RU2767457C1 - Polynuclear biligand n,o-complexes of palladium (ii) and platinum (ii) with 1-[(dimethylamino)methyl]-2-naphthol, method for production and use thereof as agents having anticancer activity - Google Patents
Polynuclear biligand n,o-complexes of palladium (ii) and platinum (ii) with 1-[(dimethylamino)methyl]-2-naphthol, method for production and use thereof as agents having anticancer activity Download PDFInfo
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- GOHHBFSPKLRUNF-UHFFFAOYSA-N 1-[(dimethylamino)methyl]naphthalen-2-ol Chemical compound C1=CC=C2C(CN(C)C)=C(O)C=CC2=C1 GOHHBFSPKLRUNF-UHFFFAOYSA-N 0.000 title claims abstract description 25
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 17
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 230000001093 anti-cancer Effects 0.000 title abstract description 4
- 239000003795 chemical substances by application Substances 0.000 title abstract 2
- 238000004519 manufacturing process Methods 0.000 title 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 230000003993 interaction Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 230000001472 cytotoxic effect Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 229960004316 cisplatin Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229910014033 C-OH Inorganic materials 0.000 description 2
- 229910014570 C—OH Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000000074 matrix-assisted laser desorption--ionisation tandem time-of-flight detection Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- -1 Palladium(II) Thiosemicarbazone Complexes Chemical class 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- WTCRPVQWYABJEI-UHFFFAOYSA-N [Pt+] Chemical compound [Pt+] WTCRPVQWYABJEI-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229910006400 μ-Cl Inorganic materials 0.000 description 1
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- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0013—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group without a metal-carbon linkage
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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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/006—Palladium compounds
- C07F15/0066—Palladium compounds without a metal-carbon linkage
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Abstract
Description
Предлагаемое изобретение относится к области координационной и медицинской химии, в частности, к синтезу новых металлорганических соединений, проявляющих противоопухолевую активность, конкретно, моноядерным билигандным N,O-комплексам палладия(II) и платины(II) с 1-[(диметиламино)метил]-2-нафтолом общей формулы (1):The present invention relates to the field of coordination and medicinal chemistry, in particular, to the synthesis of new organometallic compounds exhibiting antitumor activity, in particular, mononuclear bigand N,O-complexes of palladium(II) and platinum(II) with 1-[(dimethylamino)methyl] -2-naphthol of general formula (1):
N,O-Комплексы палладия(II) и платины(II) с 1-[(диметиламино)метил]-2-нафтолом формулы (1) проявляют противоопухолевую активность и могут найти применение в медицине в качестве лекарственных средств.N,O-Complexes of palladium(II) and platinum(II) with 1-[(dimethylamino)methyl]-2-naphthol of formula (1) exhibit antitumor activity and can be used in medicine as medicines.
Известен способ [
Известным способом не могут быть получены N,О-комплексы палладия(II) и платины(II) с 1-[(диметиламино)метил]-2-нафтолом формулы (1).The known method can not be obtained N,O-complexes of palladium(II) and platinum(II) with 1-[(dimethylamino)methyl]-2-naphthol formula (1).
Известен способ [Belli Dell' Amico D., Colalillo M, Via L.D., Dell' Acqua M., Garcia-Argaez A.N., Hyeraci M., Labella L., Marchetti F., Samaritani S. Synthesis and reactivity of cytotoxic platinum(II) complexes of bidentate oximes: a step towards the functionalization of bioactive complexes // Eur. J. Inorg. Chem. 2018, 1589] получения моноядерного монолигандного N,O-комплекса платины(II) (3) реакцией оксима с trans-[PtCl(μ-Cl)(PPh3)]2 при мольном соотношении 1:1. Комплекс (3) проявляет антипролиферативную активность на клеточных линиях HeLa и А2780.There is a method [Belli Dell' Amico D., Colalillo M, Via LD, Dell' Acqua M., Garcia-Argaez AN, Hyeraci M., Labella L., Marchetti F., Samaritani S. Synthesis and reactivity of cytotoxic platinum(II ) complexes of bidentate oximes: a step towards the functionalization of bioactive complexes // Eur. J. Inorg. Chem. 2018, 1589] obtaining a mononuclear monoligand N,O-complex of platinum(II) (3) by the reaction of oxime with trans-[PtCl(μ-Cl)(PPh 3 )] 2 at a molar ratio of 1:1. Complex (3) exhibits antiproliferative activity on HeLa and A2780 cell lines.
