MD4393C1 - Inhibitor of human myeloid leukemia HL-60 cells based on nitrato-[N′-(1-pyridine-2-ylmethylidene)-morpholine-4-carbothiohydrazido(1-)]copper - Google Patents
Inhibitor of human myeloid leukemia HL-60 cells based on nitrato-[N′-(1-pyridine-2-ylmethylidene)-morpholine-4-carbothiohydrazido(1-)]copper Download PDFInfo
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- MD4393C1 MD4393C1 MDA20150083A MD20150083A MD4393C1 MD 4393 C1 MD4393 C1 MD 4393C1 MD A20150083 A MDA20150083 A MD A20150083A MD 20150083 A MD20150083 A MD 20150083A MD 4393 C1 MD4393 C1 MD 4393C1
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- myeloid leukemia
- human myeloid
- copper
- ylmethylidene
- nitrato
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- 208000025113 myeloid leukemia Diseases 0.000 title claims abstract description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 229910052802 copper Inorganic materials 0.000 title claims abstract description 10
- 239000010949 copper Substances 0.000 title claims abstract description 10
- 239000003112 inhibitor Substances 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 238000011282 treatment Methods 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 5
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FGHSTPNOXKDLKU-UHFFFAOYSA-N nitric acid;hydrate Chemical compound O.O[N+]([O-])=O FGHSTPNOXKDLKU-UHFFFAOYSA-N 0.000 description 4
- -1 2-formylpyridine ([N′-(1-pyridin-2-ylmethylidene)morpholine-4- carbothiohydrazide]) Chemical compound 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000376 reactant Substances 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
- 229910052717 sulfur Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KZIPCMQIGBQYAS-UHFFFAOYSA-N (morpholin-4-ylamino)thiourea Chemical compound NC(=S)NNN1CCOCC1 KZIPCMQIGBQYAS-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin 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
- 206010028980 Neoplasm Diseases 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
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N thiosemicarbazide group Chemical group NNC(=S)N BRWIZMBXBAOCCF-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 anume la sinteza compuşilor coordinativi din clasa tiosemicarbazonaţilor metalelor de tranziţie şi poate găsi aplicare în medicină la profilaxia şi tratarea leucemiei umane mieloide. The invention refers to chemistry, namely to the synthesis of coordinating compounds from the thiosemicarbazonate class of transition metals and may find application in medicine for the prophylaxis and treatment of human myeloid leukemia.
Dintre compuşii coordinativi din clasa tiosemicarbazonaţilor metalelor de tranziţie care inhibă leucemia umană mieloidă, descrişi în literatură, cel mai înalt efect cancerostatic a fost obţinut în cazul hidratului nitratului de saliciliden-4-feniltiosemicarbazido(1-)aquacupru(II) [1] cu formula : Among the coordinating compounds from the class of transition metal thiosemicarbazonates that inhibit human myeloid leukemia, described in the literature, the highest cancerostatic effect was obtained in the case of salicylidene-4-phenylthiosemicarbazido(1-)aquacopper(II) nitrate hydrate [1] with the formula :
Complexul dat inhibă creşterea şi multiplicarea a 100% de celule HL-60 ale leucemiei umane mieloide la concentraţii de 10-5 şi 10-6 M. The given complex inhibits the growth and multiplication of 100% of HL-60 cells of human myeloid leukemia at concentrations of 10-5 and 10-6 M.
Dezavantajul hidratului nitratului de saliciliden-4-feniltiosemicarbazido(1-)-aquacupru(2+) constă în faptul că nu posedă o activitate anticancerigenă suficient de înaltă şi inhibă proliferarea celulelor canceroase numai la concentraţia mai mare de 10-6 mol/L şi până acum nu a găsit aplicare în medicină. The disadvantage of salicylidene-4-phenylthiosemicarbazido(1-)-aquacopper(2+) nitrate hydrate is that it does not possess a sufficiently high anticancer activity and inhibits the proliferation of cancer cells only at concentrations higher than 10-6 mol/L and up to now it has not found application in medicine.
