MD4132C1 - 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 - Google Patents
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 Download PDFInfo
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Invenţia se referă la chimie şi medicină, şi anume la o combinaţie complexă biologic activă a cuprului cu tiosemicarbazone, care poate găsi aplicare în medicină ca preparat citostatic la profilaxia şi tratarea cancerului mamar. The invention relates to chemistry and medicine, namely to a biologically active complex combination of copper with thiosemicarbazones, which can find application in medicine as a cytostatic preparation for the prophylaxis and treatment of breast cancer.
Din compuşii coordinativi, care inhibă creşterea şi multiplicarea celulelor T-47D ale cancerului mamar cel mai înalt efect cancerostatic a fost obţinut în cazul di(µ-Ofenoxi)-di{[2-(4-aminobenzensulfamido)-5-etil-1,3,4-tiadiazol]-3,5-dibromosalicilidentiosemicarbazonato(2-)cupru} (analogul proxim) [1] cu formula : Of the coordinating compounds, which inhibit the growth and multiplication of T-47D breast cancer cells, the highest cancerostatic effect was obtained in the case of di(µ-Ophenoxy)-di{[2-(4-aminobenzenesulfamido)-5-ethyl-1, 3,4-thiadiazol]-3,5-dibromosalicylidentiosemicarbazonato(2-)copper} (close analogue) [1] with the formula:
Combinaţia dată la concentraţia de 10-5 mol/L depăşeşte de 2,5 ori caracteristicile cancerostatice respective ale doxorubicinei - cel mai efectiv preparat chimioterapeutic, folosit în practica medicală pentru tratarea şi profilaxia cancerului mamar. The combination given at the concentration of 10-5 mol/L exceeds by 2.5 times the respective cancerostatic characteristics of doxorubicin - the most effective chemotherapeutic preparation, used in medical practice for the treatment and prophylaxis of breast cancer.
Dezavantajul acestui compus constă în faptul că el nu posedă o activitate anticanceroasă mai înaltă. The disadvantage of this compound is that it does not possess a higher anticancer activity.
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 sinteza unui compus coordinativ nou al cuprului di(µ-S)-bis{cloro-[fenil(piridin-2-il)-metanon-tiosemicarbazonato(1-)]cupru} cu formula : The essence of the invention consists in the synthesis of a new coordination compound of copper di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)-methanone-thiosemicarbazonato(1-)]copper} with the formula:
/ /
care manifestă proprietăţi de inhibitor al proliferării celulelor T-47D ale cancerului mamar. which exhibits inhibitory properties of T-47D breast cancer cell proliferation.
Rezultatul tehnic constă în extinderea gamei de compuşi coordinativi cu activitate anticancerigenă, care la o concentraţie de 10-6 mol/L depăşeşte aproximativ de 4 ori caracteristicile similare ale analogului proxim din clasa tiosemicarbazonaţilor de cupru sus-menţionat [1]. The technical result consists in expanding the range of coordinating compounds with anticancer activity, which at a concentration of 10-6 mol/L exceeds by approximately 4 times the similar characteristics of the proximate analogue from the above-mentioned copper thiosemicarbazonate class [1].
Compusul dat şi proprietăţile lui, precum şi procedeul de sinteză nu sunt descrise în literatură. The given compound and its properties, as well as the synthesis procedure, are not described in the literature.
Analiza comparativă a compusului revendicat cu analogul proxim demonstrează că ei se deosebesc prin aceea, că în analogul proxim fragmentul 3,5-dibromosalicilidenic este înlocuit cu cel 2-benzoilpiridinic, iar tiosemicarbazona este monodeprotonizată. În afară de aceasta, molecula de streptocidă coordinată este substituită cu ionul de clor, iar funcţia de atom-punte o îndeplineşte atomul de sulf al tiosemicarbazonei. Datorită acestor particularităţi în structura complexului revendicat se realizează o combinare nouă de legături chimice deja cunoscute. The comparative analysis of the claimed compound with the proximate analogue demonstrates that they differ in that, in the proximate analogue, the 3,5-dibromosalicylidene fragment is replaced by the 2-benzoylpyridinic one, and the thiosemicarbazone is monodeprotonated. Apart from this, the coordinated streptocide molecule is substituted with the chlorine ion, and the sulfur atom of the thiosemicarbazone fulfills the bridging atom function. Due to these particularities in the structure of the claimed complex, a new combination of already known chemical bonds is achieved.