Известным способом не могут быть получены N,О-комплексы палладия(II) и платины(II) с 1-[(диметиламино)метил]-2-нафтолом формулы (1).The known method can not be obtained N,O-complexes of palladium(II) and platinum(II) with 1-[(dimethylamino)methyl]-2-naphthol formula (1).
Наиболее близким к заявляемому способу (прототип) является способ [Iwata S., Takahashi Н., Ihara A., Hiramatsu K., Adachi J., Kawamorita S., Komiya N., Naota T. Synthesis, structures, and solid-state phosphorescence characteristics of trans-bis(salicylaldiminato)Pt(II) complexes bearing perpendicular N-aryl functionalities // Trans. Met. Chem. 2018, 43, 115] получения транс-бис(салицилальдиминато)Pt(II) комплексов (4) реакцией N-(салицилидин)арилиминов с PtCl2(CH3CN)2 при мольном соотношении 2:1 в среде диметилсульфоксида при 110°С в течение 18 ч.Closest to the claimed method (prototype) is the method [Iwata S., Takahashi N., Ihara A., Hiramatsu K., Adachi J., Kawamorita S., Komiya N., Naota T. Synthesis, structures, and solid-state phosphorescence characteristics of trans-bis(salicylaldiminato)Pt(II) complexes bearing perpendicular N-aryl functionalities // Trans. Met. Chem. 2018, 43, 115] obtaining trans-bis(salicyldiminato)Pt(II) complexes (4) by the reaction of N-(salicylidine)arylimines with PtCl 2 (CH 3 CN) 2 at a molar ratio of 2:1 in a dimethyl sulfoxide medium at 110°С within 18 hours
Изучение противоопухолевой активности данных моноядерных билигандных комплексов платины не проводилось. Известным способом не могут быть получены N,О-комплексы палладия(II) и платины(II) с 1-[(диметиламино)метил]-2-нафтолом формулы (1).The antitumor activity of these mononuclear bigand platinum complexes has not been studied. The known method can not be obtained N,O-complexes of palladium(II) and platinum(II) with 1-[(dimethylamino)methyl]-2-naphthol formula (1).
При изучении цитотоксической активности новых моноядерных билигандных Pd- и Pt-комплексов в качестве препарата сравнения взят эталонный противораковый препарат цисплатин - комплекс хлорид-аммиаката платины(II), противораковая активность которого описана в многочисленных источниках [E.R. Jamieson, S.J. Lippard. Structure, recognition, and processing of cisplatin-DNA adducts // Chem. Rev., 1999, 99, 2467-2498; S. Dasari, P.B. Tchounwou Cisplatin in cancer therapy: molecular mechanisms of action // Eur. J. Pharmacol, 2014, 740, 364-378; Машковский М.Д. Лекарственные средства. - 15-е изд. - М: Новая Волна, 2005. - 989 с.].When studying the cytotoxic activity of new mononuclear biligand Pd- and Pt-complexes, the reference anticancer drug cisplatin, a complex of platinum(II) chloride-ammonate, was taken as a reference drug, the anticancer activity of which is described in numerous sources [E.R. Jamieson, S.J. Lippard. Structure, recognition, and processing of cisplatin-DNA adducts // Chem. Rev., 1999, 99, 2467-2498; S. Dasari, P.B. Tchounwou Cisplatin in cancer therapy: molecular mechanisms of action // Eur. J. Pharmacol, 2014, 740, 364-378; Mashkovsky M.D. Medicines. - 15th ed. - M: New Wave, 2005. - 989 p.].
Цисплатин оказывает ряд побочных действий на пищеварительную, кроветворную, сердечно-сосудистую и центрально-нервную системы.Cisplatin has a number of side effects on the digestive, hematopoietic, cardiovascular and central nervous systems.
Задачей изобретения является расширение арсенала биологически активных веществ на основе металл(Pd,Pt)органических соединений, обладающих высокой противоопухолевой активностью.The objective of the invention is to expand the arsenal of biologically active substances based on metal (Pd, Pt) organic compounds with high antitumor activity.
