MD4300C1 - Inhibitor of HepG2 cell proliferation in liver cancer based on chloro-[2-phenyl(pyridine-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel - Google Patents
Inhibitor of HepG2 cell proliferation in liver cancer based on chloro-[2-phenyl(pyridine-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel Download PDFInfo
- Publication number
- MD4300C1 MD4300C1 MDA20120128A MD20120128A MD4300C1 MD 4300 C1 MD4300 C1 MD 4300C1 MD A20120128 A MDA20120128 A MD A20120128A MD 20120128 A MD20120128 A MD 20120128A MD 4300 C1 MD4300 C1 MD 4300C1
- Authority
- MD
- Moldova
- Prior art keywords
- liver cancer
- nickel
- methoxyphenyl
- thiosemicarbazono
- chloro
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Изобретение относится к химии, а именно к синтезу координационных соединений из класса тиосемикарбазидатов переходных металлов, и может быть применено в медицине в качестве цитостатического средства для профилактики и лечения рака печени.Сущность изобретения состоит в том, что в качестве ингибитора роста клеток HepG2 при раке печени предлагают применение нового соединения, хлоро-[2-фенил(пиридин-2-ил)метанон-4-(3-метоксифенил)тиосемикарбазоно]никеля формулы :Заявляемое соединение проявляет себя как эффективный ингибитор роста клеток HepG2 при раке печени в концентрациях 10-5…10-6 моль/л.The invention relates to chemistry, namely to the synthesis of coordination compounds from the class of transition metal thiosemicarbazidates, and can be used in medicine as a cytostatic agent for the prevention and treatment of liver cancer. The invention consists in the fact that as an inhibitor of HepG2 cell growth in liver cancer suggest the use of a new compound, chloro [2-phenyl (pyridin-2-yl) methanon-4- (3-methoxyphenyl) thiosemicarbazono] nickel of the formula: The inventive compound manifests itself as an effective inhibitor of cell growth HepG2 pr and liver cancer in concentrations of 10-5 ... 10-6 mol / l.
Description
Invenţia se referă la chimie, şi anume la sinteza compuşilor coordinativi din clasa tiosemicarbazonaţilor metalelor de tranziţie, şi poate fi aplicată în medicină ca remediu citostatic la profilaxia şi tratarea cancerului hepatic. The invention refers to chemistry, namely to the synthesis of coordinating compounds from the thiosemicarbazonate class of transition metals, and can be applied in medicine as a cytostatic remedy for the prophylaxis and treatment of liver cancer.
În practica medicală, pentru tratarea şi profilaxia cancerului hepatic se utilizează doxorubicina (doxorubicinum) - unul dintre antibioticele grupei antracilinelor cu următoarea formulă de structură: In medical practice, for the treatment and prophylaxis of liver cancer, doxorubicin (doxorubicinum) is used - one of the antibiotics of the anthracycline group with the following structural formula:
Mecanismul acţiunii doxorubicinei este apropiat de cel al ribomicinei şi este bazat pe intercalarea celulelor ADN. Ea se aplică în cazul cancerului glandei mamare, sarcomei ţesuturilor moi, sarcomei osteogene, tumorii Young, cancerului pulmonar, limfosarcomei, cancerului ovarian, cancerului pavimentos de diversă localizare, cancerului vizicii urinare, tumorii Williams, cancerului glandei tiroide, diverselor leucoze şi limfogranulomatozei [1]. The mechanism of action of doxorubicin is close to that of ribomycin and is based on the intercalation of DNA cells. It is applied in the case of breast cancer, soft tissue sarcoma, osteogenic sarcoma, Young's tumor, lung cancer, lymphosarcoma, ovarian cancer, squamous cell carcinoma of various locations, bladder cancer, Williams tumor, thyroid gland cancer, various leukosis and lymphogranulomatosis [1 ].
La concentraţia de 10-5 mol/L doxorubicina inhibă creşterea şi multiplicarea a 76,7%, iar la concentraţia de 10-6 mol/L - 28,6% din celulele HepG2 ale cancerului hepatic. At the concentration of 10-5 mol/L doxorubicin inhibits the growth and multiplication of 76.7%, and at the concentration of 10-6 mol/L - 28.6% of HepG2 liver cancer cells.
Dezavantajul acestui compus constă în întrebuinţarea lui limitată, deoarece nu posedă o activitate înaltă cancerostatică, precum şi în cauzarea unor efecte secundare: se pot dezvolta cardiomiopatii, dureri în regiunea cardiacă, dereglarea ritmului cardiac, insuficienţă cardiacă şi hipotensiune. The disadvantage of this compound is its limited use, because it does not possess a high cancerostatic activity, as well as in causing some side effects: cardiomyopathies, pain in the heart region, irregular heart rhythm, heart failure and hypotension can develop.
