MD4520C1 - N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)hydrazinecarbothioamide as T-47D breast cancer cells growth inhibitor - Google Patents
N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)hydrazinecarbothioamide as T-47D breast cancer cells growth inhibitor Download PDFInfo
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- MD4520C1 MD4520C1 MDA20160141A MD20160141A MD4520C1 MD 4520 C1 MD4520 C1 MD 4520C1 MD A20160141 A MDA20160141 A MD A20160141A MD 20160141 A MD20160141 A MD 20160141A MD 4520 C1 MD4520 C1 MD 4520C1
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- Moldova
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- breast cancer
- butoxyphenyl
- pyridin
- ylmethylidene
- cancer cells
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- 206010006187 Breast cancer Diseases 0.000 title claims abstract description 18
- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 18
- UUOPJNVEEGYJRI-UHFFFAOYSA-N 1-(4-butoxyphenyl)-3-(pyridin-2-ylmethylideneamino)thiourea Chemical compound C(CCC)OC1=CC=C(C=C1)NC(=S)NN=CC1=NC=CC=C1 UUOPJNVEEGYJRI-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 239000003966 growth inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 239000003112 inhibitor Substances 0.000 claims abstract description 10
- 230000009702 cancer cell proliferation Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 6
- 230000012010 growth Effects 0.000 abstract description 6
- 238000011282 treatment Methods 0.000 abstract description 3
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 150000003583 thiosemicarbazides Chemical class 0.000 abstract description 2
- 229940127089 cytotoxic agent Drugs 0.000 abstract 1
- 239000002254 cytotoxic agent Substances 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- -1 N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazine Chemical compound 0.000 description 8
- 239000000203 mixture Substances 0.000 description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- BRWIZMBXBAOCCF-UHFFFAOYSA-N thiosemicarbazide group Chemical group NNC(=S)N BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 4
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000003327 cancerostatic effect Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- QVAMIJSFEORYOS-UHFFFAOYSA-N 1-butoxy-4-isothiocyanatobenzene Chemical compound CCCCOC1=CC=C(N=C=S)C=C1 QVAMIJSFEORYOS-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- UBRIHZOFEJHMIT-UHFFFAOYSA-N 4-butoxyaniline Chemical compound CCCCOC1=CC=C(N)C=C1 UBRIHZOFEJHMIT-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 101000666730 Homo sapiens T-complex protein 1 subunit alpha Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 102100038410 T-complex protein 1 subunit alpha Human genes 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- KNDXZFMNQKSIHU-UHFFFAOYSA-N methyl 2,3,5,6-tetrachloro-4-methylsulfanylcarbonylbenzoate Chemical compound COC(=O)C1=C(Cl)C(Cl)=C(C(=O)SC)C(Cl)=C1Cl KNDXZFMNQKSIHU-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
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- 238000011002 quantification Methods 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
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- 229960005322 streptomycin Drugs 0.000 description 1
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- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Invenţia se referă la chimie şi medicină, şi anume la un compus organic biologic activ din clasa tiosemicarbazidelor. Acest compus inhibă proliferarea celulelor T-47D ale cancerului mamar şi poate găsi implementare în medicină ca preparat citostatic la profilaxia şi tratarea cancerului mamar. The invention relates to chemistry and medicine, namely to a biologically active organic compound from the thiosemicarbazide class. This compound inhibits the proliferation of T-47D breast cancer cells and may find implementation in medicine as a cytostatic preparation for the prophylaxis and treatment of breast cancer.
