WO2017116356A1 - Dna targeted mono and heterodinuclear complexes - Google Patents
Dna targeted mono and heterodinuclear complexes Download PDFInfo
- Publication number
- WO2017116356A1 WO2017116356A1 PCT/TR2016/050508 TR2016050508W WO2017116356A1 WO 2017116356 A1 WO2017116356 A1 WO 2017116356A1 TR 2016050508 W TR2016050508 W TR 2016050508W WO 2017116356 A1 WO2017116356 A1 WO 2017116356A1
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- WIPO (PCT)
- Prior art keywords
- clip
- platin
- copper
- dtq
- dpq
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- 239000010949 copper Substances 0.000 claims abstract description 112
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical class [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 101
- 229910052802 copper Inorganic materials 0.000 claims abstract description 54
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 43
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims abstract description 34
- 229960004316 cisplatin Drugs 0.000 claims abstract description 34
- 230000000694 effects Effects 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 238000001308 synthesis method Methods 0.000 claims abstract description 18
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- -1 copper platin complexes Chemical class 0.000 claims abstract description 9
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- 238000001228 spectrum Methods 0.000 claims abstract description 8
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- 125000000524 functional group Chemical group 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 84
- 239000000203 mixture Substances 0.000 claims description 70
- 239000003446 ligand Substances 0.000 claims description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 51
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 44
- 229910002651 NO3 Inorganic materials 0.000 claims description 36
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
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- 229910001868 water Inorganic materials 0.000 claims description 26
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 claims description 25
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 15
- ILLTYNYTHFEGHK-UHFFFAOYSA-N 2,3-bis(2-pyridinyl)quinoxaline Chemical compound N1=CC=CC=C1C1=NC2=CC=CC=C2N=C1C1=CC=CC=N1 ILLTYNYTHFEGHK-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 12
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- IYTQXXKVEMXZQT-UHFFFAOYSA-N 2-pyridin-2-ylquinoxaline Chemical compound N1=CC=CC=C1C1=CN=C(C=CC=C2)C2=N1 IYTQXXKVEMXZQT-UHFFFAOYSA-N 0.000 claims description 10
- QVJMLNLSWYFKPD-UHFFFAOYSA-J dichlorocopper platinum(2+) dichloride Chemical compound [Pt+2].[Cu](Cl)Cl.[Cl-].[Cl-] QVJMLNLSWYFKPD-UHFFFAOYSA-J 0.000 claims description 10
- ADGDUIDDAMQKAG-UHFFFAOYSA-N 2-thiophen-2-ylquinoxaline Chemical compound C1=CSC(C=2N=C3C=CC=CC3=NC=2)=C1 ADGDUIDDAMQKAG-UHFFFAOYSA-N 0.000 claims description 9
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 9
- WEAYBWLPGOFBED-UHFFFAOYSA-N 1,3-dichloropropan-2-amine Chemical compound ClCC(N)CCl WEAYBWLPGOFBED-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
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- 239000011591 potassium Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/08—Copper compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F19/00—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
- C07F19/005—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00 without metal-C linkages
Definitions
- the invention is related to copper and platin compounds and synthesis method of compounds which are active in cancer cells that show resistance particularly against cisplatin, having a wider effect spectrum in comparison to cisplatin, and a lower toxicity in comparison to cisplatin, having reduced side effects, which can be used as a potential antitumor drug, having anti cancer (cancer treating) and anti oxidant effects, comprising DNA targeted mono and binuclear platin and copper platin complexes and similar functional groups.
- the tissues of healthy species are renewed by means of cell division continuously all their lives until the death of cells.
- the balance between necrosis and cell division needs to be kept stable for life to continue.
- this balance is disrupted and cells reproduce and grow uncontrollably. It is not possible to generally treat tissue formation comprising damaged DNA. In many cases, these types of tissues increase the formation of tumor or cancer.
- the widespread treatment methods used in cancer are surgical treatment, radiation oncology ( radiotherapy) and chemotherapy. Less frequently hormone treatments, biological treatment methods and treatments directed to target are used alone or in combination with each other. Treatment methods and the drugs used vary according to the type of tumor and the stages of the tumor. Additionally the response received from the treatment can vary according to the metabolism of the patient.
- cancer is the 2 nd most common reason of death in Europe.
- the efficient treatment of the disease is therefore very important.
- cancer is a significantly heterogeneous and complex disease. While surgery and radiotherapy treats 40% of cancer, the remaining 60% of the patients still lose their lives due to metastasis. During this phase, due to the systematic nature of the disease, a systematic treatment such as chemotherapy is required.
- Chemotherapy does have a healing effect although it is also characterized with a high rate of metastatic propagation.
- chemotherapy does not have a long term healing effect on patients at their late stage of illness.
- the improvement of chemotherapy is significantly important in order to expand the treatable tumor spectrum and to increase the life qualities of patients undergoing treatment.
- the most frequently used chemotherapy drugs in clinical cases are molecules which target the DNA.
- One of the essential conditions for cells to carry out their functions and to be able to reproduce is for the DNA to be intact (not damaged) .
- the cell cycle control proteins are responsible to define DNA damage and either to stop cell division or to activate the pathways that may lead to the cells killing themselves according to the size of the damage.
- the DNA lesions that arise in the S phase of the cell cycle lead to stopping the replication fork, and may lead to the formation of double chain DNA fractures that may be defined as being toxic amongst the DNA damage types.
- cell necrosis shall occur.
- the pathways related to the detection of DNA damage and repair is weak in cancer cells.
- cancer cells having the characteristic to ignore the control points of cell cycles reach faster proliferation speed. This situation has caused the cancer cells to be more sensitive to DNA damage.
- cancer drugs which target DNA are presented as one of the most efficient and most effective treatment methods and said drugs are still in demand .
- Cisplatin molecule cis-diaminedichloroplatin (II), Cis-Pt (NH3)2Cl2)
- FDA American Food and Drug Administration
- Cisplatin which is used for treatment in approximately one of two cancer patients is known to be particularly efficient to treat ovarian and testicular cancer.
- cisplatin shows a successful chemotherapeutic effect, it also has significant side effects such as nausea, vomiting, kidney diseases, deformations arising from the nervous system.
- cisplatin In many cases it is possible for cisplatin to form an insufficient tumor response, to reduce the anti cancer effect of the tumor or to eliminate it.
- the resistance of tumor is a condition that is observed during the usage of some other cancer drugs and this condition may differ according to the tissue in which the tumor has developed.
- tumors show intensive resistance against the drug depending on dose and duration in several tissues during the usage of cisplatin in comparison to other known drugs, this limits the usage span of the drugs and the tumor types on which said drug can be used. Severe side effects and gained or intrinsic cisplatin resistance direct us to synthesize different compounds in order to be able to use them in cancer treatments.
- Polynuclear platin complexes are compound groups synthesized as it is deemed that they can interact with the DNA.
- Two compounds (BBR3464 and AMPZ) from this group have been able to overcome cisplatin resistance.
- BBR3464 which is a trinuclear platin complex, can carry out an interstrand interaction with the DNA.
- Clinical studies have been started on this complex as it was found to have very high cytotoxic characteristics but said clinical studies were stopped because the toxicity features of the complex was found to be very high.
- Another promising platin compound is AMPZ, because it overcomes cisplatin resistance and carries cytotoxic characteristics.
- This complex has been synthesized in order to be able to carry out insignificant degradation on the DNA structure and therefore to increase the treatment efficiency of the DNA-drug compound without said efficiency being noticed by repair enzymes. NMR studies have shown that the AMPZ complex performed a change between 10° - 15° on the DNA chain and the high antitumor activity of the complex has been associated with the fact that said activity is not noticed by NER- proteins .
- Another strategy that has been developed in order to reduce the clinical side effects of cisplatin is to form platin compounds with a second functional group without changing the activity characteristics of cisplatin.
- a cisplatin unit used in order to increase the anti cancer activity is combined with a carrier which shows selectivity features against cancer cells.
- a carrier which shows selectivity features against cancer cells.
- One of the best examples of such complexes is the compound wherein the diamineplatin structure is formed with N- ( 2-hydroxypropyl ) methacrylamide polymer. The activity of the complex that has been obtained is twice as higher than the activity of carboplatin.
- the initial compounds which have been determined to break the DNA by increasing the sugar unit contained inside the DNA chain, are neocarcinostatin, calicheamicin and esperamicine which are natural bleomycin products.
- Bleomycins have been initially isolated from Streptomyces Verticillus. These compounds are used in clinical treatment of lymphoma, head and chin cancer types and it is believed that the success of treatments carried out with bleomycin is due to the fact that it can break DNA.
- several metal complexes have been synthesized in order to mimic the effect of bleomycin. The most frequently tested and studied complexes are Fe ⁇ / ⁇ (edta) ] and [Cu ⁇ / ⁇ (phen) 2] complexes.
- the first synthetic compound which showed nuclease activity is the Cu ⁇ / ⁇ (phen) 2 ] (phen: phenanthroline ) complex . It creates a single chain breakage in the presence of a reducing agent and hydrogen peroxide or dioxygen. Interestingly it has been observed that the [Cu ⁇ / ⁇ (phen) ] complex has a much lower activity in comparison to the activity of Cu ⁇ / ⁇ (phen) 2. While the constant of the initial phenanthroline molecule to bind to a copper metal in [Cu ⁇ / ⁇ (phen) 2] complex has been calculated to be (Log Ki) 10, 3, the second phenanthroline molecule binding constant has been found to be (Log K2) 5,5.