Dintre toţi compuşii coordinativi ai nichelului, care inhibă creşterea şi multiplicarea celulelor HepG2 ale cancerului hepatic [2], cel mai înalt efect cancerostatic a fost obţinut în cazul hidroxo- [4-(p-clorofenil)-1-(piridin-2-il)tiosemicarbazido)aquanichel cu formula structurală: Among all nickel coordinating compounds, which inhibit the growth and multiplication of HepG2 liver cancer cells [2], the highest cancerostatic effect was obtained in the case of hydroxo-[4-(p-chlorophenyl)-1-(pyridin-2-yl )thiosemicarbazido)aquanickel with the structural formula:
Dezavantajul compusului menţionat constă în faptul că nu posedă o activitate cancerostatică suficientă, inhibând la concentraţia de 10-6 mol/L doar 5% de celule şi până acum nu i s-a găsit aplicare în medicină. The disadvantage of the mentioned compound is the fact that it does not possess a sufficient cancerostatic activity, inhibiting only 5% of cells at the concentration of 10-6 mol/L and so far it has not been used in medicine.
Problema pe care o rezolvă prezenta invenţie constă în extinderea arsenalului de inhibitori ai proliferării celulelor HepG2 ale cancerului hepatic cu activitate citostatică înaltă. The problem that the present invention solves consists in expanding the arsenal of HepG2 liver cancer cell proliferation inhibitors with high cytostatic activity.
Esenţa invenţiei constă în aceea că în calitate de inhibitor al proliferării celulelor HepG2 în cancerul hepatic se propune utilizarea unui nou compus, cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]nichel cu formula : The essence of the invention is that as an inhibitor of the proliferation of HepG2 cells in liver cancer it is proposed to use a new compound, chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel with formula:
. .
Compusul revendicat se manifestă ca un inhibitor efectiv al proliferării celulelor HepG2 în cancerul hepatic în concentraţii de 10-5…10-6 mol/L. The claimed compound manifests itself as an effective inhibitor of the proliferation of HepG2 cells in liver cancer in concentrations of 10-5...10-6 mol/L.
Structura moleculară a cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel are următorul aspect: The molecular structure of chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel has the following aspect:
Formarea structurii supramoleculare 1D are următorul aspect: The formation of the 1D supramolecular structure has the following aspect:
Proceseul de sinteză, proprietăţile fizico-chimice şi cancerostatice ale acestui compus nu sunt descrise în literatura de specialitate. The synthesis process, the physico-chemical and cancerostatic properties of this compound are not described in the specialized literature.
Rezultatul tehnic al invenţiei constă în stabilirea la compusul revendicat a activităţii cancerostatice, care la concentraţii de 10-5…10-6mol/L depăşeşte de 1,3…1,4 ori caracteristicile analoage ale doxorubicinei şi de 8,2 ori ale analogului structural. Proprietatea stabilită a complexului sus-numit este nouă, fiindcă până acum nu este descrisă utilizarea lui în calitate de inhibitor al creşterii şi multiplicării celulelor HepG2 ale cancerului hepatic. The technical result of the invention consists in the establishment of the claimed compound's cancerostatic activity, which at concentrations of 10-5...10-6mol/L exceeds by 1.3...1.4 times the analogous characteristics of doxorubicin and by 8.2 times of the structural analogue . The established property of the above-mentioned complex is new, because so far its use as an inhibitor of the growth and multiplication of HepG2 liver cancer cells has not been described.
Rezultatul tehnic al invenţiei este condiţionat de faptul că pentru prima dată în calitate de inhibitor al proliferării celulelor HepG2 ale cancerului hepatic se propune cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]-nichel, 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, chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]- is proposed as an inhibitor of the proliferation of HepG2 liver cancer cells nickel, which contains a new combination of already known chemical bonds.
Compusul revendicat cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]-nichel se obţine la interacţiunea soluţiilor etanolice fierbinţi (55…60°C) ale NiCl2·6H2O cu 4-(3-metoxifeni)tiosemicarbazona 2-benzoilpiridina, luate în raport molar de 1 : 1. Reacţia decurge în 45…60 min conform următoarei scheme: The claimed compound chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]-nickel is obtained by the interaction of hot ethanolic solutions (55...60°C) of NiCl2·6H2O with 4-( 3-methoxypheni)thiosemicarbazone 2-benzoylpyridine, taken in a molar ratio of 1:1. The reaction takes place in 45...60 min according to the following scheme:
Mecanismul reacţiei date constă în deprotonarea grupei tiolice a tiosemicarbazonei sus-numite în prezenţa azotului piridinic al ligandului şi coordonarea anionului format la ionul de nichel ca ligand N,N,S-tridentat monodeprotonizat. Al patrulea loc în sfera internă a atomului central îl ocupă atomul de clor. The mechanism of the given reaction consists in the deprotonation of the thiol group of the aforementioned thiosemicarbazone in the presence of the pyridinic nitrogen of the ligand and the coordination of the formed anion to the nickel ion as a monodeprotonated N,N,S-tridentate ligand. The fourth place in the inner sphere of the central atom is occupied by the chlorine atom.
