RU2629186C1 - Racemic 2,17alfabeta-disulfamoyloxy-3-methoxy-d-homo-8alpha-estra-1,3,5 (10)-triene as msf-7 tumor cells proliferation inhibitor - Google Patents
Racemic 2,17alfabeta-disulfamoyloxy-3-methoxy-d-homo-8alpha-estra-1,3,5 (10)-triene as msf-7 tumor cells proliferation inhibitor Download PDFInfo
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- estra
- methoxy
- homo
- triene
- disulfamoyloxy
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- 210000004881 tumor cell Anatomy 0.000 title claims abstract description 8
- 239000003112 inhibitor Substances 0.000 title claims abstract description 6
- 230000004663 cell proliferation Effects 0.000 title claims abstract 3
- 210000004027 cell Anatomy 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 206010006187 Breast cancer Diseases 0.000 abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 239000003966 growth inhibitor Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 150000003431 steroids Chemical class 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 210000001626 skin fibroblast Anatomy 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical group NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000005262 Sulfatase Human genes 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 2
- 108060007951 sulfatase Proteins 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229940123142 Steroid sulfatase inhibitor Drugs 0.000 description 1
- ZVSCPWTWOPVEDW-WKUFJEKOSA-N [(8R,9S,13S,14S)-13-methyl-3-sulfamoyloxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] sulfamate Chemical class NS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)OS(N)(=O)=O)[C@@H]4[C@@H]3CCC2=C1 ZVSCPWTWOPVEDW-WKUFJEKOSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Изобретение относится к синтезу рацемического 2,17аβ-дисульфамоилокси-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триена, ингибирующего пролиферацию опухолевых клеток МСF-7. Это предполагает возможность его применения в медицине.The invention relates to the synthesis of racemic 2,17aβ-disulfamoyloxy-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene, inhibiting the proliferation of tumor cells MCF-7. This suggests the possibility of its use in medicine.
Рак молочной железы (РМЖ) у женщин является «ведущим» онкологическим заболеванием [1]. 60-70% опухолей этой локализации эстрогенозависимы [1], т.е. скорость пролиферации опухолевых клеток значительно возрастает в присутствии этой группы гормонов. В настоящее время разрабатывается новая стратегическая линия лечения таких заболеваний под действием различных носителей, содержащих сульфаматную группу [2]. Этот подход считают весьма перспективным, поскольку сульфаматы стероидных эстрогенов могут ингибировать рост различных видов злокачественных опухолей [3-5]. Как правило, используют модифицированные стероидные эстрогены с сульфаматной группой при С-3, единственным исключением является соединение (I) [6] – прототип.Breast cancer (BC) in women is the "leading" oncological disease [1]. 60-70% of tumors of this localization are estrogen-dependent [1], ie the proliferation rate of tumor cells increases significantly in the presence of this group of hormones. A new strategic line is being developed for the treatment of such diseases under the influence of various carriers containing a sulfamate group [2]. This approach is considered very promising, since sulfamates of steroid estrogens can inhibit the growth of various types of malignant tumors [3-5]. As a rule, modified steroid estrogens with a sulfamate group are used at C-3, the only exception is compound (I) [6] - the prototype.
Целью изобретения является создание новых ингибиторов роста клеток рака молочной MCF-7, подобных стероиду (I).The aim of the invention is the creation of new inhibitors of breast cancer cell growth MCF-7, similar to steroid (I).
Поставленная цель достигается синтезом рацемического 2,17аβ-дисульфамоилокси-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триена (II), отличающегося от стероида (I) величиной кольца D. В принципе это должно способствовать более легкому проникновению данного соединения в опухолевые клетки. Дополнительным преимуществом схемы синтеза является большая доступность исходного стероида (III) по сравнению с использованным ранее при получении сульфамата (I).This goal is achieved by the synthesis of racemic 2,17aβ-disulfamoyloxy-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene (II), which differs from steroid (I) by the size of the ring D. In principle, this should facilitate easier penetration of this compound into tumor cells. An additional advantage of the synthesis scheme is the greater availability of the starting steroid (III) compared to that previously used in the preparation of sulfamate (I).