- nuclease activity of Cu ( 2-Clip-Phen) compound obtained from Cu complexes as mentioned above was twice as higher than the activity of [Cu I/I ⁇ (phen) 2] activity and forty times more higher than the nuclease activity of Cu ( 3-Clip-Phen) complex.
- bimetallic supramolecules comprising Pt and Ru have been synthesized according to the Patent application numbered WO2008031017 and the DNA binding and photo-disruption features of the compounds that have been synthesized have been examined.
- the aim of the invention is to develop the synthesis methods of copper and platin compounds comprising similar functional groups with the DNA targeted mono and binuclear platin and copper platin complexes, particularly showing activity in cancer cells that have been displaying resistance against cisplatin, having a wider spectrum in comparison to cisplatin and a lower toxicity than cisplatin, with reduced side effects and which can be used as a potential antitumor drug and which shows anti cancer (cancer treating) and anti oxidant effects.
- Another aim of the invention is to carry out pharmacokinetic and preclinical studies on the compounds that may be used as active drugs and therefore to decrease our country' s dependency to other countries and to utilize our resources and apply promising novel treatment methods.
- Another aim of the invention is to develop the pharmacokinetic-pharmacodynamic and toxicological studies on suitable in vitro and in vivo models in order to increase the preclinical efficiency and pharmaco safeties of the compounds that have a potential to be used as drugs.
- Another aim of the invention is to increase the efficiency of the synthesized compounds, with DNA using different spectroscopic methods and electrochemical processes.
- Another aim of the invention is to determine the pharmacologic, therapeutic and toxic effects depending on the relationship between the time dependent dose, plasma and tissue concentration by examining the absorption, distribution and elimination of the synthesized compounds and therefore to improve the transition aspects through biological membranes.
- Another aim of the invention is to examine the cytotoxic effects of the antitumor efficiencies of synthesized complexes on different cell models and to improve the yield of critical drug amount around IC50 values.
- the invention is bis [ 2 , 3-di ( 2-pyridyl ) -quinoxaline copper ( I/II ) ] chloride, bis [ 2 , 3-di ( 2-thienyl ) -quinoxaline copper (I/II) ] chloride, bis [2, 3-di (2-pyridyl) -quinoxaline platin ( I I ) ] chloride or bis [ 2 , 3-di ( 2-pyridyl ) -quinoxaline platin(II) ]nitrate, bis[2,3-di (2-thienyl ) -quinoxaline platin ( I I ) ] chloride or bis [ 2 , 3-di ( 2-thienyl ) -quinoxaline platin(II) ] nitrate, 3-clip-2-pyridylquinoxaline, 3-clip-2- thienylquinoxaline and [3-clip- (2- pyridylquinoxaline
- the copper or platin complexes subject to the invention is bis [2, 3-di (2-pyridyl) -quinoxalinemetal (I/II) ] chloride/nitrate ( [M (dpq) 2] CI2, [M(dpq) 2 ]Cl or [M (dpq) 2] (NO3) 2) obtained by adding copper chloride or Pt (H2O) 4 (NO3) 2 to the 2 , 3-di ( 2-pyridyl ) - quinoxaline (dpq) ligand that has been obtained by means of the synthesis method of the known state of the art characterized with formula I
- M Pt(II), Cu (I) or (II)
- Formul all "M”, which is a component of Formula (II), can be platin (II) or copper (I/II) ions.
- the copper or platin complexes subject to the invention are characterized by being bis [ 2 , 3-di ( 2- pyridyl ) -quinoxalinecopper ( 1/ 11 )] chloride ( [Cu (dpq) 2] CI2 or [Cu (dpq) 2] CI) if "M” is copper (I/II)or by being bis [ 2 , 3-di ( 2- pyridyl ) -quinoxalineplatin (II) ] chloride/nitrate ( [Pt(dpq)2]Cl2 or [Pt (dpq) 2] (N0 3 ) 2) if "M” is platin (II) .
- Copper or platin complexes subject to the invention is characterized by formula IV wherein it is bis [ 2 , 3-di ( 2- thienyl ) -quinoxalinemetal (I/II) ] chloride/nitrate ( [M(dtq)2]Cl2,
- M which is a component of Formula (IV), can be platin (II) or copper (I/II) ions.
- the copper or platin complexes subject to the invention is characterized in that they can be bis [2,3- di (2-thienyl) -quinoxalinecopper (I/II) ] chloride ( [Cu (dtq) 2] CI2 or [Cu (dtq) 2] CI) in the case that "M” is copper (I/II), and can be bis [ 2 , 3-di ( 2-thienyl ) quinoxalineplatin (II)] chloride / nitrate ( [Pt (dtq) 2] Cl 2 or [Pt (dtq) 2] (N0 3 ) 2) in the case that "M” is platin (II) .
- the ligand that is required for synthesizing copper, platin and copper-platin complexes is 3-clip-2-pyridylquinoxaline obtained by binding the dpq groups characterized with formula I to each other using a 2-aminopropan bridge and these complexes are characterized with formula V.
- the ligand that is required for the synthesis of copper, platin and copper platin complexes subject to the invention is 3-clip-2-thienylquinoxaline obtained by binding the dtq units characterized by formula III, using a 2-aminopropan bridge with formula VI .
- the copper complex subject to the invention characterized by formula VII wherein it is [ 3-clip- ( 2-pyridylquinoxaline ) copper ( I/II )] chloride obtained by adding copper to the 3-clip- 2-pyridylquinoxaline ligand characterized by formula V.
- the copper complex subject to the invention is characterized by formula VIII wherein it is [ 3-clip-2- ( thienylquinoxaline ) copper ( I/II )] chloride obtained by adding copper to the 3-clip- 2-thienylquinoxaline ligand characterized by formula VI.
- the platin complex subject to the invention is characterized by formula IX wherein it is [ 3-clip- ( 2-pyridylquinoxaline ) platin ( I I )] chloride or [ 3-clip- ( 2-pyridylquinoxaline ) platin(II)] nitrate obtained by adding potassiumtetrachloroplatinate to the 3-clip-2- pyridylquinoxaline ligand characterized by formula V.
- the platin complex subject to the invention is characterized by formula X wherein it is [3-clip-(2- thienylquinoxaline ) platin ( I I )] chloride or [3-clip-(2- thienylquinoxaline ) platin ( I I )] nitrate obtained by adding potassiumtetrachloroplatinate to the 3-clip-2- thienylquinoxaline ligand characterized by formula VI.
- the platin complex subject to the invention is characterized by formula XI, wherein it is (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( I I ) obtained by adding
- the platin complex subject to the invention is characterized by formula XII wherein it is (amino) (3-clip-2- thienylquinoxaline ) dichloroplatin ( 11 ) ([Pt(NH3) (3-clip-dtq) CI2] ) obtained by adding Pt (H2O) 2 (CI) 2 and ammonium (NH3) to the3-clip-2-thienylquinoxaline ligand that is characterized with formula VI .
- the bimetallic copper and platin complex subject to the invention is characterized by formula XIII wherein it is ( amino ) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH 3 ) (3-clip-dpq) Cl 2 ] -CuCl 2 ) by the addition of copper chloride to the (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( 11 ) compound characterized by formula XI .
- the bimetallic copper and platin complex subject to the invention is characterized by formula XIV wherein it is ( amino ) ( 3-clip- 2-tiyoniquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH 3 ) ( 3-clip-dtq) Cl 2 ] -CuCl 2 by the addition of copper chloride to (amino) ( 3-clip- 2 - thienylquinoxaline ) dichloroplatin ( 1 1 ) ([Pt(NH3) ( 3-clip- dtq) CI2] ) compound characterized by formula XII.
- the percentage yield of the ligand obtained by means of dpq ligand synthesis has been calculated as 76,96%.
- the synthesis of the 3-clip-2-pyridylquinoxaline ligand is carried out in 4 steps using 2 , 3-di ( 2-pyridyl ) -quinoxaline (dpq) ligand.
- Step 4 Step :
- the synthesis of copper complexes is carried out using 2,3- di ( 2-pyridyl ) -quinoxaline (dpq) , 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq) , 3-clip-2-pyridylquinoxaline (3-Clip-dpq) and 3-clip-2- thienylquinoxaline (3-Clip-dtq) ligands.
- Platin complexes are synthesized using 2 , 3-di ( 2-pyridyl ) - quinoxaline (dpq), 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq), 3- clip-2-pyridylquinoxaline (3-clip-dpq) and 3-clip-2- thienylquinoxaline (3-clip-dtq) ligands.
- Method comprises the following process steps;
- Method comprises the following process steps
- Binuclear platin and copper complexes are synthesized by using the (amino) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin ( 11 ) and ( amino ) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II)
- the compounds obtained by the invention conveys pharmacological importance due to cytotoxic efficiencies of antitumor efficiencies on different cell models and due to the fact that the critical drug amount is obtained at IC50 values.
- the copper and platin compounds and the synthesis method of compounds comprising similar functional groups with DNA targeted mono an binuclear platin and copper platin complexes subject to the invention have a structure such that they show activity on cancer cells that are resistant against cisplatin, that have a wider efficiency spectrum in comparison to cisplatin and having a lower toxicity effect compared to cisplatin, which can be used as a potential antitumor drug, having anti cancer (cancer treating) and anti oxidant effects, having superior characteristics in comparison to cancer drugs that are conventionally used as they are cost effective in terms of the expenses spent for the treatment of a cancer disease, as they speed up the treatment process, and as the increase the life standards of patients.