Procedeul de obţinere a cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]nichel este simplu în executare, substanţele iniţiale accesibile, randamentul constituie 71%. Complexul sintetizat are culoarea roşie întunecată, este stabil la contact cu aerul, puţin solubil în apă şi alcooli alifatici, este solubil în dimetilformamidă şi dimetilsulfoxidă, practic insolubil în eter. The process for obtaining chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel is simple in execution, the initial substances are accessible, the yield is 71%. The synthesized complex has a dark red color, is stable in contact with air, slightly soluble in water and aliphatic alcohols, is soluble in dimethylformamide and dimethylsulfoxide, practically insoluble in ether.
Exemplu de obţinere a cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]-nichel. Example of obtaining chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]-nickel.
La soluţia etanolică, care conţine 10 mmol de hexahidrat al clorurii de nichel în 20 mL etanol, încălzită (55…60°C) şi amestecată în permanenţă cu ajutorul agitătorului magnetic, se adaugă o soluţie ce conţine 10 mmol de 3-metoxifenitiosemicarbazonă a 2-benzoilpiridinei în 50 mL de alcool etilic. Amestecul reactant se încălzeşte în continuare cu refrigerent ascendent pe parcursul a 45…60 min. La răcire, din amestecul reactant se depun cristale mărunte de culoare roşie întunecată, care se filtrează printr-un filtru din sticlă, se spală cu C2H5OH, eter şi se usucă în aer. To the ethanolic solution, which contains 10 mmol of nickel chloride hexahydrate in 20 mL of ethanol, heated (55...60°C) and constantly mixed with the help of a magnetic stirrer, a solution containing 10 mmol of 3-methoxyphenytosemicarbazone a 2 is added -benzoylpyridine in 50 mL of ethyl alcohol. The reactant mixture is further heated with rising refrigerant during 45...60 min. On cooling, small dark red crystals are deposited from the reaction mixture, which are filtered through a glass filter, washed with C2H5OH, ether and dried in air.
S-a determinat, % : C - 52,90, H - 3,57, Cl - 7,51, N - 12,07, Ni -12,99, S - 6,88. It was determined, %: C - 52.90, H - 3.57, Cl - 7.51, N - 12.07, Ni -12.99, S - 6.88.
Pentru C20H17ClN4NiOS s-a calculat, % : C - 52,73; H - 3,76, Cl - 7,78; N - 12,30; Ni - 12,88, S - 7,04. For C20H17ClN4NiOS it was calculated, %: C - 52.73; H - 3.76, Cl - 7.78; N - 12.30; Ni - 12.88, S - 7.04.
La recristalizarea compusului sintetizat din soluţie dimetilformamid-etanolică (1:4) au fost obţinute monocristale, structura cărora a fost stabilită cu ajutorul analizei cu raze X. Experimentul s-a efectuat la difractometrul Xcalibur-Gemini “Oxford Diffraction”. Structura a fost determinată prin metoda directă şi stabilită folosind metoda celor mai mici pătrate în apropiere anizotropă pentru atomii de hidrogen după programele SHELX-97. Atomii de hidrogen sunt incluşi în poziţiile geometrice prevăzute, iar factorul lor de temperatură UH este luat de 1,2 ori mai mare, decât în cazul atomilor de carbon şi oxigen legaţi cu ei. Parametrii principali ai experimentului sunt prezentaţi în tabelele 1 şi 2. Upon recrystallization of the synthesized compound from dimethylformamide-ethanolic solution (1:4), single crystals were obtained, the structure of which was established with the help of X-ray analysis. The experiment was performed with the Xcalibur-Gemini "Oxford Diffraction" diffractometer. The structure was determined by the direct method and established using the least squares method in anisotropic approximation for hydrogen atoms according to SHELX-97 programs. Hydrogen atoms are included in the predicted geometric positions, and their temperature factor UH is taken 1.2 times higher than in the case of carbon and oxygen atoms linked with them. The main parameters of the experiment are presented in tables 1 and 2.
S-a stabilit că compusul coordinativ revendicat posedă o configuraţie plan-pătratică în care 4-(3-metoxifenil)tiosemicarbazona 2-benzoilpiridina coordinează la ionul de nichel prin intermediul atomilor de azot piridinic şi azometinic şi a sulfului, formând două metalocicluri din cinci atomi. Al patrulea loc coordinativ este ocupat de ionul de clor (vezi structura moleculară a cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel, indicată mai sus). Structura cristalină rezultă prin împachetarea lanţurilor supramoleculare de tip 1D (vezi formarea structurii supramoleculare 1D, indicată mai sus) construite prin formarea legăturii de hidrogen intermoleculară N-H...O. It was established that the claimed coordinating compound possesses a planar-square configuration in which 4-(3-methoxyphenyl)thiosemicarbazone 2-benzoylpyridine coordinates to the nickel ion via the pyridinic and azomethine nitrogen atoms and sulfur, forming two metallocycles of five atoms. The fourth coordination site is occupied by the chlorine ion (see the molecular structure of chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel, indicated above). The crystal structure results from the packing of 1D supramolecular chains (see the formation of the 1D supramolecular structure, indicated above) built by the formation of the N-H...O intermolecular hydrogen bond.