Решение задачи достигается тем, что в качестве металл органических веществ с противораковой активностью используются моноядерные билигандные N,O-комплексы палладия(II) и платины(II) с 1-[(диметиламино)метил]-2-нафтолом общей формулы (1).The solution of the problem is achieved by using mononuclear biligand N,O-complexes of palladium(II) and platinum(II) with 1-[(dimethylamino)methyl]-2-naphthol of the general formula (1) as metal organic substances with anticancer activity.
Указанные соединения и их свойства в литературе не описаны.These compounds and their properties are not described in the literature.
Заявляемые соединения формулы (1) синтезируют взаимодействием 1-[(диметиламино)метил]-2-нафтола с ацетатом палладия (для получения соединения 1а), или с тетрахлороплатинатом калия (для получения соединения 1б) при мольном соотношении 1-[(диметиламино)метил]-2-нафтол : ацетат палладия(II) или при мольном соотношении 1-[(диметиламино)метил]-2-нафтол : тетрахлороплатинат калия(II) 2:1 в этаноле при температуре 50°С и атмосферном давлении в течение 1-3 ч, предпочтительно 2 ч. Выход N,О-комплексов 1а,b составляет 47-92%.The claimed compounds of formula (1) are synthesized by the interaction of 1-[(dimethylamino)methyl]-2-naphthol with palladium acetate (to obtain compound 1a), or with potassium tetrachloroplatinate (to obtain compound 1b) at a molar ratio of 1-[(dimethylamino)methyl ]-2-naphthol : palladium (II) acetate or at a molar ratio of 1-[(dimethylamino)methyl]-2-naphthol : potassium (II) tetrachloroplatinate 2: 1 in ethanol at a temperature of 50 ° C and atmospheric pressure for 1- 3 hours, preferably 2 hours. The yield of N,O-complexes 1a,b is 47-92%.
Реакции протекают по схеме:The reactions proceed according to the scheme:
N,О-Комплекс палладия(II) общей формулы (1а) образуется только с участием 1-[(диметиламино)метил]-2-нафтола и ацетата палладия(II), взятыми в мольном соотношении 2:1.The N,O-complex of palladium(II) of general formula (1a) is formed only with the participation of 1-[(dimethylamino)methyl]-2-naphthol and palladium(II) acetate, taken in a molar ratio of 2:1.
N,О-Комплекс платины(II) общей формулы (1b) образуется только с участием 1-[(диметиламино)метил]-2-нафтола и тетрахлороплатината калия, взятыми в мольном соотношении 2:1.The N,O-Complex of platinum(II) of general formula (1b) is formed only with the participation of 1-[(dimethylamino)methyl]-2-naphthol and potassium tetrachloroplatinate, taken in a molar ratio of 2:1.
Методика получения моноядерных N,О-комплексов палладия(II) и платины(И) с 1-[(диметиламино)метил]-2-нафтолом формулы (1).Method for obtaining mononuclear N,O-complexes of palladium(II) and platinum(I) with 1-[(dimethylamino)methyl]-2-naphthol of the formula (1).
Пример 1. В стеклянный реактор, установленный на магнитной мешалке, загружают 0.2 г (1 ммоль) 1-[(диметиламино)метил]-2-нафтола и 5 мл этанола, затем добавляют 0.11 г (0.5 ммоль) ацетата палладия(И) и перемешивают при 50°С в течение 2 ч, растворитель упаривают, полученный порошок промывают водой, сушат и перекристаллизовывают из смеси CHCl3-EtOH (1:1) при -15°С, выделяют кристаллы моноядерного N,O-комплекса (1-[(диметиламино)метил]-2-нафтол}палладия(II) (1а) с выходом 89%.Example 1. 0.2 g (1 mmol) of 1-[(dimethylamino)methyl]-2-naphthol and 5 ml of ethanol are loaded into a glass reactor mounted on a magnetic stirrer, then 0.11 g (0.5 mmol) of palladium(I) acetate are added and stirred at 50°C for 2 h, the solvent is evaporated, the resulting powder is washed with water, dried and recrystallized from a mixture of CHCl 3 -EtOH (1:1) at -15°C, crystals of the mononuclear N,O-complex (1-[ (dimethylamino)methyl]-2-naphthol}palladium(II) (1a) in 89% yield.