Problema pe care o rezolvă prezenta invenţie constă în extinderea arsenalului de inhibitori ai leucemiei umane mieloide cu activitate biologică înaltă. The problem that the present invention solves is to expand the arsenal of human myeloid leukemia inhibitors with high biological activity.
Esenţa invenţiei constă în aceea că în calitate de inhibitor al leucemiei umane mieloide (celule HL-60) se propune nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]cupru cu formula: The essence of the invention is that as an inhibitor of human myeloid leukemia (HL-60 cells) nitrato-[N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbothiohydrazido(1-)]copper with formula:
Compusul coordinativ dat, proprietăţile lui şi procedeul de obţinere nu sunt descrise în stadiul tehnicii. The given coordinating compound, its properties and the method of obtaining it are not described in the state of the art.
Rezultatul tehnic al invenţiei constă în stabilirea la compusul revendicat a activităţii anticancerigene, care inhibă creşterea şi multiplicarea a 72% de celule HL-60 ale leucemiei umane mieloide la o concentraţie de 10-7 mol/L. The technical result of the invention consists in establishing the claimed compound's anticancer activity, which inhibits the growth and multiplication of 72% of HL-60 cells of human myeloid leukemia at a concentration of 10-7 mol/L.
Rezultatul tehnic al invenţiei este condiţionat de faptul că pentru prima dată în calitate de inhibitor al celulelor HL-60 leucemiei umane mieloide se propune compusul coordinativ al nitratului de cupru cu 4-morfolintiosemicarbazona 2-formilpiridinei, 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 HL-60 human myeloid leukemia cells, the coordination compound of copper nitrate with 2-formylpyridine 4-morpholinthiosemicarbazone is proposed, which contains a new combination of already known chemical bonds .
Nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]cupru revendicat se obţine la interacţiunea soluţiilor etanolice fierbinţi (50…55°C) de Cu(NO3)2 .3H2O, 4-morfolintiosemicarbazonă şi 2-formilpiridină, luate în raport echimolar. Reacţia decurge în 45…60 min conform următoarei scheme: The claimed copper nitrato-[N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbotiohydrazido(1-)] is obtained by the interaction of hot ethanolic solutions (50…55°C) of Cu(NO3)2 .3H2O , 4-morpholinthiosemicarbazone and 2-formylpyridine, taken in an equimolar ratio. The reaction proceeds in 45...60 min according to the following scheme:
Mecanismul prezentei reacţii este legat de faptul că în timpul sintezei în amestecul reactant are loc condensarea 2-formilpiridinei cu 4-morfolintiosemicarbazida şi formarea 4-morfolintiosemicarbazonei 2-formilpiridinei ([N′-(1-piridin-2-ilmetiliden)morfolin-4-carbotiohidrazida]), care coordinează la ionul de cupru(2+) în forma tiolică monodeprotonizată ca ligand tridentat-N,N,S. În afară de acest ligand în sfera internă intră şi ionul nitrat. The mechanism of the present reaction is related to the fact that during the synthesis in the reactant mixture the condensation of 2-formylpyridine with 4-morpholinethiosemicarbazide and the formation of 4-morpholinethiosemicarbazone of 2-formylpyridine ([N′-(1-pyridin-2-ylmethylidene)morpholine-4- carbothiohydrazide]), which coordinates to the copper(2+) ion in the monodeprotonated thiol form as a tridentate-N,N,S ligand. In addition to this ligand, the nitrate ion also enters the inner sphere.