Di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} revendicat se obţine la interacţiunea soluţiilor etanolice fierbinţi (55…60°C) de CuCl2 .2H2O cu tiosemicarbazona 2-benzoilpiridinei, luate în raport molar de 1 : 1. Reacţia decurge în 45…60 min conform următoarei scheme : The claimed di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} is obtained by the interaction of hot ethanolic solutions (55...60°C) of CuCl2 .2H2O with 2-benzoylpyridine thiosemicarbazone, taken in a molar ratio of 1:1. The reaction proceeds in 45...60 min according to the following scheme:
Mecanismul reacţiei date constă în deprotonizarea grupei tiolice a tiosemicarbazonei sus-numite în prezenţa azotului piridinic al ligandului şi coordinarea anionului format la ionul de cupru(2+) ca ligand N,N,S-tridentat monodeprotonizat. Al patrulea loc în sfera internă a atomului central îl ocupă atomul de sulf al moleculei vecine. La rândul său, în molecula vecină al patrulea loc coordinativ este ocupat de atomul de sulf al primului fragment de complex. Al cincilea loc în sfera coordinativă a ambilor atomi centrali de cupru este ocupat de ionii 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 copper(2+) ion as a monodeprotonated N,N,S-tridentate ligand. The fourth place in the inner sphere of the central atom is occupied by the sulfur atom of the neighboring molecule. In turn, in the neighboring molecule the fourth coordinating place is occupied by the sulfur atom of the first fragment of the complex. The fifth place in the coordination sphere of both central copper atoms is occupied by chlorine ions.
Procedeul de obţinere a di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} revendicat este simplu în realizare, substanţele iniţiale sunt accesibile, iar randamentul constituie 65%. Complexul sintetizat are culoare verde, este stabil în contact cu aerul, puţin solubil în apă şi alcooli alifatici, solubil în dimetilformamidă şi dimetilsulfoxidă, practic insolubil în eter. The process for obtaining the claimed di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} is simple to perform, the initial substances are accessible, and the yield is 65% . The synthesized complex has a green color, is stable in contact with air, slightly soluble in water and aliphatic alcohols, soluble in dimethylformamide and dimethylsulfoxide, practically insoluble in ether.
Exemplu de obţinere a di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} Example of obtaining di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper}
La soluţia etanolică, care conţine 10 mmol de dihidrat al clorurii de cupru(2+) în 20 mL etanol, încălzită (55…60°C) şi amestecată în permanenţă cu ajutorul agitatorului magnetic, se adaugă soluţia ce conţine 10 mmol de tiosemicarbazonă a 2-benzoilpiridinei în 50 mL de alcool etilic. După aceasta, amestecul reactant se refluxează pe parcursul a 45…60 min. La răcire din amestecul reactant se precipită cristale mărunte de culoare verde, care se filtrează printr-un filtru poros din sticlă, se spală cu C2H5OH, eter şi se usucă în aer. The solution containing 10 mmol of thiosemicarbazone of 2-benzoylpyridine in 50 mL of ethyl alcohol. After this, the reactant mixture is refluxed for 45...60 min. Upon cooling, small green crystals precipitate from the reaction mixture, which are filtered through a porous glass filter, washed with C2H5OH, ether and dried in air.
Pentru C26H22Cl2Cu2N8S2 determinat, %: C - 43,95, H - 2,99, Cu - 17,79; N - 15,70, S - 8,88. For determined C26H22Cl2Cu2N8S2, %: C - 43.95, H - 2.99, Cu - 17.79; N - 15.70, S - 8.88.
calculat, %: C - 44,07; H - 3,13; Cu - 17,93; N - 15,81; S - 9,05. calculated, %: C - 44.07; H - 3.13; With - 17.93; N - 15.81; S - 9.05.
Cercetarea la microscop a compusului coordinativ sintetizat demonstrează că el posedă omogenitate fazică. Din cauza dimensiunilor mici şi absenţei monocristalelor acestui complex, pentru determinarea individualităţii componenţei şi structurii lui au fost utilizate metoda de analiză a elementelor, spectroscopia IR, magnetochimia şi termogravimetria. Microscopic examination of the synthesized coordinating compound demonstrates that it possesses phase homogeneity. Due to the small size and the absence of single crystals of this complex, the elemental analysis method, IR spectroscopy, magnetochemistry and thermogravimetry were used to determine the individuality of its composition and structure.
În baza măsurării în dimetilformamidă a conductibilităţii electrice molare (æ) a complexului revendicat s-a stabilit că el este neelectrolit [æ =3 Ω-1 . cm2 . mol-1, 20° C, CM=0,001 mol/L]. Based on the measurement in dimethylformamide of the molar electrical conductivity (æ) of the claimed complex, it was established that it is non-electrolyte [æ =3 Ω-1 . cm2. mol-1, 20° C, CM=0.001 mol/L].