Пример 2. В стеклянный реактор, установленный на магнитной мешалке, загружают 0.2 г (1 ммоль) 1-[(диметиламино)метил]-2-нафтола в 5 мл этанола, затем добавляют 0.21 г (0.5 ммоль) тетрахлороплатината(II) калия растворенного в 5 мл воды и перемешивают при 50°С в течение 2 ч, растворитель упаривают, полученный порошок промывают водой, сушат и перекристаллизовывают из смеси CHCl3-EtOH (1:1) при -15°С, выделяют кристаллы моноядерного N,О-комплекса {1-[(диметиламино)метил]-2-нафтол}платины(II) (1b) с выходом 52%.Example 2. 0.2 g (1 mmol) of 1-[(dimethylamino)methyl]-2-naphthol in 5 ml of ethanol is loaded into a glass reactor mounted on a magnetic stirrer, then 0.21 g (0.5 mmol) of dissolved potassium tetrachloroplatinate (II) is added in 5 ml of water and stirred at 50°C for 2 h, the solvent is evaporated, the resulting powder is washed with water, dried and recrystallized from a mixture of CHCl 3 -EtOH (1:1) at -15°C, crystals of mononuclear N,O- {1-[(dimethylamino)methyl]-2-naphthol}platinum(II) complex (1b) in 52% yield.
Другие примеры, подтверждающие способ, приведены в таблице 1.Other examples supporting the method are shown in Table 1.
Все опыты проводили при мольном соотношении 1-[(диметиламино)метил]-2-нафтол: соль палладия(II) или платины(II), равном 2:1, в этаноле при 50°С.All experiments were carried out at a molar ratio of 1-[(dimethylamino)methyl]-2-naphthol:salt of palladium(II) or platinum(II) equal to 2:1 in ethanol at 50°C.
Спектральные характеристики соединений (1а,b).Spectral characteristics of compounds (1а,b).
N,O-Комплекс {1-[(диметиламино)метил]-2-нафтол}палладия(II) (1а).N,O-Complex of {1-[(dimethylamino)methyl]-2-naphthol}palladium(II) (1a).
Желтые кристаллы. Т.пл. 222-224°С. Структура соединения доказана методом рентгеноструктурного анализа (Рис. 1). Спектр ЯМР 1H (CDCl3, 400 Hz), δ, м. д. (J, Гц): 2.75 (с, 12Н; (CH3)2N); 3.65 (с, 4Н, CH2N); 7.08-7.76 (с, 12Н, HAr). Спектр ЯМР 13С (CDCl3, 100.6 Hz), δ, м. д. (J, Гц): 48.25 (CH3)2N); 57.06 (CH2N); 116.88, 119.50, 121.02, 124.44, 126.28, 127.07, 128.96, 129.82, 134.21 (CAr), 165.71 (С-ОН). ИК-спектр, ν, см-1: 588, 747, 818, 844, 979, 1024, 1246, 1590, 1615. УФ-спектр (CHCl3, λmax, нм): 280.92, 291.56, 321.29, 406.22. MALDI TOF/TOF: m/z (%): 506.0835 [М]+, М (mass calculated) 506.1186. C26H28N2O2Pd.Yellow crystals. So pl. 222-224°C. The structure of the compound was proven by X-ray diffraction analysis (Fig. 1). 1H NMR spectrum (CDCl 3 , 400 Hz), δ, ppm (J, Hz): 2.75 (s, 12Н; (CH 3 ) 2 N); 3.65 (s, 4H, CH 2 N); 7.08-7.76 (s, 12H, H Ar ). 13С NMR spectrum (CDCl 3 , 100.6 Hz), δ, ppm (J, Hz): 48.25 (CH 3 ) 2 N); 57.06 ( CH2N ); 116.88, 119.50, 121.02, 124.44, 126.28, 127.07, 128.96, 129.82, 134.21 ( CAr ), 165.71 (C-OH). IR spectrum, ν, cm -1 : 588, 747, 818, 844, 979, 1024, 1246, 1590, 1615. UV spectrum (CHCl 3 , λ max , nm): 280.92, 291.56, 321.29, 406.22. MALDI TOF/TOF: m/z (%): 506.0835 [M]+, M (mass calculated) 506.1186. C 26 H 28 N 2 O 2 Pd.
