) for 12 min at a temperature of 35 ° C. Analysis of 5-oxo-Pro-Arg-Pro was carried out by increasing the concentration of methanol from 1 to 30%. The flow rate of the eluent is 0.2 ml / min, the retention time of 5-oxo-Pro-Arg-Pro is 8.11 minutes.
Препаративное выделение меченого пептида проводили на колонке Kromasil 100 С18 (8×150 мм, 7 мкм), в градиенте метанола и 0.1% водной трифторуксусной кислоты в течение 30 мин, увеличивая концентрацию метанола с 0 до 50%. Скорость подачи элюента - 2 мл/мин, время удерживания 5-oxo-Pro-Arg-Pro - 20.9 мин.Preparative isolation of the labeled peptide was carried out on a Kromasil 100 C18 column (8 × 150 mm, 7 μm), in a gradient of methanol and 0.1% aqueous trifluoroacetic acid for 30 min, increasing the methanol concentration from 0 to 50%. The flow rate of the eluent is 2 ml / min, the retention time of 5-oxo-Pro-Arg-Pro is 20.9 minutes.
Таким образом, получен меченный тритием по всем аминокислотным остаткам 5-охо-Pro-Arg-Pro.Thus, tritium-labeled 5-oxo-Pro-Arg-Pro was obtained for all amino acid residues.
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| RU2513852C1 (en) * | 2013-02-11 | 2014-04-20 | Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук (ИМГ РАН) | UNIFORMLY TRITIUM-LABELLED PYRO-Glu-His-Pro-NH2 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2513852C1 (en) * | 2013-02-11 | 2014-04-20 | Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук (ИМГ РАН) | UNIFORMLY TRITIUM-LABELLED PYRO-Glu-His-Pro-NH2 |
Non-Patent Citations (1)
| Title |
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| V. P. Shevchenko et al, "Deuterium labeling of glyprolines by isotope exchange", Doklady Chemistry, February 2016, Volume 466, Issue 2, pp 48-52. * |
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