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Abstract
The invention is related to copper and platin compounds and synthesis method of compounds which are active in cancer cells that show resistance particularly against cisplatin, having a wider effect spectrum in comparison to cisplatin, and a lower toxicity in comparison to cisplatin, having reduced side effects, which can be used as a potential antitumor drug, having anti cancer (cancer treating) and anti oxidant effects, comprising DNA targeted mono and binuclear platin and copper platin complexes and similar functional groups.
Description
DESCRIPTION
DNA TARGETED MONO AND HETERODINUCLEAR COMPLEXES
Technical Field
The invention is related to copper and platin compounds and synthesis method of compounds which are active in cancer cells that show resistance particularly against cisplatin, having a wider effect spectrum in comparison to cisplatin, and a lower toxicity in comparison to cisplatin, having reduced side effects, which can be used as a potential antitumor drug, having anti cancer (cancer treating) and anti oxidant effects, comprising DNA targeted mono and binuclear platin and copper platin complexes and similar functional groups.
Prior Art
The tissues of healthy species are renewed by means of cell division continuously all their lives until the death of cells. The balance between necrosis and cell division needs to be kept stable for life to continue. When the genetic materials are damaged, this balance is disrupted and cells reproduce and grow uncontrollably. It is not possible to generally treat tissue formation comprising damaged DNA. In many cases, these types of tissues increase the formation of tumor or cancer.
The widespread treatment methods used in cancer are surgical treatment, radiation oncology ( radiotherapy) and chemotherapy. Less frequently hormone treatments, biological treatment methods and treatments directed to target are used alone or in combination with each other. Treatment methods and the drugs used vary according to the type of tumor and the stages of the
tumor. Additionally the response received from the treatment can vary according to the metabolism of the patient.
Nowadays, cancer is the 2nd most common reason of death in Europe. The efficient treatment of the disease is therefore very important. However cancer is a significantly heterogeneous and complex disease. While surgery and radiotherapy treats 40% of cancer, the remaining 60% of the patients still lose their lives due to metastasis. During this phase, due to the systematic nature of the disease, a systematic treatment such as chemotherapy is required. Chemotherapy does have a healing effect although it is also characterized with a high rate of metastatic propagation. However chemotherapy does not have a long term healing effect on patients at their late stage of illness. The improvement of chemotherapy is significantly important in order to expand the treatable tumor spectrum and to increase the life qualities of patients undergoing treatment.
The most frequently used chemotherapy drugs in clinical cases are molecules which target the DNA. One of the essential conditions for cells to carry out their functions and to be able to reproduce is for the DNA to be intact (not damaged) . In normal cells, the cell cycle control proteins, are responsible to define DNA damage and either to stop cell division or to activate the pathways that may lead to the cells killing themselves according to the size of the damage. Especially the DNA lesions that arise in the S phase of the cell cycle lead to stopping the replication fork, and may lead to the formation of double chain DNA fractures that may be defined as being toxic amongst the DNA damage types. In the case that the damaged DNA cannot be repaired, cell necrosis shall occur. Generally the pathways related to the detection
of DNA damage and repair is weak in cancer cells. Additionally, cancer cells having the characteristic to ignore the control points of cell cycles, reach faster proliferation speed. This situation has caused the cancer cells to be more sensitive to DNA damage. Nowadays, cancer drugs which target DNA, are presented as one of the most efficient and most effective treatment methods and said drugs are still in demand .
The attention towards antitumor drugs comprising platin, depends on the incidental finding that platin complexes stop cell division. Cisplatin molecule ( cis-diaminedichloroplatin (II), Cis-Pt (NH3)2Cl2) , has started to be commonly used in a short period of time and has been entered into the American Food and Drug Administration (FDA) certified drug list due to its antitumor characteristics. Nowadays, Cisplatin which is used for treatment in approximately one of two cancer patients is known to be particularly efficient to treat ovarian and testicular cancer. Although cisplatin shows a successful chemotherapeutic effect, it also has significant side effects such as nausea, vomiting, kidney diseases, deformations arising from the nervous system. In many cases it is possible for cisplatin to form an insufficient tumor response, to reduce the anti cancer effect of the tumor or to eliminate it. The resistance of tumor is a condition that is observed during the usage of some other cancer drugs and this condition may differ according to the tissue in which the tumor has developed. However as tumors show intensive resistance against the drug depending on dose and duration in several tissues during the usage of cisplatin in comparison to other known drugs, this limits the usage span of the drugs and the tumor types on which said drug can be used. Severe side effects and gained or intrinsic cisplatin resistance direct us to
synthesize different compounds in order to be able to use them in cancer treatments.
Polynuclear platin complexes are compound groups synthesized as it is deemed that they can interact with the DNA. Two compounds (BBR3464 and AMPZ) from this group have been able to overcome cisplatin resistance. BBR3464 which is a trinuclear platin complex, can carry out an interstrand interaction with the DNA. Clinical studies have been started on this complex as it was found to have very high cytotoxic characteristics but said clinical studies were stopped because the toxicity features of the complex was found to be very high. Another promising platin compound is AMPZ, because it overcomes cisplatin resistance and carries cytotoxic characteristics. This complex, has been synthesized in order to be able to carry out insignificant degradation on the DNA structure and therefore to increase the treatment efficiency of the DNA-drug compound without said efficiency being noticed by repair enzymes. NMR studies have shown that the AMPZ complex performed a change between 10° - 15° on the DNA chain and the high antitumor activity of the complex has been associated with the fact that said activity is not noticed by NER- proteins .
Another strategy that has been developed in order to reduce the clinical side effects of cisplatin, is to form platin compounds with a second functional group without changing the activity characteristics of cisplatin. In this drug design, a cisplatin unit used in order to increase the anti cancer activity is combined with a carrier which shows selectivity features against cancer cells. One of the best examples of such complexes is the compound wherein the diamineplatin structure is formed with N- ( 2-hydroxypropyl ) methacrylamide
polymer. The activity of the complex that has been obtained is twice as higher than the activity of carboplatin.
The initial compounds which have been determined to break the DNA by increasing the sugar unit contained inside the DNA chain, are neocarcinostatin, calicheamicin and esperamicine which are natural bleomycin products. Bleomycins have been initially isolated from Streptomyces Verticillus. These compounds are used in clinical treatment of lymphoma, head and chin cancer types and it is believed that the success of treatments carried out with bleomycin is due to the fact that it can break DNA. Following the finding of bleomycin, several metal complexes have been synthesized in order to mimic the effect of bleomycin. The most frequently tested and studied complexes are Fe∑∑/∑∑∑ (edta) ] and [Cu∑/∑∑ (phen) 2] complexes. The first synthetic compound which showed nuclease activity is the Cu∑/∑∑ (phen) 2 ] (phen: phenanthroline ) complex . It creates a single chain breakage in the presence of a reducing agent and hydrogen peroxide or dioxygen. Interestingly it has been observed that the [Cu∑/∑∑ (phen) ] complex has a much lower activity in comparison to the activity of Cu∑/∑∑ (phen) 2. While the constant of the initial phenanthroline molecule to bind to a copper metal in [Cu∑/∑∑ (phen) 2] complex has been calculated to be (Log Ki) 10, 3, the second phenanthroline molecule binding constant has been found to be (Log K2) 5,5. For this reason the amount of phenanthroline used in order to synthesize [Cu∑/∑∑ (phen) 2] complexes is much higher than stoichiometric values. It has been decided to use a bridge to couple the phenanthroline structures in order to keep these two phenanthroline units around a Cu(I/II) ion. The first trial carried out with a long bridge comprising sulphur atoms has not been able to increase the clinical effect of the bis- phenanthroline copper complex. Two phenanthroline structures
have been combined with a serinol group in the studies and more efficient Cu complexes have been obtained. It has been determined that the nuclease activity of Cu ( 2-Clip-Phen) compound obtained from Cu complexes as mentioned above, was twice as higher than the activity of [CuI/I∑ (phen) 2] activity and forty times more higher than the nuclease activity of Cu ( 3-Clip-Phen) complex.
Cu-2-Clip-Phen Cu-3-Clip-Phen
Following the synthesis of the active Cu ( 3-Clip-Phen) complex, different geometrical platin complexes comprising this unit and only a Clip-Phen unit have been synthesized and the nuclease activity of complexes have been studied. It has been observed that cis- [Pt (Cu- 3-Clip-Phen) 2CI2] from such structures having Cis-, trans- and asymmetrical geometry was not stable however that cis- [Pt (Cu- 3-Clip-Phen) 2CI2] carried more antiproliferative characteristics in comparison to all other platin complexes.
Following this Pt complexes comprising similar Cu-3Clip-Phen have been synthesized between the platin group and serine group using (-CH2-) chain having different lengths.
The nuclease activity of 3-Clip-Phen-lO-Pt, 3-Cu-Clip-Phen-10- Pt, 3-Clip-Phen-6-Pt and 3-Cu-3-Clip-Phen-l 6-Pt complexes have been studied on different tumor cells and it has been decided that 3-Clip-Phen-10-Pt and 3-Cu-Clip-Phen-lO-Pt complexes were more efficient than platin complexes comprising 6 (-CH2-) chain .
In the known state of the art, bimetallic supramolecules comprising Pt and Ru have been synthesized according to the Patent application numbered WO2008031017 and the DNA binding and photo-disruption features of the compounds that have been synthesized have been examined.
In another patent application numbered US2013237503 compounds that can be used in treatment of cancer which showed resistance against cisplatin and carboplatin which are phosphate complexes (phosphoplatin) comprising platin (II) and (IV) within their pharmaceutical composition, have been examined .
DNA targeted, Mono and binuclear complexes having anti cancer and anti oxidant effect, which can be used as a potential antitumor drug, having lower toxicity effects in comparison to cisplatin and which has a wider effect spectrum in comparison to cisplatin have been obtained following the synthesis method subject to the invention, by taking into consideration the above mentioned descriptions and studies.