Схема синтеза сульфамата (II) представлена ниже.The synthesis scheme for sulfamate (II) is presented below.
Ацетат 2-ацето-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триен-17аβ-ола (IV).2-Aceto-3-methoxy-D-homo-8α-estra-1,3,5 (10) -trien-17aβ-ol (IV) acetate.
К раствору 5 г соединения (Ш) [7] в 50 мл нитробензола и 2 мл уксусного ангидрида добавляют раствор 7 г хлористого алюминия в 50 мл нитробензола при 0oC. Реакционную смесь перемешивают при 5oC в течение 24 ч, после чего выливают в 300 мл воды со льдом. Продукты реакции экстрагируют тремя порциями хлороформа по 150 мл, объединенный экстракт промывают равным объемом 1%-ного раствора бикарбоната натрия, затем равным объемом воды, сушат над сульфатом натрия. Осушитель отфильтровывают, растворители удаляют в вакууме при давлении 4 мм рт. столба и температуре 75ºC, остаток кристаллизуют из смеси хлороформ-метанол. Получают 4.44 г соединения (IV) (выход 79%, т. пл. 191.5-193ºС).To a solution of 5 g of compound (III) [7] in 50 ml of nitrobenzene and 2 ml of acetic anhydride, a solution of 7 g of aluminum chloride in 50 ml of nitrobenzene was added at 0 ° C. The reaction mixture was stirred at 5 ° C for 24 hours, after which it was poured. in 300 ml of ice water. The reaction products are extracted with three 150 ml portions of chloroform, the combined extract is washed with an equal volume of 1% sodium bicarbonate solution, then with an equal volume of water, dried over sodium sulfate. The desiccant is filtered off, the solvents are removed in vacuo at a pressure of 4 mm Hg. column and a temperature of 75ºC, the residue is crystallized from a mixture of chloroform-methanol. 4.44 g of compound (IV) are obtained (yield 79%, mp 191.5-193 ° C).
Найдено, %: С 74.85; Н 8.44. С24Н32О4. Вычислено, %: С 74.97; Н 8.39.Found,%: C 74.85; H 8.44. C 24 H 32 O 4 . Calculated,%: C 74.97; H, 8.39.
2,17аβ-Диацетокси-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триен (V). К раствору 1 г соединения (IV) в 20 мл хлористого метилена добавляли 600 мг Na2HPO4 и 800 мг м-хлор-надбензойной кислоты в 20 мл хлористого метилена. Реакционную смесь перемешивали 20 ч при комнатной температуре, а затем выливали в 350 мл диэтилового эфира. После обычной обработки органическую фазу промывали равным объемом насыщенного раствора бикарбоната натрия, а затем водой до нейтральной реакции. Растворители удаляли в вакууме, остаток кристаллизовали из смеси этилацетат-гексан, получали 780 мг (75%) соединения (V), т. пл. 178.5-179.5ºС.2.17aβ-diacetoxy-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene (V). To a solution of 1 g of compound (IV) in 20 ml of methylene chloride were added 600 mg of Na 2 HPO 4 and 800 mg of m-chlorobenzoic acid in 20 ml of methylene chloride. The reaction mixture was stirred for 20 hours at room temperature, and then poured into 350 ml of diethyl ether. After conventional treatment, the organic phase was washed with an equal volume of saturated sodium bicarbonate solution and then with water until neutral. The solvents were removed in vacuo, the residue was crystallized from ethyl acetate-hexane to give 780 mg (75%) of compound (V), mp 178.5-179.5ºС.