Astfel, în baza rezultatelor analizei elementelor şi analizei cu raze X a fost stabilită compoziţia şi structura compusului revendicat. Thus, based on the results of elemental analysis and X-ray analysis, the composition and structure of the claimed 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 de utilizare a cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel în calitate de inhibitor al proliferării celulelor HepG2 ale cancerului hepatic. Example of use of chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel as an inhibitor of the proliferation of HepG2 liver cancer cells.
Celulele de hepatom uman HepG2 au fost crescute în mediul DMEM (Dulbecco's Modified Eagle Medium), conţinând 100 µmol/L aminoacizi neesenţiali, 100 U/mL penicilină, 100 µg/mL streptomicină şi 10% ser fetal bovin în atmosferă umidificată (5% CO2, 37°C). Tipic, 106 celule per un godeu au fost însămânţate pe plăci cu 6 godeuri şi cultivate până la o confluenţă de 70…80%. Human hepatoma HepG2 cells were grown in DMEM (Dulbecco's Modified Eagle Medium), containing 100 µmol/L non-essential amino acids, 100 U/mL penicillin, 100 µg/mL streptomycin and 10% fetal bovine serum in a humidified atmosphere (5% CO2 , 37°C). Typically, 106 cells per well were seeded in 6-well plates and grown to 70–80% confluence.
Testarea proliferării celulelor. Cell proliferation assay.
Viabilitatea celulelor a fost stabilită cu ajutorul testului MTT. Aproximativ 2000 de celule de HepG2 au fost introduse în fiecare godeu al unei plăci cu 96 godeuri. După incubare peste noapte, celulele au fost tratate cu ds ARN timp de 48…72 ore. La momente diferite după tratament, mediul a fost îndepărtat, MTT (20 µl de 5 mg/ml) a fost adăugat în fiecare godeu şi incubat la 37°C timp de 4 ore. Plăcile au fost centrifugate, iar precipitatele de formazan, colorate în violet, au fost dizolvate în 150 µL de dimetilsulfoxid. Absorbanţa a fost măsurată la 490 nm utilizând cititorul de absorbanţă MRX II (Dynex Technologies, Chantilly, Virginia, SUA). Reducerea viabilităţii celulelor de HepG2 tratate cu ds Control a fost exprimată în procente faţă de celulele simulate, care se consideră a fi 100% viabile. Cell viability was determined using the MTT assay. Approximately 2000 HepG2 cells were plated in each well of a 96-well plate. After overnight incubation, cells were treated with ds RNA for 48…72 hours. At various times after treatment, the medium was removed, MTT (20 µl of 5 mg/ml) was added to each well and incubated at 37°C for 4 hours. The plates were centrifuged, and the purple-stained formazan precipitates were dissolved in 150 µL of dimethylsulfoxide. Absorbance was measured at 490 nm using MRX II absorbance reader (Dynex Technologies, Chantilly, Virginia, USA). The reduction in viability of HepG2 cells treated with ds Control was expressed as a percentage of mock cells, which are considered to be 100% viable.
Datele experimentale obţinute în urma studiului cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel, declarat în calitate de inhibitor al multiplicării celulelle HepG2 ale cancerului hepatic demonstrează că acest compus la concentraţia de 10-5 mol/L inhibă creşterea şi multiplicarea a 100%, iar la 10-6 mol/L - 40,1% de celule HepG2 ale cancerului hepatic. Datele obţinute denotă că acest compus, după activitatea cancerostatică, depăşeşte de 1,3…1,4 ori caracteristicile analoage ale doxorubicinei (soluţia apropiată) şi de 8,2 ori ale celei mai apropiate soluţii, tabelul 3. The experimental data obtained from the study of chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel, declared as an inhibitor of the multiplication of HepG2 liver cancer cells, demonstrate that this compound at the concentration of 10-5 mol/L inhibits the growth and multiplication of 100%, and at 10-6 mol/L - 40.1% of HepG2 liver cancer cells. The obtained data show that this compound, according to the cancerostatic activity, surpasses 1.3...1.4 times the analogue characteristics of doxorubicin (the closest solution) and 8.2 times that of the closest solution, table 3.
Proprietăţile depistate ale cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]nichel prezintă interes pentru medicină din punct de vedere al extinderii arsenalului de inhibitori ai celulelor cancerului hepatic. The detected properties of chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel are of interest for medicine from the point of view of expanding the arsenal of liver cancer cell inhibitors.