Problems aimed to be resolved by the Invention
The aim of the invention is to develop the synthesis methods of copper and platin compounds comprising similar functional groups with the DNA targeted mono and binuclear platin and copper platin complexes, particularly showing activity in cancer cells that have been displaying resistance against cisplatin, having a wider spectrum in comparison to cisplatin and a lower toxicity than cisplatin, with reduced side effects and which can be used as a potential antitumor drug and which shows anti cancer (cancer treating) and anti oxidant effects.
Another aim of the invention is to carry out pharmacokinetic and preclinical studies on the compounds that may be used as active drugs and therefore to decrease our country' s dependency to other countries and to utilize our resources and apply promising novel treatment methods.
Another aim of the invention is to develop the pharmacokinetic-pharmacodynamic and toxicological studies on suitable in vitro and in vivo models in order to increase the preclinical efficiency and pharmaco safeties of the compounds that have a potential to be used as drugs.
Another aim of the invention is to increase the efficiency of the synthesized compounds, with DNA using different spectroscopic methods and electrochemical processes.
Another aim of the invention is to determine the pharmacologic, therapeutic and toxic effects depending on the relationship between the time dependent dose, plasma and tissue concentration by examining the absorption, distribution
and elimination of the synthesized compounds and therefore to improve the transition aspects through biological membranes.
Another aim of the invention is to examine the cytotoxic effects of the antitumor efficiencies of synthesized complexes on different cell models and to improve the yield of critical drug amount around IC50 values.
Description of the Invention
The invention is bis [ 2 , 3-di ( 2-pyridyl ) -quinoxaline copper ( I/II ) ] chloride, bis [ 2 , 3-di ( 2-thienyl ) -quinoxaline copper (I/II) ] chloride, bis [2, 3-di (2-pyridyl) -quinoxaline platin ( I I ) ] chloride or bis [ 2 , 3-di ( 2-pyridyl ) -quinoxaline platin(II) ]nitrate, bis[2,3-di (2-thienyl ) -quinoxaline platin ( I I ) ] chloride or bis [ 2 , 3-di ( 2-thienyl ) -quinoxaline platin(II) ] nitrate, 3-clip-2-pyridylquinoxaline, 3-clip-2- thienylquinoxaline and [3-clip- (2- pyridylquinoxaline ) copper (I/II) ] chloride, [3-clip-2- ( thienylquinoxaline ) copper (I/II) ] chloride, [3-clip- (2- pyridylquinoxaline ) platin ( I I ) ] chloride comprising these ligand groups or [ 3-clip- ( 2-pyridylquinoxaline ) platin ( I I ) ] nitrate, [ 3-clip- ( 2-thienylquinoxaline ) platin ( I I ) ] chloride or [3-clip- (2-thienylquinoxaline) platin ( II ) ] nitrate, (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( I I ) , (amino) (3-clip-2- thienylquinoxaline ) dichloroplatin ( I I ) , (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( I I ) -copper ( I I ) chloride and ( amino ) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II)- copper ( I I ) chloride compounds comprising functional groups similar with DNA targeted mono and binuclear platin and copper platin complexes, having anti cancer (Cancer treating) and antioxidant effects, which is shown by formula II, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII and XIV, which is especially
active on cancer cells that are resistant against cisplatin, having a more extensive effect spectrum in comparison to cisplatin and a lower toxicity than cisplatin, with reduced side effects and which can be used as a potential antitumor drug .
The copper or platin complexes subject to the invention is bis [2, 3-di (2-pyridyl) -quinoxalinemetal (I/II) ] chloride/nitrate ( [M (dpq) 2] CI2, [M(dpq)2]Cl or [M (dpq) 2] (NO3) 2) obtained by adding copper chloride or Pt (H2O) 4 (NO3) 2 to the 2 , 3-di ( 2-pyridyl ) - quinoxaline (dpq) ligand that has been obtained by means of the synthesis method of the known state of the art characterized with formula I
Formul I
Wherein said formula is characterized by formula II
M= Pt(II), Cu (I) or (II)
Formul all
"M", which is a component of Formula (II), can be platin (II) or copper (I/II) ions. The copper or platin complexes subject to the invention are characterized by being bis [ 2 , 3-di ( 2- pyridyl ) -quinoxalinecopper ( 1/ 11 )] chloride ( [Cu (dpq) 2] CI2 or [Cu (dpq) 2] CI) if "M" is copper (I/II)or by being bis [ 2 , 3-di ( 2- pyridyl ) -quinoxalineplatin (II) ] chloride/nitrate ( [Pt(dpq)2]Cl2 or [Pt (dpq) 2] (N03) 2) if "M" is platin (II) .
Copper or platin complexes subject to the invention is characterized by formula IV wherein it is bis [ 2 , 3-di ( 2- thienyl ) -quinoxalinemetal (I/II) ] chloride/nitrate ( [M(dtq)2]Cl2,
[M(dtq)2]Cl or [M(dtq)2] (NO3) 2) obtained by adding copper chloride or Pt (H2O) 4 (NO3) 2 to the 2 , 3-di ( 2-thienyl ) -quinoxaline
(dtq) ligand characterized by formula III which is obtained by means of the synthesis method of the known state of the art,
Formula III
M= Pt(II), Cu (I) °r (II)
Formula IV
"M" which is a component of Formula (IV), can be platin (II) or copper (I/II) ions. The copper or platin complexes subject to the invention is characterized in that they can be bis [2,3- di (2-thienyl) -quinoxalinecopper (I/II) ] chloride ( [Cu (dtq) 2] CI2 or [Cu (dtq) 2] CI) in the case that "M" is copper (I/II), and can be bis [ 2 , 3-di ( 2-thienyl ) quinoxalineplatin (II)] chloride / nitrate ( [Pt (dtq) 2] Cl2 or [Pt (dtq) 2] (N03) 2) in the case that "M" is platin (II) .
The ligand that is required for synthesizing copper, platin and copper-platin complexes is 3-clip-2-pyridylquinoxaline obtained by binding the dpq groups characterized with formula I to each other using a 2-aminopropan bridge and these complexes are characterized with formula V.
Formula V
The ligand that is required for the synthesis of copper, platin and copper platin complexes subject to the invention, is 3-clip-2-thienylquinoxaline obtained by binding the dtq units characterized by formula III, using a 2-aminopropan bridge with formula VI .
Formula VI
The copper complex subject to the invention characterized by formula VII wherein it is [ 3-clip- ( 2-pyridylquinoxaline ) copper ( I/II )] chloride obtained by adding copper to the 3-clip- 2-pyridylquinoxaline ligand characterized by formula V.
Formula VI I
The copper complex subject to the invention is characterized by formula VIII wherein it is [ 3-clip-2- ( thienylquinoxaline )
copper ( I/II )] chloride obtained by adding copper to the 3-clip- 2-thienylquinoxaline ligand characterized by formula VI.
The platin complex subject to the invention is characterized by formula IX wherein it is [ 3-clip- ( 2-pyridylquinoxaline ) platin ( I I )] chloride or [ 3-clip- ( 2-pyridylquinoxaline ) platin(II)] nitrate obtained by adding potassiumtetrachloroplatinate to the 3-clip-2- pyridylquinoxaline ligand characterized by formula V.
Formula X
The platin complex subject to the invention is characterized by formula XI, wherein it is (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( I I ) obtained by adding
Pt (H20) 2 (CI) 2 and ammonium (NH3) to the 3-clip-2- pyridylquinoxaline ligand characterized with formula 5.
Formula XI
The platin complex subject to the invention is characterized by formula XII wherein it is (amino) (3-clip-2- thienylquinoxaline ) dichloroplatin ( 11 ) ([Pt(NH3) (3-clip-dtq) CI2] ) obtained by adding Pt (H2O) 2 (CI) 2 and ammonium (NH3) to the3-clip-2-thienylquinoxaline ligand that is characterized with formula VI .
Formula XII
The bimetallic copper and platin complex subject to the invention is characterized by formula XIII wherein it is ( amino ) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH3) (3-clip-dpq) Cl2] -CuCl2) by the addition of copper chloride to the (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( 11 ) compound characterized by formula XI .
Formula XI 1 1
The bimetallic copper and platin complex subject to the invention is characterized by formula XIV wherein it is ( amino ) ( 3-clip- 2-tiyoniquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH3) ( 3-clip-dtq) Cl2] -CuCl2 by the addition of copper chloride to (amino) ( 3-clip- 2 - thienylquinoxaline ) dichloroplatin ( 1 1 ) ([Pt(NH3) ( 3-clip- dtq) CI2] ) compound characterized by formula XII.