Dintre toţi compuşi chimici, care conţin în componenţa lor fragmentul tiosemicarbazidic şi care inhibă creşterea şi multiplicarea celulelor T-47D ale cancerului mamar, cel mai înalt efect cancerostatic a fost obţinut în cazul compusului coordinativ di(µ-S)-bis{cloro[fenil(piridin-2-il)metanontiosemicarbazono(1-)]cupru} (prototip) [1] cu formula: Among all the chemical compounds, which contain in their composition the thiosemicarbazide fragment and which inhibit the growth and multiplication of T-47D breast cancer cells, the highest cancerostatic effect was obtained in the case of the coordinating compound di(µ-S)-bis{chloro[phenyl (pyridin-2-yl)methanonthiosemicarbazono(1-)]copper} (prototype) [1] with the formula:
, ,
care la concentraţia 10-6 mol/L depăşeşte de 10,5…8,8 ori caracteristicile cancerostatice respective ale doxorubicinei: which at the concentration of 10-6 mol/L exceeds by 10.5...8.8 times the respective cancerostatic characteristics of doxorubicin:
, ,
care este cel mai efectiv preparat chimioterapeutic organic, folosit în practica medicinală pentru tratarea şi profilaxia cancerului mamar. which is the most effective organic chemotherapeutic preparation, used in medicinal practice for the treatment and prophylaxis of breast cancer.
Dezavantajul prototipului constă în faptul că el nu posedă o activitate anticancer relativ înaltă şi până în prezent nu a găsit o aplicare în medicină. The disadvantage of the prototype lies in the fact that it does not possess a relatively high anticancer activity and has not yet found an application in medicine.
Problema pe care o rezolvă prezenta invenţie constă în extinderea arsenalului de inhibitori ai proliferării celulelor T-47D ale cancerului mamar cu activitate citostatică înaltă. The problem that the present invention solves is to expand the arsenal of T-47D breast cancer cell proliferation inhibitors with high cytostatic activity.
Esenţa invenţiei constă în utilizarea în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar a N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamidei ([N-(4-butoxifenil)tiosemicarbazonei 2-formilpiridinei]) cu formula: The essence of the invention consists in the use of N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazine carbotioamide ([N-(4-butoxyphenyl)thiosemicarbazone 2- formylpyridine]) with the formula:
Rezultatul tehnic al invenţiei constă în stabilirea la compusul revendicat a activităţii anticancerigene, care la concentraţia 10-6 mol/L se află la nivelul di(µ-S)-bis{cloro[fenil(piridin-2-il)metanontiosemicarbazono(1-)]cupru} (prototipului), iar la concentraţia 10-7 mol/L inhibă creşterea şi multiplicarea a 44,2% de celule T-47D ale cancerului mamar, în timp ce prototipul nu manifestă la această concentraţie activitate anticancerigenă. Proprietatea stabilită a N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamidei susnumită este nouă, deoarece până în prezent nu este descrisă utilizarea ei în calitate de inhibitor al creşterii şi multiplicării celulelor T-47D ale cancerului mamar. The technical result of the invention consists in the establishment of the claimed compound's anticancer activity, which at the concentration of 10-6 mol/L is at the level of di(µ-S)-bis{chloro[phenyl(pyridin-2-yl)methanonthiosemicarbazono(1- )]copper} (of the prototype), and at the concentration of 10-7 mol/L inhibits the growth and multiplication of 44.2% of breast cancer T-47D cells, while the prototype does not show anticancer activity at this concentration. The established property of the aforementioned N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazinecarbotioamide is novel, as its use as an inhibitor of the growth and proliferation of T-47D breast cancer cells has not been described so far .
Rezultatul tehnic al invenţiei este condiţionat de faptul, că pentru prima dată în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar se propune N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamida, care conţine o combinare nouă de legături chimice deja cunoscute. The technical result of the invention is conditioned by the fact that, for the first time, as an inhibitor of the proliferation of T-47D breast cancer cells, N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazinecarbothioamide is proposed, which contains a new combination of already known chemical bonds.
Compusul revendicat, proprietăţile lui şi procedeul de sinteză nu sunt descrise în literatură. The claimed compound, its properties and the synthesis process are not described in the literature.
N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamida revendicată se obţine conform următoarei scheme: The claimed N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazinecarbothioamide is obtained according to the following scheme:
. .