Analiza magnetochimică la temperatura camerei (292 K) a compusului coordinativ sintetizat a demonstrat că el posedă un moment magnetic efectiv redus (µef. = 1,32 m.B.) comparativ cu cel de spin (S = 1⁄2), fapt care indică despre structura lui polinucleară. Magnetochemical analysis at room temperature (292 K) of the synthesized coordination compound demonstrated that it possesses a reduced effective magnetic moment (µeff. = 1.32 m.B.) compared to the spin moment (S = 1⁄2), a fact that indicates about the structure his polynuclear.
Pentru determinarea modului de coordinare a ligandului la ionul de cupru(2+), a fost efectuată analiza comparativă a spectrelor IR ale compusului revendicat cu cele ale analogului proxim [1], tiosemicarbazonelor iniţiale şi ale complexului clorurii de cupru cu tiosemicarbazona 2-formilpiridinei [2], structura căruia a fost stabilită folosind analiza cu raze X. S-a constatat că tiosemicarbazona studiată în complexul revendicat se comportă ca un ligand tridentat monodeprotonizat, unindu-se cu ionul central prin intermediul atomilor de azot piridinic şi azometinic şi a sulfului, formând două metalocicluri din cinci atomi. În favoarea acestui fapt indică absenţa în spectrele IR ale substanţei revendicate şi ale analogului proxim a benzilor de absorbţie ν(NH) şi ν(C=S), care în tiosemicarbazonele libere se observă în domeniile 1540…1535 şi, respectiv, 1125…1120 cm-1. În structurile ambelor tipuri de complecşi se observă banda de absorbţie ν(C-S) în domeniul 755…745 cm-1, iar banda ν(C=N) se deplasează cu 25…20 cm-1 spre frecvenţe mai mici (în tiosemicarbazona iniţială ν(C=N) se observă la 1615 cm-1), fiind însoţită de scindare în două componente. La 1575 cm-1 în spectrul di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} se observă banda de absorbţie, care este condiţionată de oscilaţiile de valenţă >C=N-N=C<. Acest caracter al spectrelor IR demonstrează enolizarea tiosemicarbazonei în procesul de formare a complexului revendicat. În afară de aceasta în domeniul 535…405 cm-1 în spectrul di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} se observă o serie de benzi de absorbţie noi, care conform datelor luate din literatură, pot fi atribuite la ν(Cu-N) = 530 şi 410 cm-1 şi ν(Cu-S) = 465 cm-1. To determine the mode of coordination of the ligand to the copper(2+) ion, the comparative analysis of the IR spectra of the claimed compound with those of the proximate analogue [1], the initial thiosemicarbazones and the copper chloride complex with the 2-formylpyridine thiosemicarbazone [ 2], the structure of which was established using X-ray analysis. It was found that the thiosemicarbazone studied in the claimed complex behaves as a monodeprotonated tridentate ligand, uniting with the central ion through the pyridinic and azomethine nitrogen atoms and sulfur, forming two metallocycles of five atoms. In favor of this fact, the absence in the IR spectra of the claimed substance and its close analogue of the absorption bands ν(NH) and ν(C=S), which in the free thiosemicarbazones are observed in the ranges 1540...1535 and 1125...1120, respectively cm-1. In the structures of both types of complexes, the absorption band ν(C-S) is observed in the range 755…745 cm-1, and the band ν(C=N) moves by 25…20 cm-1 towards lower frequencies (in the initial thiosemicarbazone ν (C=N) is observed at 1615 cm-1), being accompanied by splitting into two components. At 1575 cm-1 in the spectrum of di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} the absorption band is observed, which is conditioned by the valence oscillations >C=N-N=C<. This character of the IR spectra demonstrates the enolization of the thiosemicarbazone in the process of forming the claimed complex. In addition, in the range 535...405 cm-1 in the spectrum of di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} a series of bands is observed new absorption bands, which according to the data taken from the literature, can be assigned to ν(Cu-N) = 530 and 410 cm-1 and ν(Cu-S) = 465 cm-1.
Analiza termică a demonstrat că pe derivatograma compusului revendicat se observă un singur efect exotermic la 280°C, care corespunde procesului de distrucţie termooxidativă a ligandului organic în complex. The thermal analysis demonstrated that on the derivatogram of the claimed compound a single exothermic effect is observed at 280°C, which corresponds to the thermooxidative destruction process of the organic ligand in the complex.