Formula XIV
The copper, platin and binuclear copper platin compounds subject to the invention is characterized by being formed of 4 steps comprising;
A. Ligand synthesis, ( 2 , 3-di ( 2-pyridyl ) -quinoxaline (dpq) , 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq) , 3-clip-2- pyridylquinoxaline (3-clip-dpq) and 3-clip-2- thienylquinoxaline (3-clip-dtq) ) ,
B. Synthesis of copper complexes, (bis [ 2 , 3-di ( 2-pyridyl ) - quinoxalinecopper ( I/II )] chloride (Cu(dpq)2Cl2 or [Cu (dpq) 2] CI) , bis [2, 3-di (2-thienyl) -quinoxalinecopper (I/II) ] chloride
(Cu(dtq)2Cl2 or [Cu (dtq) 2] CI) , [ 3-clip- ( 2-pyridylquinoxaline ) copper ( I/II )] chloride ( [Cu (3-clip-dpq) CI2] or [Cu (3-clip- dpq) CI]) and [ 3-clip-2- ( thienylquinoxaline ) copper ( I/II ) ] chloride ( [Cu (3-clip-dtq) Cl2] or [Cu ( 3-clip-dtq) CI ])) ,
C. Synthesis of platin complexes, (bis [ 2 , 3-di ( 2-pyridyl ) - quinoxalineplatin ( I I )] chloride/nitrate (Pt(dpq)2Cl2 or [Pt(dpq)2] ( 03)2), bis [ 2 , 3-di ( 2-thienyl ) -quinoxalineplatin (II) ] chloride/nitrate (Pt(dtq)2Cl2 or [Pt (dtq) 2] (N03) 2) , [3- clip- ( 2-pyridylquinoxaline ) platin ( I I )] chloride or [3-clip- (2- pyridylquinoxaline ) platin (II)] nitrate ( [Pt ( 3-clip-dpq) CI2] or [Pt (3-clip-dpq) (N03)2]), [ 3-clip- ( 2-thienylquinoxaline ) platin (II)] chloride or [ 3-clip- ( 2-thienylquinoxaline ) platin (II) ] nitrate ( [Pt (3-clip-dtq) Cl2] or [ Pt ( 3-clip-dtq) (N03)2.), (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( 11 ) ([Pt(NH3) (3-clip- dpq) CI2] ) and (amino) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II) ([Pt(NH3) ( 3-clip-dtq) Cl2 ])) ,
D. Synthesis of binuclear copper and platin complexes ( ( amino ) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH3) (3-clip-dpq) Cl2] -CuCl2) and
( amino ) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH3) (3-clip-dtq) Cl2] -CuCl2) ) .
A. Ligand Synthesis;
In order to synthesize 3-clip-2-pyridylquinoxaline and 3-clip- 2-thienylquinoxaline ligands, first of all 2 , 3-di ( 2-pyridyl ) - quinoxaline (dpq) and 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq) ligands need to be synthesized with the known methods in literature, by means of a synthesis method of the known state of the art.
1. Synthesis of the 2 , 3-di (2-pyridyl) -quinoxaline (dpq) Ligand comprises the following steps (Formula I);
• Dissolving of 2, 2' -pyridyl (1.96 g) inside ethyl alcohol ,
• Addition of o-phenylene diamine (lg) at the same stochiometric ratio of (1/1) as the mol amount within the 2, 2' -pyridyl solution which is being mixed,
• Refluxing the obtained solution for a period of 1,5 hours ,
• Cooling the mixture to room temperature,
• Evaporating the mixture under vacuum until its volume is reduced by half,
• Recrystallizing the obtained product inside toluene.
The percentage yield of the ligand obtained by means of dpq ligand synthesis has been calculated as 76,96%.
2. Synthesis of 2 , 3-di (2-thienyl) -quinoxaline (dtq) Ligand comprises the following steps (Formula III) ;
• Dissolving of 2 , 2 ' -thienyl (0,1 g) inside ethyl alcohol ,
• Addition of o-phenylene diamine (4,86 g) at the same stochiometric ratio of (1/1) as the mol amount within the 2, 2' -thienyl solution which is being mixed,
• Refluxing the obtained solution for a period of 1,5 hours ,
• Cooling the mixture to room temperature,
• Evaporating the mixture under vacuum until its volume is reduced by half,
• Recrystallizing the obtained product inside toluene.
e percentage yield of the ligand obtained by means of dtq gand synthesis has been calculated as 80,77%.
3. Synthesis of 3-clip-2-pyridylquinoxaline (3-clip-dpq) Ligand (Formula V) ;
The synthesis of the 3-clip-2-pyridylquinoxaline ligand is carried out in 4 steps using 2 , 3-di ( 2-pyridyl ) -quinoxaline (dpq) ligand.
1. Step:
Comprises ;
• Dissolving 4-bromobenzene-l , 2-diamine and l,2-di(2- dipyridyl ) ethane-1 , 2-dione at an equivalent amount inside ethanol,
• Refluxing the mixture for a period of 1-3 hours,
• Cooling the mixture to room temperature,
• Evaporating the mixture until its volume is reduced by half,
• Recrystallizing the obtained product inside toluene.
1. Step
p:
• Comprises the process step of refluxing the equivalent 6-Bromo-2 , 3-di ( 2-pyridyl ) quinoxaline and magnesium (Mg) inside dry ether for 1-3 hours
2. Step p:
• Cooling the equivalent thionyl chloride (SOCI2) up to 5-10°C inside a three necked flask,
• Adding pyridine and ethanol onto thionyl chloride,
• Cooling the mixture up to 0-5°C,
• Adding 2-aminopropane-l , 3diol to the mixture dropwise, for 1-3 hours,
• Leaving the mixture to reflux for 8-12 hours,
• Carrying out extraction of the mixture inside pentane,
• And extracting the organic phase with sodium salt.
3. Step
4 . Step :
Drying the equivalent 1,3 dichloropropan-2-amin under vacuum, in the presence of phosphor pentoxide (P2O5) for 1-5 hours,
Dissolving dry 1,3 dichloropropan-2-amin in an anaerobic medium inside 50-100 mL dimethylformamide (DMF) ,
Adding 5-7 equivalent sodium hydride (NaH) and 1-3 equivalent ditertbutylmethoxyphenyl (DTBM) to the solution that has been obtained,
Cooling the mixture to 0-5°C, and mixing it for 10-30 minutes at this temperature,
Adding equivalent 2, 3-di (2-pyridyl) quinoxaline magnesium bromide inside 25-50mL DMF,
Mixing the mixture for 10-30 minutes in an ice bath and then further mixing it for 20-50 minutes at room temperature,
Refluxing the mixture for 25-50 hours at 30-60°C by adding the mixture into an oil bath,
Extracting the mixture with dichloromethane (CH2CI2) and removing it from the solvent.
4. Step
4. Synthesis of 3-clip-2-tiyoniquinoxaline (3-clip-dtq) ligand (Formula VI) ;
The synthesis of the 3-clip-2-thienylquinoxaline ligand using 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq) ligand has been carried out in 4 steps.
1. Step:
• Dissolving equivalent amounts of 4-bromobenzene-l , 2- diamine and 1, 2-di (2-dithienyl) ethane-1, 2-dione by mixing inside ethanol,
· Refluxing the mixture for a period of 1-3 hours,
• Cooling the mixture to room temperature,
• Evaporating the mixture until its volume is reduced by half,
• Recrystallizing the obtained product inside toluene.
1. Step
2. Step:
• Comprises the step of refluxing equivalent 6-Bromo-
2 , 3-di ( 2-thienyl ) quinoxaline and magnesium (Mg) for 1-3 hours inside dry ether.
2. Step
Cooling equivalent thionyl chloride (SOCI2) up to 5- 10°C inside a three necked flask,
Adding pyridine and ethanol on top of thionyl chloride,
Cooling the mixture to 0-5°C,
Adding equivalent 2-aminoperopan-l , 3diol to the mixture, dropwise for 1-3 hours,
Refluxing the mixture for 8-12 hours,
Extracting the mixture inside pentane,
Extracting the organic phase with sodium salt.
3. Step
Drying equivalent 1 , 3-dichloropropan-2-amin under vacuum for 1-5 hours in the presence of phosphor pentoxide (P2O5) ,
Dissolving dry 1 , 3-dichloropropan-2-amin inside 50- 100 mL dimethylformamide (DMF) in an anaerob medium, Adding 5-7 equivalent sodium hidrate (NaH) and 1-3 equivalent ditertbutylmethoxy phenyl (DTBM) to the obtained solution,
Cooling the mixture to 0-5°C and mixing it for 10-30 minutes at this temperature,
Addition of dissolved equivalent 2,3-di(2- thienyl ) quinoxaline magnesium bromide inside 25-50 mL DMF,
Mixing the mixture for 10-30 minutes in an ice bath and then further mixing it for 20-50 minutes at room temperature,
Refluxing the mixture for 25-50 hours at 30-60°C by adding the mixture into an oil bath,
Removing the solution by extracting the mixture with dichloromethane (CH2CI2) .
4. Step
B. Synthesis of Copper Complexes;
The synthesis of copper complexes is carried out using 2,3- di ( 2-pyridyl ) -quinoxaline (dpq) , 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq) , 3-clip-2-pyridylquinoxaline (3-Clip-dpq) and 3-clip-2- thienylquinoxaline (3-Clip-dtq) ligands.
Synthesis of Bis [2 , 3-di (2-pyridyl) -quinoxaline copper (I/II) ] chloride ( [Cu (dpq) 2] Cl2 or [Cu (dpq) 2] CI) and Bis [2 , 3-di (2-thienyl) -quinoxaline copper (I/II) ] chloride ( [Cu (dtq) 2] CI2 or [Cu (dtq) 2] CI) comprises the following steps, (Formula II and IV);
• Completely dissolving dpq or dtq ligands inside DMF,
• Adding copper chloride (CUCI2) solution dropwise to the prepared inside an amount of water equivalent to the solution,
• Refluxing the solution for 1-5 hours,
• Separating the product via filtering,
• Drying the obtained product.