Exemplu de obţinere a nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]cupru Example of obtaining nitrato-[N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbothiohydrazido(1-)]copper
4-Morfolintiosemicarbazida a fost sintetizată conform metodei descrise în literatură (Amandha Kaiser da Silva. Complexos Heterolepticos de Ouro(III) como Potenciais Antitumorais e Anti-Trypanosoma cruzi// Dissertacao apresentada ao Instituto de Quimica de Sao Carlos. P. 31 // Sao Carlos, 2015, url: http://www.teses.usp.br/.../AmandhaKaiserdaSilvarevi/). 4-Morpholinthiosemicarbazide was synthesized according to the method described in the literature (Amandha Kaiser da Silva. Complexos Heterolepticos de Ouro(III) como Potenciais Antitumorais e Anti-Trypanosoma cruzi// Dissertacao presentada ao Instituto de Quimica de Sao Carlos. P. 31 // Sao Carlos, 2015, url: http://www.teses.usp.br/.../AmandhaKaiserdaSilvarevi/).
Se amestecă 20 mL de soluţie etanolică, care conţine 10 mmol de 4-morfolintiosemicarbazidă şi 10 mmol 2-formilpiridină cu 10 mmol de Cu(NO3)2·3H2O, dizolvaţi în 10 mL de alcool. Amestecul reactant este încălzit la 50…55°C şi amestecat în continuu cu ajutorul agitatorului magnetic timp de 45…60 min. La răcire din soluţie se depun cristale mici de culoare verde întunecată, care sunt filtrate prin filtru de sticlă, spălate cu etanol, eter şi uscate în aer liber. Mix 20 mL of ethanolic solution, which contains 10 mmol of 4-morpholinthiosemicarbazide and 10 mmol of 2-formylpyridine with 10 mmol of Cu(NO3)2·3H2O, dissolved in 10 mL of alcohol. The reactant mixture is heated to 50...55°C and continuously mixed with the help of the magnetic stirrer for 45...60 min. Upon cooling, small dark green crystals are deposited from the solution, which are filtered through a glass filter, washed with ethanol, ether and dried in the open air.
S-a determinat, %: C - 35,05; H - 3,31; Cu - 16,77; N - 18,50; S - 8,37. Pentru C11H13CuN5O4S s-a calculat, % : C - 35,25; H -3,50; Cu - 16,95; N- 18,68; S - 8,55. Momentul magnetic efectiv µeff= 1,84 M. B. (294K). It was determined, %: C - 35.05; H - 3.31; With - 16.77; N - 18.50; S - 8.37. For C11H13CuN5O4S it was calculated, %: C - 35.25; H -3.50; With - 16.95; N- 18.68; S - 8.55. Effective magnetic moment µeff= 1.84 M. B. (294K).
Procedeul de obţinere a compusului revendicat este simplu în executare, substanţele iniţiale accesibile, randamentul constituie 80% faţă de cel teoretic calculat. Complexul este stabil în contact cu aerul, puţin solubil în apă şi alcooli, bine solubil în dimetilformamidă şi dimetilsulfoxid, practic insolubil în eter. The procedure for obtaining the claimed compound is simple in execution, the initial substances are accessible, the yield is 80% compared to the theoretically calculated one. The complex is stable in contact with air, slightly soluble in water and alcohols, well soluble in dimethylformamide and dimethylsulfoxide, practically insoluble in ether.