Tabelul 1 Table 1
Date cristalografice şi detalii privind experimentul cu raze X pentru cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel Crystallographic data and X-ray experimental details for chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel
Formula moleculară C20H17ClN4NiOS Masa molară, g/mol 455,60 Temperatura, K 200,0 Singonia, grupa spaţială, Z Ortorombic, P212121 a, Å 7,15501(15) b, Å 15,9430(4) c, Å 16,8131(4) α, grad 90,00 β, grad 90,00 γ, grad 90,00 V, Å 3 1917,91(7) Z 4 ρcalcmg/mm3 1,578 µ/mm-1 1,279 Dimensiunea monocristalului, mm 0,15 × 0,15 × 0,1 Numărul parametrilor 5306 S 1,041 Final R index[I≥2Σ(I)] R1= 0,0284, wR2= 0,0626 Final R index R1= 0,0312, wR2= 0,0640 Programe SHELX-97 Molecular formula C20H17ClN4NiOS Molar mass, g/mol 455.60 Temperature, K 200.0 Singonia, space group, Z Orthorhombic, P212121 a, Å 7.15501(15) b, Å 15.9430(4) c, Å 16, 8131(4) α, degree 90.00 β, degree 90.00 γ, degree 90.00 V, Å 3 1917.91(7) Z 4 ρcalcmg/mm3 1.578 µ/mm-1 1.279 Single crystal size, mm 0, 15 × 0.15 × 0.1 Number of parameters 5306 S 1.041 Final R index[I≥2Σ(I)] R1= 0.0284, wR2= 0.0626 Final R index R1= 0.0312, wR2= 0.0640 SHELX-97 programs
Tabelul 2 Table 2
Valorile unor distanţe interatomice (d, Å) şi ale unghiurilor de valenţă (Ω, grad °) pentru cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel The values of interatomic distances (d, Å) and valence angles (Ω, degree °) for chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel
Legătura d,Å Legătura d,Å Ni1 - S1 2,1462(8) C7 - C12 1,396(3) Ni1 - Cl1 2,1575(8) C7 - C8 1,401(3) Ni1 - N1 1,923(2) C7 - C6 1,471(3) Ni1 - N2 1,849(2) N1 - C5 1,366(3) S1 - C13 1,743(3) N1 - C1 1,335(3) O1 - C20 1,424(3) C5 - C4 1,374(3) O1 - C18 1,372(3) C5 - C6 1,483(3) N4 - C13 1,358(3) C4 - C3 1,391(3) N4 - C14 1,409(3) C2 - C3 1,368(4) C15 - C14 1,404(3) C2 - C1 1,389(4) C15 - C16 1,379(4) C12 - C11 1,380(4) C13 - N3 1,321(3) C19 - C18 1,382(4) C17 - C18 1,395(4) C8 - C9 1,379(4) C17 - C16 1,383(4) C9 - C10 1,381(4) N3 - N2 1,374(3) C10 - C11 1,376(4) C14 - C19 1,388(4) C6 - N2 1,316(3) Unghiul Ω,grad Unghiul Ω,grad S1 -Ni1 -Cl1 92,82(3) N1 -C5 -C4 121,7(2) N1 - Ni1 - S1 170,80(6) N1 - C5 - C6 113,1(2) N1 - Ni1 - Cl1 96,28(6) C4 - C5 - C6 125,1(2) N2 -Ni1 - S1 86,99(7) C5 -C4 -C3 118,9(2) N2 -Ni1 -Cl1 179,52(7) C3 -C2 -C1 119,3(2) N2 -Ni1 -N1 83,90(9) C11 -C12 -C7 120,5(3) C13 -S1 -Ni1 95,25(8) C18 -C19 -C14 121,3(2) C18 -O1 -C20 117,5(2) C9 -C8 -C7 120,3(2) C13 -N4 -C14 131,0(2) O1 -C18 -C17 124,0(2) C16 -C15 -C14 118,4(3) O1 -C18 -C19 116,1(2) N4 -C13 -S1 116,67(18) C19 -C18 -C17 119,9(2) N3 -C13 -S1 123,29(19) C8 -C9 -C10 120,3(3) N3 -C13 -N4 120,0(2) C11 -C10 -C9 120,1(3) C16 -C17 -C18 118,2(2) C10 -C11 -C12 120,3(3) C13 -N3 -N2 110,2(2) C15 -C16 -C17 122,9(2) C15 -C14 -N4 124,1(2) C2 -C3 -C4 119,3(2) C19 -C14 -N4 116,6(2) C7 -C6 -C5 121,9(2) C19 -C14 -C15 119,3(2) N2 -C6 -C7 125,8(2) C12 -C7 -C8 118,5(2) N2 -C6 -C5 112,2(2) C12 -C7 -C6 122,0(2) N1 -C1 -C2 121,9(3) C8 -C7 -C6 119,5(2) N3 -N2 -Ni1 124,24(16) C5 -N1 -Ni1 112,66(16) C6 -N2 -Ni1 117,72(18) C1 -N1 -Ni1 128,54(19) C6 -N2 -N3 118,0(2) C1 -N1 -C5 118,7(2) d,Å bond d,Å bond Ni1 - S1 2.1462(8) C7 - C12 1.396(3) Ni1 - Cl1 2.1575(8) C7 - C8 1.401(3) Ni1 - N1 1.923(2) C7 - C6 1.471(3) Ni1 - N2 1.849(2) N1 - C5 1.366(3) S1 - C13 1.743(3) N1 - C1 1.335(3) O1 - C20 1.424(3) C5 - C4 1.374(3) O1 - C18 1.372 (3) C5 - C6 1.483(3) N4 - C13 1.358(3) C4 - C3 1.391(3) N4 - C14 1.409(3) C2 - C3 1.368(4) C15 - C14 1.404(3) C2 - C1 1.389( 4) C15 - C16 1.379(4) C12 - C11 1.380(4) C13 - N3 1.321(3) C19 - C18 1.382(4) C17 - C18 1.395(4) C8 - C9 1.379(4) C17 - C16 1.383(4) ) C9 - C10 1.381(4) N3 - N2 1.374(3) C10 - C11 1.376(4) C14 - C19 1.388(4) C6 - N2 1.316(3) Angle Ω, degree Angle Ω, degree S1 -Ni1 -Cl1 92 .82(3) N1 -C5 -C4 121.7(2) N1 - Ni1 - S1 170.80(6) N1 - C5 - C6 113.1(2) N1 - Ni1 - Cl1 96.28(6) C4 - C5 - C6 125.1(2) N2 -Ni1 - S1 86.99(7) C5 -C4 -C3 118.9(2) N2 -Ni1 -Cl1 179.52(7) C3 -C2 -C1 119, 3(2) N2 -Ni1 -N1 83.90(9) C11 -C12 -C7 120.5(3) C13 -S1 -Ni1 95.25(8) C18 -C19 -C14 121.3(2) C18 - O1 -C20 117.5(2) C9 -C8 -C7 120.3(2) C13 -N4 -C14 131.0(2) O1 -C18 -C17 124.0(2) C16 -C15 -C14 118.4 (3) O1 -C18 -C19 116.1(2) N4 -C13 -S1 116.67(18) C19 -C18 -C17 119.9(2) N3 -C13 -S1 123.29(19) C8 -C9 -C10 120.3(3) N3 -C13 -N4 120.0(2) C11 -C10 -C9 120.1(3) C16 -C17 -C18 118.2(2) C10 -C11 -C12 120.3( 3) C13 -N3 -N2 110.2(2) C15 -C16 -C17 122.9(2) C15 -C14 -N4 124.1(2) C2 -C3 -C4 119.3(2) C19 -C14 - N4 116.6(2) C7 -C6 -C5 121.9(2) C19 -C14 -C15 119.3(2) N2 -C6 -C7 125.8(2) C12 -C7 -C8 118.5(2 ) N2 -C6 -C5 112.2(2) C12 -C7 -C6 122.0(2) N1 -C1 -C2 121.9(3) C8 -C7 -C6 119.5(2) N3 -N2 -Ni1 124.24(16) C5 -N1 -Ni1 112.66(16) C6 -N2 -Ni1 117.72(18) C1 -N1 -Ni1 128.54(19) C6 -N2 -N3 118.0(2) C1 -N1 -C5 118.7(2)
Tabelul 3 Table 3
Partea celulelor Hep G2 ale cancerului hepatic inhibate, % The fraction of Hep G2 cells of liver cancer inhibited, %
Compusul Concentraţie, mol/L 10-5 10-6 10-7 Doxorubicina (soluţia apropiată) 76,7 28,6 0 Hidroxo-{[4-(p-clorofenil)-1-(piridin-2-il)tiosemicarbazido)aquanichel (cea mai apropiată soluţie) 100 5 0 Cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)-tiosemicarbazono]nichel (invenţia revendicată) 100 40,1 0 Compound Concentration, mol/L 10-5 10-6 10-7 Doxorubicin (proximate solution) 76.7 28.6 0 Hydroxo-{[4-(p-chlorophenyl)-1-(pyridin-2-yl)thiosemicarbazido) aquanickel (closest solution) 100 5 0 Chloro-[2-phenyl(pyridin-2-yl)methanone-4-(3-methoxyphenyl)-thiosemicarbazono]nickel (claimed invention) 100 40.1 0
1. Горбунова В. А. Новые цитостатики в лечении злокачественных опухолей. Медицина, 1998, 128с 1. Горбунова В. A. New cytostatics in the treatment of malignant tumors. Medicine, 1998, 128с
2. Mohammad M. Hassanien, Wael I. Mortada, Ali M. Hassan, Ahmed A. El-Asmy Synthesis, characterization and biological activities of 4-(p-chlorophenyl)-1-(pyridine-2-yl)thiosemicarbazibe and its metal complexes. Journal of the Korean Chemical Society, 2012, vol. 56. Nr. 6. p. 679 - 691 2. Mohammad M. Hassanien, Wael I. Mortada, Ali M. Hassan, Ahmed A. El-Asmy Synthesis, characterization and biological activities of 4-(p-chlorophenyl)-1-(pyridine-2-yl)thiosemicarbazibe and its metal complexes. Journal of the Korean Chemical Society, 2012, vol. 56. No. 6. pp. 679 - 691
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDA20120128A MD4300C1 (en) | 2012-12-28 | 2012-12-28 | Inhibitor of HepG2 cell proliferation in liver cancer based on chloro-[2-phenyl(pyridine-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDA20120128A MD4300C1 (en) | 2012-12-28 | 2012-12-28 | Inhibitor of HepG2 cell proliferation in liver cancer based on chloro-[2-phenyl(pyridine-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MD4300B1 MD4300B1 (en) | 2014-08-31 |
| MD4300C1 true MD4300C1 (en) | 2015-03-31 |
Family
ID=51485231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MDA20120128A MD4300C1 (en) | 2012-12-28 | 2012-12-28 | Inhibitor of HepG2 cell proliferation in liver cancer based on chloro-[2-phenyl(pyridine-2-yl)methanone-4-(3-methoxyphenyl)thiosemicarbazono]nickel |
Country Status (1)
| Country | Link |
|---|---|
| MD (1) | MD4300C1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MD891G2 (en) * | 1996-06-24 | 1998-07-31 | Николае ЕРЕМИЯ | Method for animals immunologic system potentiation remedy |
| CN101205233A (en) * | 2007-12-14 | 2008-06-25 | 中国科学院南海海洋研究所 | A dimeric flavonoid compound and its preparation method and anticancer application |