Mecanismul prezentei reacţii este următorul: la prima etapă de sinteză 4-butoxianilina (I) reacţionează cu tetrametiltiuram (DTMT) în raport molar de 1:0,5 la încălzire în solvenţi polari (etanol, dimetilformamidă sau dimetilsulfoxidă). La următoarea etapă, 3-(4-butoxifenil)-1,1-dimetiltioureea (II) obţinută, se supune procesului de deaminare, care constă în încălzirea compusului II cu H2SO4 (raport molar al reagenţilor 1:1) în dioxan cu formarea 1-butoxi-4-izotiocianatobenzenului (III). N-(4-butoxifenil)hidrazintiocarbamida IV se obţine prin picurarea soluţiei de izotiocianat III la exces de hidrat de hidrazină în dioxan. Astfel se exclude adiţia tiosemicarbazidei IV formate la izotiocianatul iniţial. N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamida finală se sintetizează prin condensarea tiosemicarbazidei IV cu 2-formilpiridina la încălzire într-un amestec de dimetilformamidă:etanol (1:3). Sinteza compuşilor iniţiali I-IV a fost efectuată după metodicile standarde descrise în literatură. Puritatea lor a fost confirmată cromatografic, prin analiza elementală şi spectrală (IR, 1H şi 13C-RMN). The mechanism of the present reaction is as follows: in the first stage of synthesis, 4-butoxyaniline (I) reacts with tetramethylthiuram (DTMT) in a molar ratio of 1:0.5 when heated in polar solvents (ethanol, dimethylformamide or dimethylsulfoxide). In the next step, the obtained 3-(4-butoxyphenyl)-1,1-dimethylthiourea (II) undergoes the deamination process, which consists in heating compound II with H2SO4 (reagent molar ratio 1:1) in dioxane with the formation of 1 -butoxy-4-isothiocyanatobenzene (III). N-(4-butoxyphenyl)hydrazinethiourea IV is obtained by dropping the isothiocyanate solution III to an excess of hydrazine hydrate in dioxane. Thus, the addition of the formed thiosemicarbazide IV to the initial isothiocyanate is excluded. The final N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazinecarbothioamide is synthesized by heating thiosemicarbazide IV with 2-formylpyridine in a mixture of dimethylformamide:ethanol (1:3). The synthesis of the initial compounds I-IV was carried out according to the standard methods described in the literature. Their purity was confirmed chromatographically, through elemental and spectral analysis (IR, 1H and 13C-NMR).
Exemplu de obţinere al N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamidei. Example of obtaining N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazine carbotioamide.
La soluţia obţinută din 0,32 g (0,003 mol) 2-formilpiridină şi 2,0 mL etanol se adaugă 0,72 g (0,003 mol) N-(4-butoxifenil)hidrazintiocarbamida (IV), dizolvată în 3 mL dimetilformamidă, apoi amestecul se încălzeşte la baia de apă 1 oră. Sfârşitul reacţiei se verifică după consumul aldehidei. După răcire produsul final se filtrează, se spală pe filtru cu etanol şi se usucă. Se obţin 0,84 g (80%) de produs final. Compoziţia substanţei a fost stabilită în baza rezultatelor analizei elementelor. To the solution obtained from 0.32 g (0.003 mol) of 2-formylpyridine and 2.0 mL of ethanol, add 0.72 g (0.003 mol) of N-(4-butoxyphenyl)hydrazinethiocarbamide (IV), dissolved in 3 mL of dimethylformamide, then the mixture is heated in a water bath for 1 hour. The end of the reaction is checked after the consumption of the aldehyde. After cooling, the final product is filtered, washed on the filter with ethanol and dried. 0.84 g (80%) of the final product is obtained. The composition of the substance was established based on the results of elemental analysis.