Astfel, în baza rezultatelor analizei elementelor şi cercetărilor fizico-chimice a fost stabilită compoziţia şi structura probabilă a compusului revendicat. Thus, based on the results of elemental analysis and physico-chemical research, the composition and probable 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 di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar Example of use of di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} 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) 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 (2 mM), 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) 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 (2 mM), 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/godeu) în trei exemplare. După 48 ore mediul s-a schimbat, urmând diluarea specifică cu diferiţi inhibitori în mediul de creştere. Celulele 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 di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} revendicat în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar demonstrează că acest compus la concentraţia de 10-5 mol/L inhibă creşterea şi multiplicarea a 100%, iar la 10-6 mol/L - 38±3,5% de celule T-47D ale cancerului mamar (vezi tabelul). Datele obţinute indică că acest compus după activitatea anticancerigenă depăşeşte de aproximativ 4 ori caracteristicile analoage ale di(µ-Ofenoxi)-di{[2-(4-aminobenzensulfamido)-5-etil-1,3,4-tiadiazol]-3,5-dibromosalicilidentiosemicarbazonato(2-)cupru} (analogul proxim). Experimental data obtained following the study of di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} claimed as an inhibitor of T-47D breast cancer cell proliferation demonstrates that this compound at a concentration of 10-5 mol/L inhibits the growth and multiplication of 100%, and at 10-6 mol/L - 38±3.5% of breast cancer T-47D cells (see table). The data obtained indicate that this compound, after anticancer activity, exceeds the analogous characteristics of di(µ-Ophenoxy)-di{[2-(4-aminobenzenesulfamido)-5-ethyl-1,3,4-thiadiazole]-3 by approximately 4 times, 5-dibromosalicylidentiosemicarbazonato(2-)copper} (close analogue).
Tabel Table
Rata inhibării celulelor T-47D ale cancerului mamar, % Breast cancer T-47D cell inhibition rate, %
Concentraţie, mol/L Compusul 10-5 10-6 10-7 Di(µ-Ofenoxi)-di{[2-(4-aminobenzensulfamido)-5-etil-1,3,4-tiadiazol]-3,5-dibromosalicilidentiosemicarbazonato(2-) cupru} (analogul proxim) 100 10 0 Di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} 100 38±3,5 0 Concentration, mol/L Compound 10-5 10-6 10-7 Di(µ-Ophenoxy)-di{[2-(4-aminobenzenesulfamido)-5-ethyl-1,3,4-thiadiazole]-3,5- dibromosalicylidentiosemicarbazonato(2-) copper} (close analog) 100 10 0 Di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} 100 38±3.5 0
Proprietăţile depistate ale di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} 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 di(µ-S)-bis{chloro-[phenyl(pyridin-2-yl)methanone-thiosemicarbazonato(1-)]copper} are of interest for medicine from the point of view of expanding the arsenal of T-cell proliferation inhibitors -47D of breast cancer.
1. MD 3995 B1 (2009.12.31) 1. MD 3995 B1 (2009.12.31)
2. Chumakov Iu. M., Tsapkov V. I., Jeanneau E., Bairac N. N., Bocelli G., Poirier D., Roy J., Gulea A. Crystal structures of copper(II) chloride, copper(II) bromide and copper(II) nitrate complexes with pyridin-2-carbaldehyde thiosemicarbazone. Cryst. Report. 2008, Vol.53, N 5, P. 786-792 2. Chumakov Yu. M., Tsapkov V. I., Jeanneau E., Bairac N. N., Bocelli G., Poirier D., Roy J., Gulea A. Crystal structures of copper(II) chloride, copper(II) bromide and copper(II) nitrate complexes with pyridine-2-carbaldehyde thiosemicarbazone. Cryst. Report. 2008, Vol. 53, N 5, P. 786-792
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| CN112028911A (en) * | 2020-09-22 | 2020-12-04 | 广西师范大学 | A kind of zinc complex with 2-benzoylpyridine thiosemicarbazide as ligand and its synthesis method and application |
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| MD4327C1 (en) * | 2013-10-22 | 2015-09-30 | Институт Химии Академии Наук Молдовы | N-(D8,13-Bicyclohomofarnesenoyl)-3-amino-1,2,4-triazole compound and process for cultivation of Nostoc linckia cyanobacterium with its use |
| MD4326C1 (en) * | 2013-10-22 | 2015-09-30 | Институт Химии Академии Наук Молдовы | N-(D8,13-Bicyclohomofarnesenoylamino)carbazole compound and process for cultivation of Nostoc linckia cyanobacterium with its use |
| CN112028911A (en) * | 2020-09-22 | 2020-12-04 | 广西师范大学 | A kind of zinc complex with 2-benzoylpyridine thiosemicarbazide as ligand and its synthesis method and application |
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