Спектр ЯМР 13С, δ, м.д.: 122.4 (С1), 137.6 (С2), 148.5 (С3), 111.9 (С4), 134.8 (С5), 31.0 (С6), 20.8 (C7), 37.1 (С8), 39.6 (С9), 134.1 (С10), 27.6 (С11), 37.1 (С12), 41.2 (С13), 46.4 (С14), 23.9 (С15), 25.4 (С16), 27.0 (С17), 81.5 (C17a), 13.5 (С18), 55.7 (СН3О), 20.9 и 170.7 (ацетильная группа при С17а), 20.3 и 169.2 (ацетильная группа при С2). 13 C NMR spectrum, δ, ppm: 122.4 (С 1 ), 137.6 (С 2 ), 148.5 (С 3 ), 111.9 (С 4 ), 134.8 (С 5 ), 31.0 (С 6 ), 20.8 ( C 7 ), 37.1 (C 8 ), 39.6 (C 9 ), 134.1 (C 10 ), 27.6 (C 11 ), 37.1 (C 12 ), 41.2 (C 13 ), 46.4 (C 14 ), 23.9 (C 15 ), 25.4 (С 16 ), 27.0 (С 17 ), 81.5 (С 17a ), 13.5 (С 18 ), 55.7 (СН 3 О), 20.9 and 170.7 (acetyl group at С 17а ), 20.3 and 169.2 (acetyl group at C 2 ).
Масс-спектр, m/z (%): 400 (15), 358 (100), 243 (2), 189 (6), 188 (4), 187(4), 176 (9), 175 (8), 163 (4), 150 (4), 137 (6).Mass spectrum, m / z (%): 400 (15), 358 (100), 243 (2), 189 (6), 188 (4), 187 (4), 176 (9), 175 (8) , 163 (4), 150 (4), 137 (6).
Найдено, %: С 72.12; Н 8.14. С24Н32О5. Вычислено, %: С 71.97; Н 8.05.Found,%: C 72.12; H 8.14. C 24 H 32 O 5 . Calculated,%: C 71.97; H, 8.05.
2,17аβ-Дигидрокси-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триен (VI).2.17aβ-dihydroxy-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene (VI).
К раствору 200 мг 2,17aβ-диацетокси-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триенa (V) в смеси 5 мл бензола и 3 мл метанола добавляют 150 мг NaOH и перемешивают 2 часа при 50ºС, ход реакции контролируют методом ТСХ. Реакционную смесь выливают в 1н HCl (10 мл), экстрагируют этилацетатом (3×10 мл). Органические слои промывают водой (2×5 мл), насыщенным раствором хлористого натрия (1×15 мл), сушат над сульфатом натрия. Растворитель удаляют на роторном испарителе, остаток кристаллизуют из метанола. Получают 145 мг (95%) продукта гидролиза, т. пл. 210-212ºС.To a solution of 200 mg of 2.17aβ-diacetoxy-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene (V) in a mixture of 5 ml of benzene and 3 ml of methanol, 150 mg of NaOH are added and stirred 2 hours at 50 ° C, the progress of the reaction is controlled by TLC. The reaction mixture was poured into 1N HCl (10 ml), extracted with ethyl acetate (3 × 10 ml). The organic layers are washed with water (2 × 5 ml), saturated sodium chloride solution (1 × 15 ml), dried over sodium sulfate. The solvent is removed on a rotary evaporator, the residue is crystallized from methanol. Get 145 mg (95%) of the hydrolysis product, so pl. 210-212ºС.
Спектр ЯМР 1Н (DMSO, δ, м.д.): 8.49 с (1H), 6.51 с (1Н), 6.48 с (1Н), 4.26 с (1Н), 3.69 с (3H), 3.01 д (1H, J=21.1 Гц) 2.59 т (1H, J=13.8 Гц), 2.47-2.37 м (2H), 1.83-1.49 м (9H), 1.35-1.24 м (3H) 1.16-1.03 м (2H) 0.78 с (3Н). 1H NMR spectrum (DMSO, δ, ppm): 8.49 s (1H), 6.51 s (1H), 6.48 s (1H), 4.26 s (1H), 3.69 s (3H), 3.01 d (1H, J = 21.1 Hz) 2.59 t (1H, J = 13.8 Hz), 2.47-2.37 m (2H), 1.83-1.49 m (9H), 1.35-1.24 m (3H) 1.16-1.03 m (2H) 0.78 s (3H) .