N,О-Комплекс {1-[(диметиламино)метил]-2-нафтол}платины(II) (1b).N,O-Complex of {1-[(dimethylamino)methyl]-2-naphthol}platinum(II) (1b).
Оранжевые кристаллы. Т.пл. 150-152°С. Структура соединения доказана методом рентгеноструктурного анализа (Рис. 2). Спектр ЯМР 1Н (CDCl3, 400 Hz), δ, м. д. (J, Гц): 2.75 (с, 12Н; (CH3)2N); 3.65 (с, 4Н, CH2N); 7.09 - 7.76 (с, 12Н, HAr). Спектр ЯМР 13С (CDCl3, 100.6 Hz), δ, м. д. (J, Гц): 48.25 (CH3)2N); 57.08 (CH2N); 116.84, 119.49, 121.00, 124.45, 126.27, 127.08, 128.96, 129.82, 134.23 (CAr), 165.77 (С-ОН). ИК спектр, ν, см-1: 304, 340, 483, 610, 733, 843, 1011, 1270, 1377, 1462, 1568. УФ-спектр (CHCl3, λmax, нм): 279.64, 292.94, 320.11, 644.52. MALDI TOF/TOF: m/z (%):595.1375 [М]+, М (mass calculated) 595.1799. C26H28N2O2Pt.orange crystals. So pl. 150-152°C. The structure of the compound was proven by X-ray diffraction analysis (Fig. 2). 1Н NMR spectrum (CDCl 3 , 400 Hz), δ, ppm (J, Hz): 2.75 ( s , 12Н; (CH 3 ) 2 N); 3.65 (s, 4H, CH 2 N); 7.09 - 7.76 (s, 12Н, H Ar ). 13С NMR spectrum (CDCl 3 , 100.6 Hz), δ, ppm (J, Hz): 48.25 (CH 3 ) 2 N); 57.08 (CH2N); 116.84, 119.49, 121.00, 124.45, 126.27, 127.08, 128.96, 129.82, 134.23 ( CAr ), 165.77 (C-OH). IR spectrum, ν, cm -1 : 304, 340, 483, 610, 733, 843, 1011, 1270, 1377, 1462, 1568. UV spectrum (CHCl 3 , λ max , nm): 279.64, 292.94, 320.11, 644.52. MALDI TOF/TOF: m/z (%):595.1375 [M]+, M (mass calculated) 595.1799. C 26 H 28 N 2 O 2 Pt.
Оценка противоопухолевой активности соединений формулы (1а,b) осуществлена методом проточной цитофлуориметрии по отношению к трем клеточным линиям: Jurkat, K562 и U937. В качестве препарата сравнения использовали цисплатин.Evaluation of the antitumor activity of the compounds of formula (1a,b) was carried out by flow cytometry in relation to three cell lines: Jurkat, K562 and U937. Cisplatin was used as a reference drug.
В целом значение ингибирующей концентрации IC50 для соединения (1а,b), полученное в результате экспозиции на упомянутых выше клеточных линиях с последующим окрашиванием клеток красителем 7AAD, варьируется в зависимости от клеточной культуры. Наименьшее значение IC50 для культур Jurcat, K562, U937 демонстрирует соединение 1а. Активность соединения (1b) превышает более чем в 139 раз препарат сравнения Цисплатин в отношении клеточной линии K562 и U937, и в 90 раз в отношении клеточной линии Jurkat (Таблица 2).In general, the inhibitory IC 50 value for compound (1a,b) obtained by exposure to the above cell lines followed by cell staining with 7AAD dye varies depending on the cell culture. The lowest IC 50 value for Jurcat, K562, U937 cultures is demonstrated by compound 1a. The activity of compound (1b) exceeds more than 139 times the reference drug Cisplatin against the K562 and U937 cell lines, and 90 times against the Jurkat cell line (Table 2).
Таким образом, соединения (1а,b) являются более активными цитостатиками, чем цисплатин, причем моноядерный билигандный комплекс платины 1а проявляет большую цитотоксическую активность, чем комплекс 1b.Thus, compounds (1a,b) are more active cytostatics than cisplatin, and the platinum mononuclear bigand complex 1a exhibits greater cytotoxic activity than complex 1b.
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