Determinat, %: C - 62,19; H - 5,99; N - 16,81; S - 9,54. Calculat pentru compusul C17H20N4OS , %: C - 62,17; H - 6,14; N - 17,06; S - 9,76. Determined, %: C - 62.19; H - 5.99; N - 16.81; S - 9.54. Calculated for the compound C17H20N4OS, %: C - 62.17; H - 6.14; N - 17.06; S - 9.76.
P. t. = 242…244°C. P. t. = 242...244°C.
1H-RMN(DMSO, d6), δ, ppm: 9,31(s, 1H, NH); 8,95(s, 1H, NH); 8,56 (d, 1H, CH piridinic); 8,27 (s, 1H, CH=N); 7,95 (d, 1H, CH piridinic); 7,76 (t, 1H, CH piridinic); 7,33 (t, 1H, CH piridinic); 7,18 (d, 2H, CH fenilenic); 7,16 (d, 2H, CH fenilenic); 3,91 (t, 2H, CH2); 1,65 (m, 2H, CH2); 1,42 (m, 2H, CH2); 0,90 (t, 3H, CH3). 1H-NMR(DMSO, d6), δ, ppm: 9.31(s, 1H, NH); 8.95(s, 1H, NH); 8.56 (d, 1H, pyridinic CH); 8.27 (s, 1H, CH=N); 7.95 (d, 1H, pyridinic CH); 7.76 (t, 1H, pyridinic CH); 7.33 (t, 1H, pyridinic CH); 7.18 (d, 2H, phenylenic CH); 7.16 (d, 2H, phenylenic CH); 3.91 (t, 2H, CH2); 1.65 (m, 2H, CH2); 1.42 (m, 2H, CH2); 0.90 (t, 3H, CH3).
13C-RMN (DMSO, d6), δ, ppm: 177,26 (C=S); 159,24; 156,44; 149,51; 136,55; 133,20; 125,51; 123,70; 122,74; 116,02 (С aromatic); 141,53 (HC=N), 68,18; 31,25; 19,20 (CH2); 13,80 (CH3). 13 C-NMR (DMSO, d6), δ, ppm: 177.26 (C=S); 159.24; 156.44; 149.51; 136.55; 133.20; 125.51; 123.70; 122.74; 116.02 (C aromatic); 141.53 (HC=N), 68.18; 31.25; 19.20 (CH 2 ); 13.80 (CH 3 ).
Procedeul de obţinere al compusului declarat este simplu în executare, iar substanţele iniţiale accesibile. Compusul obţinut este stabil în contact cu aerul, puţin solubil în apă, bine solubil în alcooli, cloroform, eter, dimetilformamidă şi dimetilsulfoxidă. The procedure for obtaining the declared compound is simple in execution, and the initial substances are accessible. The obtained compound is stable in contact with air, slightly soluble in water, well soluble in alcohols, chloroform, ether, dimethylformamide and dimethylsulfoxide.
La recristalizarea compusului declarat din soluţie etanolică au fost obţinute monocristale, structura cărora a fost stabilită cu ajutorul analizei cu raze X (Formula empirică C17H20N4OS, grupa spaţială Pc, parametrii celulei elementare, Å: a = 9,596(2); b = 5,6455(12), c = 31,145(9); volumul celulei elementare 1673,2 Å3). A fost stabilit (Fig.), că în celula elementară a compusului se află două molecule de azometină, care au structură practic planară. Fragmentul tiosemicarbazidic în componenţa ambelor molecule se află în forma tionică [ d(C=S) 1,69(3) Å]. Upon recrystallization of the declared compound from ethanolic solution, single crystals were obtained, the structure of which was established with the help of X-ray analysis (Empirical formula C17H20N4OS, space group Pc, unit cell parameters, Å: a = 9.596(2); b = 5.6455 (12), c = 31.145(9); unit cell volume 1673.2 Å3). It was established (Fig.), that in the elementary cell of the compound there are two molecules of azomethine, which have a practically planar structure. The thiosemicarbazide fragment in the composition of both molecules is in the ionic form [d(C=S) 1.69(3) Å].
