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MD4434C1 - Use of N'-[1-(2-pyridyl)ethylidene]morpholin-4-carbothiohydrazide as a human myeloid leukemia HL-60 cell proliferation inhibitor - Google Patents

Use of N'-[1-(2-pyridyl)ethylidene]morpholin-4-carbothiohydrazide as a human myeloid leukemia HL-60 cell proliferation inhibitor Download PDF

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MD4434C1
MD4434C1 MDA20150097A MD20150097A MD4434C1 MD 4434 C1 MD4434 C1 MD 4434C1 MD A20150097 A MDA20150097 A MD A20150097A MD 20150097 A MD20150097 A MD 20150097A MD 4434 C1 MD4434 C1 MD 4434C1
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Moldova
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myeloid leukemia
human myeloid
carbothiohydrazide
ethylidene
pyridyl
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MDA20150097A
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Romanian (ro)
Russian (ru)
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MD4434B1 (en
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Анастасия ПАХОЛНИЦКАЯ
Дональд ПОЙРИЕР
Виктор ЦАПКОВ
Аурелиан ГУЛЯ
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Государственный Университет Молд0
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Publication of MD4434C1 publication Critical patent/MD4434C1/en

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Abstract

The invention relates to chemistry and medicine, namely to the use of an organic compound from the class of thiosemicarbazones as a human myeloid leukemia HL-60 cell proliferation inhibitor and can be used in medicine in the prevention and treatment of leukoses.Summary of the invention consists in the use as a human myeloid leukemia HL-60 cell proliferation inhibitor of N'-[1-(2-pyridyl)ethylidene]morpholin-4-carbothiohydrazide of formula:This compound has a significant cytostatic activity, inclusively at a concentration of 10-7 mol/L, with respect to human myeloid leukemia HL-60 cells.

Description

Invenţia se referă la chimie şi medicină, şi anume la utilizarea unui compus organic din clasa tiosemicarbazonelor în calitate de inhibitor al proliferării celulelor HL-60 ale leucemiei mieloide umane şi poate găsi aplicare în medicină la profilaxia şi tratarea leucozelor. The invention relates to chemistry and medicine, namely to the use of an organic compound from the class of thiosemicarbazones as an inhibitor of the proliferation of HL-60 cells of human myeloid leukemia and may find application in medicine for the prophylaxis and treatment of leukosis.

Din compuşii chimici, care conţin în componenţa sa fragmentul tiosemicarbazidic, care inhibă leucemia mieloidă umană, descrişi în literatură, cel mai înalt efect cancerostatic a fost obţinut în cazul hidratului nitrat de saliciliden-4-feniltiosemicarbazido(1-)aquacupru(2+) [1] cu formula: Of the chemical compounds, which contain in its composition the thiosemicarbazido fragment, which inhibits human myeloid leukemia, described in the literature, the highest cancerostatic effect was obtained in the case of salicylidene-4-phenylthiosemicarbazido(1-)aquacopper(2+) nitrate hydrate [ 1] with the formula:

Complexul dat inhibă creşterea şi multiplicarea a 100% de celule HL-60 ale leucemiei mieloide umane 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 nitrat de saliciliden-4-feniltiosemicarbazido(1-)-aquacupru(2+) constă în faptul că el nu posedă o activitate anticanceroasă suficient de înaltă şi nu inhibă proliferarea celulelor canceroase la o concentraţie mai mică de 10-6 mol/L. The disadvantage of salicylidene-4-phenylthiosemicarbazido(1-)-aquacopper(2+) nitrate hydrate is that it does not possess a sufficiently high anticancer activity and does not inhibit the proliferation of cancer cells at a concentration lower than 10-6 mol/L .

Este cunoscut compusul organic N'-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazida cu formula: The organic compound N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide with the formula:

Procedeul de sinteză a lui şi proprietăţile fizico-chimice sunt descrise în literatura ştiinţifică [2]. Totodată a fost stabilit că acest compus manifestă proprietăţi antimicrobiene, dar din cauza activităţii joase nu a găsit deocamdată aplicare în medicină. Its synthesis procedure and physico-chemical properties are described in the scientific literature [2]. At the same time, it was established that this compound exhibits antimicrobial properties, but due to its low activity, it has not yet found application in medicine.

Problema pe care o rezolvă prezenta invenţie este extinderea arsenalului de inhibitori ai proliferării celulelor HL-60 ale leucemiei mieloide umane cu activitate citostatică înaltă, inclusiv la concentraţii de 10-7 mol/L. The problem that the present invention solves is the expansion of the arsenal of inhibitors of the proliferation of HL-60 cells of human myeloid leukemia with high cytostatic activity, including at concentrations of 10-7 mol/L.

Esenţa invenţiei constă în utilizarea în calitate de inhibitor al proliferării celulelor HL-60 ale leucemiei mieloide umane a N'-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazidei. The essence of the invention consists in the use of N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide as an inhibitor of the proliferation of HL-60 cells of human myeloid leukemia.