La recristalizarea compusului revendicat din soluţie etanolică au fost obţinute monocristale, structura cărora a fost stabilită cu ajutorul analizei cu raze X (Formula empirică C11H13CuN5O4S, grupa spaţială P-1, parametrii celulei elementare [Å]: a = 8,1655(7); b = 8,7809(7), c = 21,388(2); α = 89,140(7)°, β = 80,813(7)°, γ = 77,828(7)°; volumul celulei elementare 1479,58 Å3). A fost stabilită pentru complexul dat structura piramidală (vezi figura). Molecula de N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazidă din sfera internă se comportă ca un ligand tridentat coordinând la atomul central de cupru prin atomii de azot piridinic, azometinic şi atomul de sulf al fragmentului tiosemicarbazidic, formând două metalocicluri din cinci atomi. Al patrulea şi cincilea locuri în sfera internă este ocupat de doi atomi de oxigen ai ionului nitrat, care se comportă ca un ligand bidentat. Upon recrystallization of the claimed compound from ethanolic solution, single crystals were obtained, the structure of which was established with the help of X-ray analysis (Empirical formula C11H13CuN5O4S, space group P-1, unit cell parameters [Å]: a = 8.1655(7); b = 8.7809(7), c = 21.388(2); α = 89.140(7)°, β = 80.813(7)°, γ = 77.828(7)°; unit cell volume 1479.58 Å3). The pyramidal structure was established for the given complex (see figure). The molecule of N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbothiohydrazide in the inner sphere behaves as a tridentate ligand coordinating to the central copper atom through the pyridinic and azomethine nitrogen atoms and the sulfur atom of the thiosemicarbazide fragment, forming two five-atom metallocycles. The fourth and fifth places in the inner sphere are occupied by two oxygen atoms of the nitrate ion, which behaves as a bidentate ligand.
Astfel, în baza rezultatelor analizei elementelor şi a cercetărilor fizico-chimice, a fost stabilită compoziţia şi structura compusului revendicat. Thus, based on the results of elemental analysis and physico-chemical research, the composition and structure of the claimed compound was established.
Exemplu de utilizare a nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]cupru în calitate de inhibitor al leucemiei umane mieloide Example of use of nitrato-[N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbothiohydrazido(1-)]copper as an inhibitor of human myeloid leukemia
Celulele leucemiei umane mieloide HL-60 obţinute din Colecţia Culturilor Tip American (American Type Culture Collection, Rockville, MD) au fost cultivate în formă de suspensie în mediul RPMI-1640 suplimentat cu 10% (V/V) ser embrionic de Sovine, 2 mM de L-glutamină, 100 UI penicilină/mL, 100 µg de streptomicină/mL şi incubate în atmosferă umedă de 95% aer / 5% CO2 la 37°C. Celulele au fost amestecate de 2…3 ori pe parcursul săptămânii, pentru a le păstra în fază omogenă. După aceasta celulele au fost plasate în vase Falcon din plastic pentru culturi cu 24 compartimente (2 cm2/celulă) la densitatea iniţială de 105 celule/mL/compartiment şi tratate cu soluţii de diferită concentraţie ale compusului revendicat în apă sterilă. Fiecare procedură de tratare cu aceeaşi concentraţie a fost efectuată în trei compartimente. Human myeloid leukemia HL-60 cells obtained from the American Type Culture Collection (American Type Culture Collection, Rockville, MD) were cultured in suspension in RPMI-1640 medium supplemented with 10% (V/V) fetal bovine serum, 2 mM L-glutamine, 100 IU penicillin/mL, 100 µg streptomycin/mL and incubated in a humid atmosphere of 95% air / 5% CO2 at 37°C. The cells were mixed 2...3 times during the week to keep them in homogeneous phase. The cells were then placed in 24-compartment Falcon plastic culture dishes (2 cm 2 /cell) at the initial density of 10 5 cells/mL/compartment and treated with different concentration solutions of the claimed compound in sterile water. Each treatment procedure with the same concentration was performed in three compartments.
Datele experimentale obţinute privind studierea proprietăţilor anticanceroase ale nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]cupru sunt prezentate în tabel, din care se observă că la concentraţia de 10-5 mol/L el inhibă creşterea şi multiplicarea a 97,25%, la 10-6 mol/L - 96,35%, iar la concentraţia de 10-7 mol/L - 71,7% de celule HL-60 ale leucemiei umane mieloide. Datele obţinute relevă faptul că acest complex de cupru, după activitatea anticancerigenă, depăşeşte de 1,72 ori caracteristicile respective ale analogului proxim. The experimental data obtained regarding the study of the anticancer properties of nitrato-[N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbothiohydrazido(1-)]copper are presented in the table, from which it can be seen that at the concentration of 10- 5 mol/L it inhibits the growth and multiplication of 97.25%, at 10-6 mol/L - 96.35%, and at the concentration of 10-7 mol/L - 71.7% of HL-60 leukemia cells human myeloid. The obtained data reveal the fact that this copper complex, according to the anticancer activity, exceeds by 1.72 times the respective characteristics of the close analog.