Astfel, în baza rezultatelor analizei elementelor şi a cercetărilor fizico-chimice, a fost stabilită compoziţia şi structura compusului declarat. Thus, based on the results of elemental analysis and physico-chemical research, the composition and structure of the declared compound was established.
Esenţa invenţiei poate fi confirmată prin următoarele date experimentale. The essence of the invention can be confirmed by the following experimental data.
Exemplu al utilizării N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamidei în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar. Example of the use of N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazine carbotioamide as an inhibitor of T-47D breast cancer cell proliferation.
Cultivarea celulelor. Seria de celule T-47D ER-pozitive ale cancerului mamar a fost obţinută din colecţia de cultivare de tip american (CCTA) şi păstrată în fiole de 75 cm3 la 37ºC în atmosferă de CO2 cu umiditatea de 5%. Celulele T-47D au fost cultivate în mediul RPMI cu adaos de 10% ser de bovine fetal (SBF), L-glutamină (2mM), penicilină (100 IU/mL), streptomicină (100 µg/mL) şi estradiol (1nM). Cell culture. The T-47D ER-positive breast cancer cell line was obtained from the American Type Culture Collection (CCTA) and maintained in 75 cm3 vials at 37ºC in a CO2 atmosphere with 5% humidity. T-47D cells were cultured in RPMI medium supplemented with 10% fetal bovine serum (SBF), L-glutamine (2mM), penicillin (100 IU/mL), streptomycin (100 µg/mL) and estradiol (1nM) .
Testarea proliferării celulelor. Pentru determinarea cuantificării creşterii celulelor s-a utilizat Testarea Proliferării Celulelor cu Soluţii Apoase CellTiter 96® (Promega, Nepean, On, Canada) în conformitate cu cerinţele de preparare. Celulele T-47D au fost resuspendate în mediul cu adaos de insulină (50 ng/mL) şi 5% de cărbune activat acoperit cu dextran tratat cu ser de bovine fetal (SBF) pentru a înlătura rămăşiţele de estrogen din ser şi mediu. Părţile alicote (100 µL) ale suspensiei de celule au fost semănate în 96 plăci cu godeuri (3000 celule/godeuri) în trei exemplare. După 48 ore mediul s-a schimbat, urmând diluarea specifică cu diferiţi inhibitori în mediul de creştere. Celule au fost cultivate în absenţa sau prezenţa inhibitorilor timp de 3 zile. Cell proliferation assay. The CellTiter 96® Aqueous Cell Proliferation Assay (Promega, Nepean, On, Canada) was used to determine the quantification of cell growth according to preparation requirements. T-47D cells were resuspended in media supplemented with insulin (50 ng/mL) and 5% fetal bovine serum (SBF)-treated dextran-coated activated charcoal to remove residual estrogen from serum and media. Aliquots (100 µL) of the cell suspension were seeded in 96-well plates (3000 cells/well) in triplicate. After 48 hours the medium was changed, following the specific dilution with different inhibitors in the growth medium. Cells were cultured in the absence or presence of inhibitors for 3 days.
Datele experimentale obţinute în urma studiului N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamidei declarate în calitate de inhibitor al multiplicării celulelor T-47D indică, că la concentraţia 10-6 mol/L activitatea ei se află la nivelul di(µ-S)-bis{cloro[fenil(piridin-2-il)metanontiosemicarbazono(1-)]cupru} (prototipului), iar la concentraţia 10-7 mol/L este inhibată creşterea şi multiplicarea a 44,2% de celule T-47D ale cancerului mamar, în timp ce prototipul la această concentraţie nu manifestă activitate anticancerigenă. În baza datelor experimentale a fost stabilit, că compusul declarat are concentraţia de inhibare semimaximală (IC50) egală cu 0,8 µmol/L. The experimental data obtained from the study of N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazine carbotioamide declared as an inhibitor of the multiplication of T-47D cells indicate that at a concentration of 10-6 mol/L its activity is at the level of di(µ-S)-bis{chloro[phenyl(pyridin-2-yl)methanonthiosemicarbazono(1-)]copper} (prototype), and at the concentration of 10-7 mol/L the growth and multiplication of 44 .2% of breast cancer T-47D cells, while the prototype at this concentration does not show anticancer activity. Based on the experimental data, it was established that the declared compound has a semi-maximal inhibition concentration (IC50) equal to 0.8 µmol/L.