Rezultatul tehnic al invenţiei constă în stabilirea la compusul dat a unei activităţi citostatice semnificative la concentraţii de 10-7 mol/L faţă de celulele HL-60 ale leucemiei mieloide umane. The technical result of the invention consists in establishing with the given compound a significant cytostatic activity at concentrations of 10-7 mol/L against HL-60 cells of human myeloid leukemia.

Rezultatul tehnic al invenţiei este condiţionat de faptul că pentru prima dată în calitate de inhibitor al proliferării celulelor HL-60 ale leucemiei mieloide umane se propune un compus organic, care conţine o combinaţie nouă de legături chimice deja cunoscute. The technical result of the invention is conditioned by the fact that for the first time an organic compound is proposed as an inhibitor of the proliferation of HL-60 cells of human myeloid leukemia, which contains a new combination of already known chemical bonds.

Exemplu de utilizare a N'-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazidei în calitate de inhibitor al leucemiei mieloide umane Example of use of N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide as an inhibitor of human myeloid leukemia

Celulele leucemiei mieloide umane HL-60 obţinute din Colecţia Americană a Culturilor Tip (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 şi 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 1·105 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 câte trei compartimente. Human myeloid leukemia HL-60 cells obtained from the 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 and 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 1·10 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 N'-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazidei sunt prezentate în tabel, din care se observă că la o concentraţie de 10-5 mol/L se inhibă creşterea şi multiplicarea a 94,2%, la 10-6 mol/L - 82,85%, iar la o concentraţie de 10-7 mol/L - 77,1% de celule HL-60 ale leucemiei mieloide umane. Datele obţinute indică faptul că acest compus organic posedă o activitate anticanceroasă semnificativă la concentraţia de 10-7 mol/L, spre deosebire de analogul proxim, care este inactiv la această concentraţie. The experimental data obtained regarding the study of the anticancer properties of N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide are presented in the table, from which it is observed that at a concentration of 10-5 mol/L growth is inhibited and multiplication of 94.2%, at 10-6 mol/L - 82.85%, and at a concentration of 10-7 mol/L - 77.1% of HL-60 cells of human myeloid leukemia. The data obtained indicate that this organic compound possesses a significant anticancer activity at the concentration of 10-7 mol/L, unlike the close analogue, which is inactive at this concentration.

Proprietăţile depistate ale N'-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazidei prezintă interes pentru medicină din punct de vedere al extinderii arsenalului de inhibitori ai leucemiei mieloide umane. The detected properties of N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide 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 mieloide umane inhibate, % The fraction of inhibited human myeloid leukemia HL-60 cells, %

Compusul Concentraţie, mol/L 10-5 10-6 10-7 Hidratul nitrat de saliciliden-4-feniltiosemicarbazido(1-)aqua-cupru(2+) (analogul proxim) 100 100 0 N'-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazidă 94,2 82,85 77,1 Compound Concentration, mol/L 10-5 10-6 10-7 Salicylidene-4-phenylthiosemicarbazido(1-)aqua-copper(2+) nitrate hydrate (close analogue) 100 100 0 N'-[1-(2- pyridyl)ethylidene]morpholine-4-carbothiohydrazide 94.2 82.85 77.1

1. MD 3890 B1 2009.04.30 1. MD 3890 B1 2009.04.30

2. Kasuga N.C., Onodera K., Nakano S., Hazashi K., Nomiya K. Synthesis, crystal structures and antimicrobial activities of 6-coordinate antimony(III) complexes with tridentate 2-acetylpyridine thiosemicarbazone, bis(thiosemicarbazone) and semicarbazone ligands. J. Inorg. Biochem. 2006 July, 100, p. 1176-1186 DOI: 10.1016/j.inorbio.2006.01.037 2. Kasuga N.C., Onodera K., Nakano S., Hazashi K., Nomiya K. Synthesis, crystal structures and antimicrobial activities of 6-coordinate antimony(III) complexes with tridentate 2-acetylpyridine thiosemicarbazone, bis(thiosemicarbazone) and semicarbazone ligands . J. Inorg. Biochem. 2006 July, 100, p. 1176-1186 DOI: 10.1016/j.inorbio.2006.01.037

Claims (1)

Utilizare a N′-[1-(2-piridil)etiliden]morfolin-4-carbotiohidrazidei în calitate de inhibitor al proliferării celulelor HL-60 ale leucemiei mieloide umane.Use of N′-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide as an inhibitor of human myeloid leukemia HL-60 cell proliferation.
MDA20150097A 2015-10-09 2015-10-09 Use of N'-[1-(2-pyridyl)ethylidene]morpholin-4-carbothiohydrazide as a human myeloid leukemia HL-60 cell proliferation inhibitor MD4434C1 (en)

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