Спектр ЯМР 13С (DMSO, δ, м.д.): 146.50, 145.22, 134.79, 127.10, 116.39, 112.93, 79.35, 56.41, 47.02, 42.07, 42.23, 39.10, 38.70, 31.58, 31.33, 29.00, 26.54, 25.25, 22.01 13.35 13C NMR (DMSO, δ, ppm): 146.50, 145.22, 134.79, 127.10, 116.39, 112.93, 79.35, 56.41, 47.02, 42.07, 42.23, 39.10, 38.70, 31.58, 31.33, 29.00, 26.54, 25.25, 01/22 13.35
Найдено, %: С 75.84, Н 8.90. С20Н28О3. Вычислено, %: С 75.91; Н 8.92.Found,%: C 75.84, H 8.90. C 20 H 28 O 3 . Calculated,%: C 75.91; H, 8.92.
2,17аβ-Дисульфамоил-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триен (II).2.17aβ-Disulfamoyl-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene (II).
К раствору 100 мг 2,17аβ-дигидрокси-3-метокси-D-гомо-8α-эстра-1,3,5(10)-триена (VI) в 2 мл сухого диметилацетамида при комнатной температуре добавляют 150 мг сульфамоилхлорида, реакционную смесь перемешивают 8 ч при комнатной температуре в атмосфере аргона. Реакционную смесь выливают в насыщенный раствор хлористого натрия (10 мл), продукты реакции экстрагируют тремя порциями этилацетата по 5 мл. Объединенную органическую фазу промывают двумя порциями воды по 5 мл, равным объемом насыщенного раствора хлористого натрия, сушат над сульфатом натрия. Осушитель отфильтровывают, растворители удаляют в вакууме, остаток кристаллизуют из метанола, получают 105 мг (70%) целевого продукта, т. пл. 212-214ºС.To a solution of 100 mg of 2.17aβ-dihydroxy-3-methoxy-D-homo-8α-estra-1,3,5 (10) -triene (VI) in 2 ml of dry dimethylacetamide, 150 mg of sulfamoyl chloride are added at room temperature, the reaction mixture stirred for 8 hours at room temperature in an argon atmosphere. The reaction mixture was poured into a saturated solution of sodium chloride (10 ml), the reaction products were extracted with three 5 ml portions of ethyl acetate. The combined organic phase is washed with two 5 ml portions of water, an equal volume of a saturated solution of sodium chloride, dried over sodium sulfate. The desiccant is filtered off, the solvents are removed in vacuo, the residue is crystallized from methanol, 105 mg (70%) of the expected product are obtained, so pl. 212-214ºС.
Спектр ЯМР 1Н (DMSO, δ, м.д.): 7.80 с (2H), 7.35 с (2H), 7.05 с (1Н), 6.78 с (1Н), 4.00 м (1Н), 3.74 с (3H), 2.85-2.61 м (4H) 2.05-1.92 м (2H), 1.87-1.15 м (11H), 0.88 с (3Н). 1H NMR spectrum (DMSO, δ, ppm): 7.80 s (2H), 7.35 s (2H), 7.05 s (1H), 6.78 s (1H), 4.00 m (1H), 3.74 s (3H), 2.85-2.61 m (4H) 2.05-1.92 m (2H), 1.87-1.15 m (11H), 0.88 s (3H).
Спектр ЯМР 13С (DMSO, δ, м.д.): δ 150.23, 137.85, 135.86, 134.27 124.01, 113.77, 89.14, 56.58, 47.04, 41.55, 41.22, 38.78, 37.95, 31.58, 28.58, 28.43, 25.92, 24.81, 14.09. 13C NMR spectrum (DMSO, δ, ppm): δ 150.23, 137.85, 135.86, 134.27 124.01, 113.77, 89.14, 56.58, 47.04, 41.55, 41.22, 38.78, 37.95, 31.58, 28.58, 28.43, 25.92, 24.81, 09/14.