| CN101204401A (en) * | 2007-12-14 | 2008-06-25 | 中国科学院南海海洋研究所 | A kind of sea urchin extract and its preparation method and anticancer application |
| CN101333236A (en) * | 2008-08-05 | 2008-12-31 | 浙江大学 | Preparation method of critocin and application in antitumor drugs |
| RU2008144584A (en) * | 2006-04-12 | 2010-05-20 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | 4,5-DIHYDRO- [1,2,4] TRIAZOLO [4,3-F] PERIDINES AS PLK1 PROTEINKINASE INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
| CN102038934A (en) * | 2005-11-03 | 2011-05-04 | 福建医科大学 | Application of cucurmosin in preparation of drug for treating breast cancer |
| CN102219822A (en) * | 2011-03-24 | 2011-10-19 | 上海交通大学 | Ganoderic acid T amide derivative TLTO-A and synthetic method and application thereof |
-
2012
- 2012-12-28 MD MDA20120128A patent/MD4300C1/en not_active IP Right Cessation
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MD891G2 (en) * | 1996-06-24 | 1998-07-31 | Николае ЕРЕМИЯ | Method for animals immunologic system potentiation remedy |
| CN102038934A (en) * | 2005-11-03 | 2011-05-04 | 福建医科大学 | Application of cucurmosin in preparation of drug for treating breast cancer |
| RU2008144584A (en) * | 2006-04-12 | 2010-05-20 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | 4,5-DIHYDRO- [1,2,4] TRIAZOLO [4,3-F] PERIDINES AS PLK1 PROTEINKINASE INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
| CN101205233A (en) * | 2007-12-14 | 2008-06-25 | 中国科学院南海海洋研究所 | A dimeric flavonoid compound and its preparation method and anticancer application |
| CN101204401A (en) * | 2007-12-14 | 2008-06-25 | 中国科学院南海海洋研究所 | A kind of sea urchin extract and its preparation method and anticancer application |
| CN101333236A (en) * | 2008-08-05 | 2008-12-31 | 浙江大学 | Preparation method of critocin and application in antitumor drugs |
| CN102219822A (en) * | 2011-03-24 | 2011-10-19 | 上海交通大学 | Ganoderic acid T amide derivative TLTO-A and synthetic method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| Mohammad M. Hassanien, Wael I. Mortada, Ali M. Hassan, Ahmed A. El-Asmy Synthesis, characterization and biological activities of 4-(p-chlorophenyl)-1-(pyridine-2-yl)thiosemicarbazibe and its metal complexes. Journal of the Korean Chemical Society, 2012, vol. 56. Nr. 6. p. 679 - 691 * |
| Poma P., Notarbartolo M ., Labbozzetta M., Sanguedolce R., Alaimo A., Carina V., Maurici A., Cusimano A., Cervello M., D'Alessandro N. Antitumor effects of the novel NF-kappaB inhibitor dehydroxymethyl-epoxyquinomicin on human hepatic cancer cells: analysis of synergy with cisplatin and of possible correlation with inhibition of pro-survival genes and IL-6 production. 2006.04.28 Nr.4, p.923-30: <URL: <http://www.ncbi.nlm.nih.gov/pubmed/16525642>> * |
| Qi Qin, Yi-Wei Lin, Xiang-Yi Zheng, Hong Chen, Qi-Qi Mao, Kai Yang, Shou-Jiang Huang, Zheng-Yan Zhao. RNAa-mediated overexpression of WT1 induces apoptosis in HepG2 cells. World Journal of Surgical Oncology 2012,10:11, p. 1-8 * |
| Горбунова В. А. Новые цитостатики в лечении злокачественных опухолей. Медицина, 1998, 128с * |
Also Published As
| Publication number | Publication date |
|---|---|
| MD4300B1 (en) | 2014-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tshuva et al. | Modern cytotoxic titanium (IV) complexes; Insights on the enigmatic involvement of hydrolysis | |
| Eremina et al. | Mixed-ligand copper (II) complexes with tetrazole derivatives and 2, 2′-bipyridine, 1, 10-phenanthroline: Synthesis, structure and cytotoxic activity | |
| Massoud et al. | Copper (II) complexes based on tripodal pyrazolyl amines: Synthesis, structure, magnetic properties and anticancer activity | |
| Stanojkovic et al. | Zinc (II) complexes of 2-acetyl pyridine 1-(4-fluorophenyl)-piperazinyl thiosemicarbazone: Synthesis, spectroscopic study and crystal structures–Potential anticancer drugs | |