Synthesis of (3-clip-2-pyridylquinoxaline) copper (I/II) chloride ( [Cu (3-clip-dpq) CI2] or [Cu (3-clip-dpq) CI ] ) and (3-clip-2-thienylquinoxaline) copper (I/II) chloride ( [Cu (3- clip-dtq) CI2] or [Cu (3-clip-dtq) CI ]) comprises the
following steps (Formula VII and VIII) ;
• Preparing 3-clip-2-pyridylquinoxaline or 3-clip-2- thienylquinoxaline ligands inside DMF,
• Adding copper chloride (CUCI2) solution prepared inside an amount of water equivalent to the solution dropwise,
• Refluxing the solution for 1-5 hours,
• Separating the product formed by filtering,
• Drying the product that has been obtained.
C. Synthesis of platin complexes;
Platin complexes are synthesized using 2 , 3-di ( 2-pyridyl ) - quinoxaline (dpq), 2 , 3-di ( 2-thienyl ) -quinoxaline (dtq), 3- clip-2-pyridylquinoxaline (3-clip-dpq) and 3-clip-2- thienylquinoxaline (3-clip-dtq) ligands.
Synthesis of Bis [2 , 3-di (2-pyridyl) -quinoxalineplatin (II) ] chloride/nitrate ( [Pt (dpq) 2] CI2 or [Pt (dpq) 2] (NO3) 2) and Bis [2 , 3-di (2-thienyl) - quinoxalineplatin (II) ] chloride/ nitrate ( [Pt (dtq) 2] CI2 or [Pt (dtq) 2] (NO3) 2) comprises the following steps (Formula II and IV) ;
• Mixing the silver nitrate (AgN03) aqueous solutions having an equivalent amount with Potassium tetrachloroplatinate ( I I ) (K2PtCl4) for 1-5 hours,
• Dissolving the obtained Pt (H2O) 4 (NO3) 2 complex inside 2-10ml water,
• Adding a solution of an equivalent amount of 2,3- di ( 2-pyridyl ) -quinoxaline or 2 , 3-di ( 2-thienyl ) - quinoxaline ligand into the obtained solution prepared inside DMF,
• Refluxing the mixture at 25-50°C for 3-7 hours,
• Separating the obtained product by filtration and drying .
Synthesis of (3-clip-2-pyridylquinoxaline) platin (II) chloride/nitrate ( [Pt (3-clip-dpq) CI2] or [Pt(3-clip- dpq) (N03)2]) and (3-clip-2-thienylquinoxaline) platin
(II) chloride/nitrate ( [Pt (3-clip-dtq) Cl2] or [Pt(3-clip- dtq) ( θ3>2]) comprises the following steps (Formula IX and X) ;
• Mixing silver nitrate (AgN03) aqueous solution for 1- 5 hours in an equivalent amount with potassium tetrachloroplatinate (II) (K2PtCl4) ,
• Dissolving the obtained Pt (H2O) 4NO3) 2 compound inside 2-10 mL water,
• Adding a solution of an equivalent amount of 3-clip- 2-pyridylquinoxaline or 3-clip-2-thienylquinoxaline ligand into the obtained solution prepared inside DMF,
• Refluxing the mixture at 25-50°C for 3-7 hours,
• Separating the obtained product by filtration and drying .
3. Synthesis of (amino) (3-clip-2-pyridylquinoxaline)
dichloroplatin (II) ( [Pt (NH3) (3-clip-dpq) Cl2] ) , and
(amino) (3-clip-2-thienylquinoxaline) dichloroplatin (II) ( [Pt (NH3) (3-clip-dtq) CI2] ) comprises the steps of (Formula XI and XII) ;
(Amino ) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II)
( [Pt (NH3) (3-clip-dpq) Cl2] ) , and (amino) (3-clip-2- thienylquinoxaline ) dichloroplatin ( 11 ) ([Pt(NH3) (3-clip- dtq) CI2] ) compounds can be synthesized with 2 methods.
1. Method comprises the following process steps;
• Dissolving Cis- [Pt (NH3) 2CI2] (cis-platin) inside 50-150 mL DMF,
• Adding solid tetraethylammonium (C2H5)4 C1 chloride which is equivalent in amount to the obtained solution,
• Mixing the mixture at 80-120°C for 4-8 hours with the passage of argon gas and cooling said mixture inside ice,
• Adding the mixture of 100-250 mL (C2H5) 20/hexane (3:1 v/v) into the obtained mixture,
• Separating the obtained oily tetraethylammonium aminotrichloroplatinate (II) ( [ (C2H5) 4N] [Pt (NH3) Cl3] ) solution from the solution and mixing it with 5-20 mL methanol,
• Preparing a solution of an equivalent amount of 3- clip- ( 2-pyridyl ) quinoxaline or 3-Clip- (2-thienyl ) quinoxaline inside 2-10 mL DMF,
► Adding the prepared 3-clip- (2-pyridyl ) / (2- thienyl ) quinoxaline solution prepared inside methanol, dropwise to the [ (C2H5) 4N] [Pt (NH3) Cl3] solution,
► Mixing the mixture at room temperature for 1-2 hours,
► Separating the obtained solid product by filtration and drying.
Method comprises the following process steps;
► Mixing silver nitrate (AgN03) aqueous solutions in an equal amount with potassium tetrachloroplatinate (II) (K2PtCl4)for 1-5 hours,
► Dissolving the obtained Pt(H20)2Cl2 compound inside 2- 10 mL water,
► Adding an equivalent amount of ammonium solution into the obtained solution and mixing the solution for 30-90 minutes,
► Adding the acidic solution of 3-clip-2- pyridylquinoxaline or 3-clip-2-thienylquinoxaline ligand prepared inside DMF into the mixture,
► Refluxing the obtained mixture for 3-7 hours at 25- 50°C,
► Separating the obtained solid product by filtration and drying.
D. Synthesis of Binuclear Copper and Platin Complexes;
Binuclear platin and copper complexes are synthesized by using the (amino) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin ( 11 ) and ( amino ) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II)
complexes obtained following the synthesis of platin complexes as starting agents.
The synthesis of (amino) (3-clip-2- pyridylquinoxaline) dichloroplatin (II) -copper (II) chloride
( [Pt(NH3) (3-clip-dpq)Cl2] -CUCI2) , and (amino) (3-clip-2- thienylquinoxaline) dichloroplatin (II) -copper (II) chloride
( [Pt (NH3) (3-clip-dtq) CI2] -CUCI2) comprises the following steps (Formula XIII and XIV) ;
• Dissolving (amino) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin ( I I ) or (amino) (3-clip-2- thienylquinoxaline ) dichloroplatin ( I I ) complexes inside DMF,
· Adding an equivalent amount of CUCI2 inside an amount of water equivalent to the solution,
• Separating the obtained product by filtration and drying.
The compounds obtained by the invention, conveys pharmacological importance due to cytotoxic efficiencies of antitumor efficiencies on different cell models and due to the fact that the critical drug amount is obtained at IC50 values.
The application of the invention to the Industry: The copper and platin compounds and the synthesis method of compounds comprising similar functional groups with DNA targeted mono an binuclear platin and copper platin complexes subject to the invention have a structure such that they show activity on cancer cells that are resistant against cisplatin, that have a wider efficiency spectrum in comparison to cisplatin and having a lower toxicity effect compared to cisplatin, which can be used as a potential antitumor drug, having anti cancer (cancer treating) and anti oxidant effects, having superior characteristics in comparison to cancer drugs that are conventionally used as they are cost effective in terms of the expenses spent for the treatment of a cancer
disease, as they speed up the treatment process, and as the increase the life standards of patients.