Proprietăţile depistate ale nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]-cupru prezintă interes pentru medicină din punct de vedere al extinderii arsenalului de inhibitori ai leucemiei umane mieloide. The detected properties of nitrato-[N′-(1-pyridin-2-ylmethylidene)-morpholin-4-carbotiohydrazido(1-)]-copper are of interest for medicine from the point of view of expanding the arsenal of human myeloid leukemia inhibitors.
Tabel Table
Partea celulelor HL-60 ale leucemiei umane mieloide inhibate, % The fraction of inhibited human myeloid leukemia HL-60 cells, %
Compusul Concentraţia, mol/L 10-5 10-6 10-7 Hidratul nitratului de saliciliden-4-feniltiosemicarbazido(1-)-aquacupru(2+) (analogul proxim) 100 100 0 Nitrato-[N′-(1-piridin-2-ilmetiliden)-morfolin-4-carbotiohidrazido(1-)]cupru 97,25 96,35 71,7 Compound Concentration, mol/L 10-5 10-6 10-7 Salicylidene-4-phenylthiosemicarbazido(1-)-aquacopper(2+) nitrate hydrate (close analogue) 100 100 0 Nitrato-[N′-(1-pyridine) -2-ylmethylidene)-morpholin-4-carbothiohydrazido(1-)]copper 97.25 96.35 71.7
1. MD 3890 G2 2009.04.30 1. MD 3890 G2 2009.04.30
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| WO1985000955A1 (en) * | 1983-08-22 | 1985-03-14 | A/S Cheminova | A biocidal, particularly fungicidal and/or bactericidal composition and thiosemicarbazones and metal complexes thereof for use in the composition |
| US5281715A (en) * | 1992-05-13 | 1994-01-25 | Yale University | 2-formylpyridine thiosemicarbazone compounds |
| MD3098G2 (en) * | 2006-01-03 | 2007-02-28 | Государственный Университет Молд0 | Dihydrate of di( -Ophenoxy)-di[N-(2-oxy-1-benzal)-N1- -oxyfuralhydrazine(2-)copper] with properties of inhibitor of the human myeloid leukemia |
| MD3655G2 (en) * | 2007-09-03 | 2009-02-28 | Государственный Университет Молд0 | Inhibitor of human myeloid leukemia on base of bis(2-hydroxy-8-phenyl-tricyclo/7.3.1.0.2,7/-tridecane-13-on-thiosemicarbazonato)copper |
| MD3890G2 (en) * | 2008-09-08 | 2009-12-31 | Государственный Университет Молд0 | Inhibitors of human myeloid leukemia on base of coordinative compounds of copper(II) with salicylidene thiocarbazides |
| MD20110040A1 (en) * | 2011-05-10 | 2012-11-30 | Государственный Университет Молд0 | Inhibitors of human myeloid leukemia based on 2-[2-(pyridine-2-ilmethylidene)hydrazine]-1,3-benzothiazole and 2-[2-(1-pyridine-2-ilethylidene)hydrazine]-1,3-benzothiazole dihydrate |
| MD4190C1 (en) * | 2011-06-16 | 2013-07-31 | Государственный Университет Молд0 | Inhibitor of human myeloid leukemia based on {bis[2-(3,5-dibrom-2-hydroxyphenyl)-2-oxoethyl-piperidin-1-carbodithioato(1-)-O,O′]copper} |
| 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 |
-
2015
- 2015-09-04 MD MDA20150083A patent/MD4393C1/en not_active IP Right Cessation
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