Найдено, %: С 50.72, Н 6.43 N 5.74. С20Н30N2О7S2. Вычислено, %: С 50.61; Н 6.37 N 5.90.Found,%: C 50.72, H 6.43 N 5.74. C 20 H 30 N 2 O 7 S 2 . Calculated,%: C 50.61; H 6.37; N 5.90.
Исследовали влияние стероида (II) на рост перевиваемой культуры клеток человека MCF-7 (аденокарцинома молочной железы). В качестве отрицательного контроля использовали нормальные кожные фибробласты человека (КФЧ) ранних пассажей. Клетки культивировали во флаконах Карреля в среде DMEM/F12 (Биолот) с добавлением 1% эмбриональной сыворотки крупного рогатого скота (Биолот), без антибиотиков, в 5% СО2 атмосфере, при 37оС. Клетки высаживались на флаконы Карреля по 50 х 104 клеток на флакон. Для изучения пролиферативной активности клеток через 24 часа после посева в культуральную среду заменяли на среду, содержащую ингибитор сульфатазы до конечной концентрации 50 мкг/мл, после чего инкубировали данные опухолевые клеточные линии в течение различных промежутков времени (от 24 до 72 ч). Конечная концентрация ДМСО в культуральной среде не превышала 0.5%. Для исключения цитотоксического действия ДМСО проводили опыты с добавлением ДМСО без ингибитора сульфатазы. Для исключения неспецифического губительного действия веществ использовались нормальные кожные фибробласты человека. Далее клетки снимали раствором версена-трипсина (Биолот), рассеивали на флаконы Карреля, содержащие новую полную культуральную среду. Подсчет клеток проводили в момент достижения необработанными контрольными клетками максимальной плотности клеток на единицу площади поверхности культурального флакона (монослой), при этом их количество определялось как 100 %. Оказалось, что при концентрации стероида (II) 20 мкг/мл рост опухолевых клеток тормозится примерно в той же степени, что и под действием применяемого в клинической практике тамоксифена. При этом стероид (II) не тормозил рост нормальных кожных фибробластов человека. Этот результат весьма важен, так как механизмы действия стероида (II) и тамоксифена различны.The effect of steroid (II) on the growth of transplantable human cell culture MCF-7 (mammary adenocarcinoma) was investigated. As a negative control, normal human skin fibroblasts (CPFs) of the early passages were used. Cells were cultured in flasks Carrel in DMEM / F12 medium (Biolot) supplemented with 1% fetal bovine serum (Biolot), without antibiotics, in 5% CO 2 atmosphere at 37 ° C. Cells were planted at vials Carrel 50 x 104 cells per vial. To study the proliferative activity of cells, 24 hours after plating, the culture medium was replaced with a medium containing a sulfatase inhibitor to a final concentration of 50 μg / ml, after which these tumor cell lines were incubated for various periods of time (from 24 to 72 hours). The final concentration of DMSO in the culture medium did not exceed 0.5%. To exclude the cytotoxic effect of DMSO, experiments were carried out with the addition of DMSO without a sulfatase inhibitor. To exclude the nonspecific deleterious effect of the substances, normal human skin fibroblasts were used. Then the cells were removed with a solution of versene-trypsin (Biolot), scattered on Carrel vials containing a new complete culture medium. Cell counting was performed at the time the untreated control cells reached the maximum cell density per unit surface area of the culture vial (monolayer), and their number was determined as 100%. It turned out that at a concentration of steroid (II) of 20 μg / ml, the growth of tumor cells is inhibited approximately to the same extent as under the influence of tamoxifen used in clinical practice. In this case, the steroid (II) did not inhibit the growth of normal human skin fibroblasts. This result is very important, since the mechanisms of action of the steroid (II) and tamoxifen are different.
ЛитератураLiterature
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| RU2562242C1 (en) * | 2014-07-10 | 2015-09-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Санкт-Петербургский государственный университет" (СПбГУ) | RACEMIC 2,17β-DISULFOMOYLOXY-3-METHOXY-8α-EXTRA-1,3,5(10)-TRIENE AS INHIBITOR OF TUMOUR CELL PROLIFERATION OF MCF-7 |
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