Partea celulelor T-47D ale cancerului mamar inhibate, % The fraction of breast cancer T-47D cells inhibited, %
Compus Concentraţie, mol/L 10-5 10-6 10-7 Doxorubicina 40 0 0 Di(µ-S)-bis{cloro[fenil(piridin-2-il)metanontiosemi-carbazono(1-)]cupru} (prototipul) 100 38±3,5 0 N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)hidrazin-carbotioamida 100 46,6 44,2 Compound Concentration, mol/L 10-5 10-6 10-7 Doxorubicin 40 0 0 Di(µ-S)-bis{chloro[phenyl(pyridin-2-yl)methanonthiosemi-carbazono(1-)]copper} (prototype ) 100 38±3.5 0 N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)hydrazine-carbothioamide 100 46.6 44.2
Proprietăţile depistate ale N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)-hidrazincarbotioamidei prezintă interes pentru medicină din punct de vedere al extinderii arsenalului de inhibitori ai proliferării celulelor T-47D ale cancerului mamar. The detected properties of N-(4-butoxyphenyl)-2-(pyridin-2-ylmethylidene)-hydrazine carbotioamide are of interest for medicine from the point of view of expanding the arsenal of inhibitors of the proliferation of T-47D breast cancer cells.
1. MD 4132 B1 2011.10.31 1. MD 4132 B1 2011.10.31
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| US5281715A (en) * | 1992-05-13 | 1994-01-25 | Yale University | 2-formylpyridine thiosemicarbazone compounds |
| CA2713288A1 (en) * | 2008-02-11 | 2009-08-20 | The Government Of The United States Of America As Represented By The Sec Retary Of Department Of Health And Human Services | Compounds with mdr1-inverse activity |
| MD3995C2 (en) * | 2009-05-11 | 2010-07-31 | Государственный Университет Молд0 | Use of di(m-Ophenoxy)-di{[2-(4-aminobenzenesulfamido)-5-ethyl-1,3,4-thiadiazole]-3,5-dibromosalicylidenethiosemicarbazonato(-1)-copper} as inhibitor of mammary cancer T-47D cell proliferation |
| WO2012033601A1 (en) * | 2010-08-20 | 2012-03-15 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Thiosemicarbazones with mdr1 - inverse activity |
| MD4132C1 (en) * | 2010-12-13 | 2012-05-31 | Государственный Университет Молд0 | Di(µ-S)-bis{chloro-[phenyl(pyridine-2-yl)methanone-thiosemicarbazonato(1-)]-copper} manifesting the property of inhibiting the proliferation of mammary cancer T-47D cells |
| MD4215C1 (en) * | 2012-07-09 | 2013-11-30 | Государственный Университет Молд0 | Inhibitor of human myeloid leukemia based on N-(4-(5-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-2-(pyridin-2-ylmethylen)-hydrazinecarbothioamide |
| MD4349C1 (en) * | 2014-06-23 | 2015-12-31 | Государственный Университет Молд0 | N-(3-methoxyphenyl)-2-(pyridine-2-ylmethylene)-hydrazinecarbothioamide compound - inhibitor of human melanoma MeW-164 cell proliferation |
| MD4407C1 (en) * | 2015-04-29 | 2016-10-31 | Государственный Университет Молд0 | Inhibitor of human myeloid leukemia HL-60 cells based on bis[N-(prop-2-en-1-yl)-2-(pyridine-2-ylmethylidene)hydrazinecarbothioamide]nickel(II) chloride hydrate |
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