Claims
1. The invention is related to;
Copper complexes, shown with formula II; wherein it is bis [2, 3-di (2-pyridyl) -quinoxalinecopper (I/II) ] chloride obtained by adding copper chloride into the 2, 3-di (2- pyridyl ) -quinoxaline (dpq) ligand when M is Copper (I/II) ,
Platin complexes, shown with formula II; wherein it is bis [ 2 , 3-di (2-pyridyl ) -quinoxalineplatin (II)] chloride or bis [ 2 , 3-di (2-pyridyl ) -quinoxalineplatin (II) ] nitrate obtained by the addition of Pt (H2O) 4 (NO3) 2 into the 2,3- di ( 2-pyridyl ) -quinoxaline (dpq) ligand in the case that M, is Platin (II) ,
Copper complexes; shown with formula IV; wherein it is bis [2, 3-di (2-thienyl) -quinoxalinecopper (I/II) ] chloride obtained by adding copper chloride into the 2, 3-di (2- thienyl ) -quinoxaline (dtq) ligand in the case that M is Copper ( I/II ) ,
Platin complexes, shown with the formula IV; wherein it is bis [ 2 , 3-di (2-thienyl ) -quinoxalineplatin (II)] chloride or bis [ 2 , 3-di (2-thienyl ) -quinoxalineplatin (II) ] nitrate
obtained by adding Pt (H2O) 4 (NO3) 2 into the 2,3-di(2- thienyl ) -quinoxaline (dtq) ligand in the case that M is Platin (II),
• A ligand for synthesizing copper, platin and copper-platin complexes, shown with formula V, wherein it is 3-clip-2- pyridylquinoxaline obtained by the binding of dpq groups characterized with formula I, using a 2-aminopropane bridge ;
Formula V
• A ligand for synthesizing copper, platin and copper-platin complexes, shown with formula VI, wherein it is 3-clip-2- thienylquinoxaline obtained by the binding of dtq groups characterized with formula III, using a 2-aminopropane bridge ;
Copper complexes shown with formula VII; wherein it is [3- clip- (2-pyridylquinoxaline) copper (I/II) ] chloride obtained by adding copper chloride into the 3-clip-2- pyridylquinoxaline ligand, characterized by formula V;
Copper complexes shown with formula III; wherein it is [3- clip-2- (thienylquinoxaline) copper (I/II) ] chloride;
obtained by the addition of copper chloride into the 3- clip-2-thienylquinoxaline ligand characterized with formula VI;
• Platin complexes shown with formula IX; wherein it is [3- clip- ( 2-pyridylquinoxaline ) platin ( I I )] chloride or [3- clip- ( 2-pyridylquinoxaline ) platin ( I I )] nitrate obtained by the addition of potassium tetrachloroplatinate into the 3-clip-2-pyridylquinoxaline ligand characterized by formula V;
• Platin complexes shown with Formula X; wherein it is [3- clip- ( 2-thienylquinoxaline ) platin ( I I )] chloride or [3- clip- (2-thienylquinoxaline) platin(II) ] nitrate synthesized with the addition of potassiumtetrachloroplatinate into the 3-clip-2-thienylquinoxaline ligand characterized by formula VI;
Formula X
• Platin complex shown with formula XI; wherein it is ( amino ) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II) ([Pt(NH3) ( 3-clip-dpq) CI2 ]) obtained with the addition of the 3-clip-2-pyridylquinoxaline ligand characterized by formula V to the [ (C2H5) 4N] [Pt (NH3) CI3] complex obtained as a result of the first method; and the addition of 3-clip- 2-pyridylquinoxaline and ammonium (NH3) ligands into the Pt (H2O) 2 (CI) 2 solution obtained as a result of the second method;
Formula XI
• Platin complex shown with formula XII; wherein it is ( amino ) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II) ( [Pt (NH3) (3-clip-dtq) CI2] ) obtained by the addition of 3- clip-2-thienylquinoxaline ligand characterized by formula
VI, into the [ (C2H5) 4N] [Pt (NH3) CI3] complex obtained as a result of the first method, and the addition of 3-clip-2- thienylquinoxaline and ammonium (NH3) ligands into the Pt (H2O) 2 (CI) 2 solution obtained as a result of the second method,
Formula XII
Bimetallic copper and platin complex shown with formula XIII, wherein it is (amino) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin ( 11 ) -copper ( 11 ) chloride ([Pt(NH3) (3-clip- dpq) CI2 ] -CUCI2 ) obtained by the addition of copper chloride into (amino) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II) compound characterized by formula XI;
Formula XI 11
Wherein said invention has anti-cancer (cancer treating) and anti oxidant effects; characterized in that it is particularly active on cancer cells that are resistant against cisplatin, having an efficiency spectrum that is wider than cisplatin, having a lower toxicity effect in comparison to cisplatin, having reduced side effects, and which can be used as a potential antitumor drug, which comprises similar functional groups in relation to DNA targeted mono and binuclear platin and copper-platin complexes; and in that
It is represented by
Formula XIV and
in that; M, which is a component of Formula (II) and (IV), is platin or copper.
2. A method of synthesizing Copper, platin and binuclear copper-platin compounds subject to the invention, characterized in that it comprises the below mentioned 4 steps ,
A. Ligand Synthesis ( 3-clip-2-pyridylquinoxaline (3-clip-dpq) and 3-clip-2-thienylquinoxaline ( 3-clip-dtq) ) , (Formula V and VI) ,
B. Synthesis of Copper Complexes (bis [ 2 , 3-di ( 2-pyridyl ) - quinoxalinecopper ( I/II )] chloride (Cu(dpq)2Cl2 or [Cu (dpq) 2] CI) , bis [2, 3-di (2-thienyl) -quinoxalinecopper (I/II) ] chloride (Cu(dtq)2Cl2 or [Cu (dtq) 2] CI) , [3-clip- (2- pyridylquinoxaline ) copper (I/II)] chloride ( [Cu (3-clip- dpq) CI2] or [Cu ( 3-clip-dpq) CI ] ) and [3-clip-2- ( thienylquinoxaline ) copper (I/II)] chloride ( [Cu (3-clip- dtq) Cl2] or [Cu (3-clip-dtq) CI] )) , (Formula II, IV, VII and VIII) ,
C. Synthesis of Platin Complexes (bis [ 2 , 3-di ( 2-pyridyl ) - quinoxalineplatin ( I I )] chloride/nitrate (Pt(dpq)2Cl2 or
[Pt (dpq) 2] (N03) 2) , bis[2,3-di (2-thienyl) - quinoxalineplatin ( 11 )] chloride/nitrate (Pt(dtq)2Cl2 or
[Pt(dtq)2] ( 03)2), [ 3-clip- ( 2-pyridylquinoxaline ) platin (II)] chloride or [ 3-clip- ( 2-pyridylquinoxaline ) platin(II)] nitrate ( [Pt (3-clip-dpq) Cl2] or [Pt (3-clip- dpq) (N03)2]), [ 3-clip- ( 2-thienylquinoxaline ) platin (II)] chloride or [3-clip- (2- thienylquinoxaline )platin(II) ] nitrate ( [Pt(3-clip-dtq)Cl2] or [Pt (3-clip-dtq) (N03)2]), (amino) (3-clip-2- pyridylquinoxaline ) dichloroplatin ( 11 ) ([Pt(NH3) (3-clip- dpq) CI2] ) and (amino) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II) ( [Pt (NH3) (3-clip-dtq) Cl2] )) , (Formula II, IV, IX, X, XI and XII),
D. Synthesis of Binuclear Copper and Platin Complexes ( (Amino ) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH3) (3-clip-dpq) Cl2] -CuCl2) and
( amino ) ( 3-clip-2-thienylquinoxaline ) dichloroplatin (II)- copper (II) chloride ( [Pt (NH3) (3-clip-dtq) Cl2] -CuCl2) )
(Formula XIII and XIV) .
3. A synthesizing method of copper and platin complexes according to Claim 2; characterized in that the step of obtaining 3-clip-2-pyridylquinoxaline (3-clip-dpq) ligand comprises ;
Step I. of;
• Dissolving by mixing an equal amount of 4-bromobenzene- 1,2-diamin and 1, 2-di ( 2-dipyridyl ) ethane-1, 2-dion inside ethanol
• Refluxing the mixture for 1-3 hours;
• Cooling the mixture to room temperature;
• Evaporating the mixture until it is reduced to half its volume ;
• Re-crystallizing the obtained product inside toluene.
Step II. Of;
• Refluxing an equivalent of 6-Bromo-2 , 3-di ( 2- prydyl ) quinoxaline and magnesium (Mg) inside dry ether for 1-3 hours;
Step III of;
• Cooling an equivalent of thionyl chloride (SOCI2) to 5- 10°C by adding it into a three necked balloon flask,
• Adding pyridine and ethanol onto thionyl chloride,
• Cooling the mixture to 0-5°C,
• Adding 2-aminoperopan-l , 3diol equivalent to the mixture dropwise, for 1-3 hours,
Leaving the mixture to reflux for 8-12 hours,
Extracting the mixture inside pentane, and
Extracting the organic phase with sodium salt,
Step IV. of;
• Drying the equivalent 1,3 dichloropropane-2-amin under vacuum for 1-5 hours within the presence of phosphor pentoxide (P2O5) ,
• Dissolving dry 1,3 dichloropropane-2-amin inside 50-100 mL dimethylformamide (DMF) in an anaerob medium,
• Adding a 5-7 equivalent of sodium hydride (NaH) and 1-3 equivalent of ditertbutylmethoxyiphenyl (DTBM) into the solution that has been obtained,
• Cooling the mixture to 0-5°C and mixing it at this temperature for 10-30 minutes,
• Adding an equivalent of 2 , 3-di ( 2-pyridyl ) quinoxaline magnesium bromide dissolved inside 25-50 mL DMF into the mixture,
• Mixing the mixture in an ice bath for 10-30 minutes and then further mixing it for 20-50 minutes at room temperature,
• Refluxing the mixture by adding it into an oil bath at 30- 60°C for 25-50 hours,
• Extracting the mixture with dichloromethane (CH2CI2) and removing it from the solvent.
4. Synthesis method of copper and platin complexes of Claim 2, characterized in that; the step of obtaining 3-clip-2- thienylquinoxaline (3-clip-dtq) ligand comprises; Step I of;
· Dissolving an equivalent amount of 4-bromobenzen-l , 2- diamin and 1, 2-di (2-dithienyl) ethane-1, 2-dion inside ethanol ;
• Refluxing the mixture for 1-3 hours,
• Cooling the mixture to room temperature,
· Evaporating the mixture until it is reduced to half its volume,
• Re-crystallizing the obtained product inside toluene; Step II of;
· Refluxing equivalent 6-Bromo-2 , 3-di ( 2- thienyl ) quinoxaline and magnesium (Mg) inside dry ether for 1-3 hours,
Step III of;
· Cooling an equivalent of thionyl chloride (SOCI2) to
5-10°C by adding it into a three necked balloon flask,
• Adding pyridine and ethanol onto thionyl chloride,
• Cooling the mixture to 0-5°C,
· Adding 2-aminoperopan-l , 3-diol equivalent to the mixture dropwise, for 1-3 hours,
• Leaving the mixture to reflux for 8-12 hours,
• Extracting the mixture inside pentane, and
• Extracting the organic phase with sodium salt, and
Step IV. of;
• Drying the equivalent 1,3 dichloropropane-2-amin under vacuum for 1-5 hours within the presence of phosphor pentoxide (P2O5) ,
· Dissolving dry 1,3 dichloropropane-2-amin inside 50-100 mL dimethylformamide (DMF) in an anaerob medium,
• Adding a 5-7 equivalent of sodium hydride (NaH) and 1-3 equivalent of ditertbutylmethoxyphenyl (DTBM) into the solution that has been obtained,
• Cooling the mixture to 0-5°C and mixing it at this temperature for 10-30 minutes,
• Adding an equivalent of 2 , 3-di ( 2-thienyl ) quinoxaline magnesium bromide dissolved inside 25-50 mL DMF into the mixture,
• Mixing the mixture in an ice bath for 10-30 minutes and then further mixing it for 20-50 minutes at room temperature,
• Refluxing the mixture by adding it into an oil bath at 30- 60°C for 25-50 hours,
• Extracting the mixture with dichloromethane ( CH2C I2 ) and removing it from the solvent.