| Safir Filho et al. | Straightforward synthetic route to gold (I)-thiolato glycoconjugate complexes bearing NHC ligands (NHC= N-heterocyclic carbene) and their promising anticancer activity | |
| Garza-Ortiz et al. | A new family of Ru (II) complexes with a tridentate pyridine Schiff-base ligand and bidentate co-ligands: Synthesis, characterization, structure and in vitro cytotoxicity studies | |
| Nagy et al. | Zinc (II) complexes with dithiocarbamato derivatives: Structural characterisation and biological assays on cancerous cell lines | |
| Czerwińska et al. | Cytotoxic gold (III) complexes incorporating a 2, 2′: 6′, 2′′-terpyridine ligand framework–the impact of the substituent in the 4′-position of a terpy ring | |
| Khan et al. | Observation of π-hole interactions in the solid state structures of three new copper (II) complexes with a tetradentate N4 donor Schiff base: Exploration of their cytotoxicity against MDA-MB 468 cells | |
| Seliman et al. | Synthesis, X-ray structures and anticancer activity of gold (I)-carbene complexes with selenones as co-ligands and their molecular docking studies with thioredoxin reductase | |
| Su et al. | Synthesis, structures, antiproliferative activity of a series of ruthenium (II) arene derivatives of thiosemicarbazones ligands | |
| Qi et al. | Gallium (iii)–2-benzoylpyridine-thiosemicarbazone complexes promote apoptosis through Ca 2+ signaling and ROS-mediated mitochondrial pathways | |
| Rodrigues et al. | Copper (II): phenanthroline complexes with l-asparagine and l-methionine: Synthesis, crystal structure and in-vitro cytotoxic effects on prostate, breast and melanoma cancer cells | |
| Skoczynska et al. | Synthesis, structural analysis, redox properties and in vitro antitumor evaluation of half-sandwich complexes of Ru (II) with aminocoumarins | |
| Sun et al. | Synthesis and in vitro antiproliferative activity of platinum (II) complexes with N-monoalkyl 1R, 2R-diaminocyclohexane as ligands | |
| Oyeka et al. | Biologically active acylthioureas and their Ni (II) and Cu (II) Complexes: Structural, spectroscopic, anti-proliferative, nucleolytic and antimicrobial studies | |
| CN110066241A (en) | A kind of Schiff base complex of zinc and its preparation method and application | |
| Yin et al. | Synthesis, characterization, and anticancer activity of mononuclear Schiff-base metal complexes | |
| Ermakova et al. | Mixed-ligand manganese (II) complexes with 5-phenyltetrazole and polypyridine derivatives: Synthesis, crystal structures and biological activity | |
| Al-Jaroudi et al. | Synthesis, spectroscopic characterization, X-ray structure and electrochemistry of new bis (1, 2-diaminocyclohexane) gold (III) chloride compounds and their anticancer activities against PC3 and SGC7901 cancer cell lines | |
| Öztürkkan et al. | Synthesis, crystal structure, potential drug properties for Coronavirus of Co (II) and Zn (II) 2-chlorobenzoate with 3-cyanopyridine complexes | |
| Brown et al. | Synthesis and antitumor activity of new platinum complexes | |
| Pettinari et al. | Novel osmium (II)–cymene complexes containing curcumin and bisdemethoxycurcumin ligands | |
| Jiang et al. | Designing biotin-human serum albumin nanoparticles to enhance the targeting ability of binuclear ruthenium (III) compound | |
| Kozub et al. | Binuclear iron tetranitrosyl complexes with m-and p-methoxybenzenethiolate and naphthalene-2-thiolate ligands: synthesis, structure, and properties |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG4A | Patent for invention issued | ||
| KA4A | Patent for invention lapsed due to non-payment of fees (with right of restoration) | ||
| MM4A | Patent for invention definitely lapsed due to non-payment of fees |