5. Synthesis method of copper and platin compounds of Claim 2, characterized in that; it comprises the steps of obtaining Cu(dpq)2Cl2 or [Cu (dpq) 2 ] CI, Cu(dtq)2Cl2 or [ Cu ( dtq) 2 ] CI , [Cu(3- clip-dpq) C I2 ] or [Cu (3-clip-dpq) CI] and [Cu (3-clip-dtq) C I2 ] or [Cu (3-clip-dtq) CI] copper complexes.
6. Synthesis method of copper compounds of Claim 5i characterized in that the step of obtaining [Cu (dpq) 2 ] C I2 or [Cu (dpq) 2 ] CI and [Cu (dtq) 2 ] C I2 or [Cu (dtq) 2 ] CI copper complexes comprises;
• Completely dissolving dpq or dtq ligands in DMF,
• Adding dropwise, the copper chloride ( CUC I2 ) solution prepared inside an amount of water equivalent to the solution,
· Refluxing the solution for 1-5 hours,
• Separating the obtained product by filtering,
• Drying the product obt
7. Synthesis method of the copper compounds of Claim 5, characterized in that the step of obtaining [Cu (3-clip-dpq) CI2] or [Cu ( 3-clip-dpq) CI ] and [Cu (3-clip-dtq) CI2] or [Cu(3-clip- dtq)Cl] copper complexes comprises;
• Preparing 3-clip-2-pyridylquinoxaline or 3-clip-2- thienylquinoxaline ligands inside DMF,
• Adding dropwise, the copper chloride (CUCI2) solution prepared inside an amount of water equivalent to the solution dropwise,
• Refluxing the solution for 1-5 hours,
• Separating the obtained product by filtering,
• Drying the product obtained
8. Synthesis method of the copper and platin complexes of Claim 2, characterized in that it comprises the steps of Pt(dpq)2Cl2 or [Pt (dpq) 2] (N03) 2, Pt(dtq)2Cl2 or [Pt (dtq) 2] (N03) 2, [Pt (3-clip-dpq) Cl2] or [Pt (3-clip-dpq) (N03) 2] , [Pt (3-clip- dtq) Cl2] or [Pt (3-clip-dtq) (N03)2., [Pt (NH3) ( 3-clip-dpq) Cl2] and [Pt(NH3) ( 3-clip-dtq) CI2] platin complexes.
9. Synthesis method of the platin complexes of claim 8, characterized in that the step of obtaining [Pt (dpq) 2] CI2 or [Pt (dpq) 2] (N03) 2 and [Pt (dtq) 2] Cl2 or [Pt (dtq) 2] (N03) 2 platin complexes comprises the steps of;
• Mixing the silver nitrate (AgN03) aqueous solutions having an equivalent amount with Potassium tetrachloroplatinate ( I I ) (K2PtCl4) for 1-5 hours,
• Dissolving the obtained Pt (H2O) 4 (NO3) 2 complex inside 2- 10 ml water,
• Adding a solution of an equivalent amount of 2,3-di(2- pyridyl ) -quinoxaline or 2 , 3-di ( 2-thienyl ) -quinoxaline ligand into the obtained solution prepared inside DMF,
• Refluxing the mixture at 25-50°C for 3-7 hours,
• Separating the obtained product by filtration and drying .
10. Synthesis method of the platin complexes of Claim 8, characterized in that the step of obtaining [ Pt ( 3-clip-dpq) CI2 ] or [Pt (3-clip-dpq) (N03) 2] and [ Pt ( 3-clip-dtq) Cl2 ] or [Pt(3- clip-dtq) (N03)2] platin complexes comprises;
• Mixing silver nitrate (AgN03) aqueous solution for 1- 5 hours in an equivalent amount with potassium tetrachloroplatinate (II) (K2PtCl4) ,
• Dissolving the obtained Pt (H2O) 4NO3) 2 compound inside 2-10 mL water,
• Adding a solution of an equivalent amount of 3-clip- 2-pyridylquinoxaline or 3-clip-2-thienylquinoxaline ligand into the obtained solution prepared inside DMF,
• Refluxing the mixture at 25-50°C for 3-7 hours,
• Separating the obtained product by filtration and drying .
11. Synthesis method of the platin complexes of Claim 8, characterized in that the 1st method of the step of obtaining [Pt (NH3) (3-clip-dpq) Cl2] and [Pt (NH3) (3-clip-dtq) Cl2] platin complexes comprises;
Dissolving Cis- [Pt (NH3) 2CI2] (cis-platin) inside 50-150 mL DMF,
Adding solid tetraethylammonium (C2H5)4 C1 chloride which is equivalent in amount to the obtained solution,
Mixing the mixture at 80-120°C for 4-8 hours with the passage of argon gas and cooling said mixture inside ice,
Adding the mixture of 100-250 mL (C2H5) 20/hexane (3:1 v/v) into the obtained mixture,
Separating the obtained oily tetraethylammonium aminotrichloroplatinate (II) ( [ (C2H5) 4N] [Pt (NH3) Cl3] ) solution from the solution and mixing it with 5-20 mL methanol,
Preparing a solution of an equivalent amount of 3- clip- ( 2-pyridyl ) quinoxaline or 3-Clip- (2-thienyl ) quinoxaline inside 2-10 mL DMF,
Adding the prepared 3-clip- ( 2-pyridyl )/( 2- thienyl ) quinoxaline solution prepared inside methanol, dropwise to the [ (C2H5) 4N] [Pt (NH3) Cl3] solution,
Mixing the mixture at room temperature for 1-2 hours, Separating the obtained solid product by filtration and drying.
12. Synthesis method of the platin complexes of Claim 8, characterized in that the 2nd method of the step of obtaining [Pt (NH3) (3-clip-dpq) Cl2] and [Pt (NH3) (3-clip-dtq) Cl2] platin complexes comprises;
• Mixing silver nitrate (AgN03) aqueous solutions in an equal amount with potassium tetrachloroplatinate
(II) (K2PtCl4)for 1-5 hours,
Dissolving the obtained Pt(H20)2Cl2 compound inside 2- 10 mL water,
Adding an equivalent amount of ammonium solution into the obtained solution and mixing the solution for 30-90 minutes,
Adding the acidic solution of 3-clip-2- pyridylquinoxaline or 3-clip-2-thienylquinoxaline ligand prepared inside DMF into the mixture, Refluxing the obtained mixture for 3-7 hours at 25- 50°C,
Separating the obtained solid product by filtration and drying.
13. Synthesis method of the copper and platin complexes of Claim 2, characterized in that the step of obtaining [Pt(NH3) (3-clip-dpq) Cl2] -CuCl2 and [Pt(NH3) (3-clip-dtq) Cl2] -CuCl2 binuclear copper and platin complexes comprises;
• Dissolving (amino) ( 3-clip-2-pyridylquinoxaline ) dichloroplatin (II) or (amino) (3-clip-2- thienylquinoxaline ) dichloroplatin ( I I ) complexes inside DMF,
• Adding an equivalent amount of CuCl2 inside an amount of water equivalent to the solution,
• Separating the obtained product by filtration and drying.
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| GR1009550B (en) * | 2018-02-20 | 2019-07-01 | Χριστινα Αννα Δημητριου Μητσοπουλου | Bivalent copper compounds with natural products of pyridyl quinoxaline and nitrates exhibiting anti-fugal and anti-cancer action - multi-target medications |
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| WO2008031017A2 (en) | 2006-09-07 | 2008-03-13 | Virginia Tech Intellectual Properties, Inc. | Supramolecular metallic complexes exhibiting both dna binding and photocleavage |
| US20130237503A1 (en) | 2007-08-06 | 2013-09-12 | Ohio University | Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008031017A2 (en) | 2006-09-07 | 2008-03-13 | Virginia Tech Intellectual Properties, Inc. | Supramolecular metallic complexes exhibiting both dna binding and photocleavage |
| US20130237503A1 (en) | 2007-08-06 | 2013-09-12 | Ohio University | Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin |
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| MITSOPOULOU ET AL: "Synthesis, characterization, DFT studies and DNA binding of mixed platinum (II) complexes containing quinoxaline and 1,2-dithiolate ligands", JOURNAL OF INORGANIC BIOCHEMISTRY, ELSEVIER INC, US, vol. 102, no. 1, 11 December 2007 (2007-12-11), pages 77 - 86, XP022384788, ISSN: 0162-0134, DOI: 10.1016/J.JINORGBIO.2007.07.002 * |
| XINDIAN DONG ET AL: "Promotive Effect of the Platinum Moiety on the DNA Cleavage Activity of Copper-Based Artificial Nucleases", INORGANIC CHEMISTRY, vol. 49, no. 5, 1 March 2010 (2010-03-01), EASTON, US, pages 2541 - 2549, XP055352387, ISSN: 0020-1669, DOI: 10.1021/ic100001x * |
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| GR1009550B (en) * | 2018-02-20 | 2019-07-01 | Χριστινα Αννα Δημητριου Μητσοπουλου | Bivalent copper compounds with natural products of pyridyl quinoxaline and nitrates exhibiting anti-fugal and anti-cancer action - multi-target medications |
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