CN109021021A - 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complex and its preparation method and application - Google Patents
11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complex and its preparation method and application Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title abstract description 31
- 229910052697 platinum Inorganic materials 0.000 title abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 238000010668 complexation reaction Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 210000004185 liver Anatomy 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 23
- 239000013078 crystal Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 13
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- -1 platinum metals Chemical class 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 102000003915 DNA Topoisomerases Human genes 0.000 description 4
- 108090000323 DNA Topoisomerases Proteins 0.000 description 4
- 101710183280 Topoisomerase Proteins 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 2
- IWFHBRFJOHTIPU-UHFFFAOYSA-N 4,5-dichlorobenzene-1,2-diamine Chemical compound NC1=CC(Cl)=C(Cl)C=C1N IWFHBRFJOHTIPU-UHFFFAOYSA-N 0.000 description 2
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000000246 agarose gel electrophoresis Methods 0.000 description 2
- 229960004701 amonafide Drugs 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 229950001745 mitonafide Drugs 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
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- 238000007789 sealing Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OWIRVNDMYDSKIJ-UHFFFAOYSA-N 2,4-dichloro-1h-benzimidazole Chemical compound C1=CC=C2NC(Cl)=NC2=C1Cl OWIRVNDMYDSKIJ-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 239000012625 DNA intercalator Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- NZBSAAMEZYOGBA-UHFFFAOYSA-N luminogren Chemical compound C12=NC3=CC=CC=C3N2C(=O)C2=CC=CC3=CC=CC1=C23 NZBSAAMEZYOGBA-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complexes and its preparation method and application.The preparation method of the complex, which mainly comprises the steps that, takes compound shown in compound shown in following formula (II) and formula (III) to be placed in organic solvent, carries out complexation reaction under the conditions of being heated or not heated to get target product.Complex of the present invention is significantly higher than common anti-tumor drug cis-platinum to the inhibitory activity of certain cancer cells, and lower to people's normal cell lines of human liver HL-7702 toxicity.Shown in the structure of complex of the present invention such as following formula (I), the structure for preparing compound shown in compound shown in raw material formula (II) involved in the complex and formula (III) is as follows:
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to one kind 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum
Complex and its preparation method and application.
Background technique
The anti-tumor drug of serious harm based on cancer to human health, design and synthesizing new high-efficiency low-toxicity is by people
Highest attention.Since since the platinum metals such as cis-platinum, carboplatin, base anti-tumor complex is found, design and the novel height of screening
Imitating less toxic platinum metals base anti-tumor complex becomes a kind of important research direction.
Naphthoyl imide compounds are a kind of classical small molecule DNA intercalator, representation compound Amonafide
(amonafide) and mitonafide (mitonafide) is to more plants of cancer cells very high anticancer activity.But it has not yet to see
There are 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complex preparation method and its relevant report to cytotoxicity.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of structure novel, to certain cytotoxicities height but to normal
It low 11,12- dichloro benzimidazole -1, the 8- naphthalimide-platinum complex of hepatotoxicity and its preparation method and answers
With.
The present invention relates to compound shown in following formula (I)s or its pharmaceutically acceptable salts:
The present invention also provides the preparation method of above compound, mainly comprises the steps that and take following formula (II) shownization
It closes compound shown in object and formula (III) in organic solvent, carries out complexation reaction under the conditions of being heated or not heated to get target
Product；
Pt(DMSO)2Cl2(III)。
In above-mentioned preparation method, compound shown in the formula (II) is 11,12- dichloro benzimidazole -1,8- naphthalimide,
The compound can refer to existing literature (Banerji K D, Sen K K, Mazumdar A K D, Synthesis of some
naphthoylenebenzimidazole,Journal of the Indian Chemical Society,197653(11),
1159-61) synthesized, can also designed, designed synthetic route synthesized.It is preferred that being synthesized using following methods:
Stoichiometrically take 1,8- naphthalene anhydride and 4,5- dichloro o-phenylenediamine be placed in polar solvent (selected from acetic acid, dimethylbenzene,
The combination of one or more of toluene, DMF, DMSO and ethylene glycol monomethyl ether) in back flow reaction (about 4-8h), reaction terminates
Afterwards, it cools down, there is solid precipitation, collect solid, dry to get compound 11 shown in the formula (II), 12- dichloro benzo miaow is arrived
Azoles -1,8- naphthalimide (yellow crystals or powder), specific synthetic route is as follows:
In above-mentioned preparation method, compound shown in the formula (III) is that cis- dichloro two (dimethyl sulfoxide) closes platinum
(II), it can refer to existing literature (Al-Allaf T AK, et al.Transit.Met.Chem., 1998) to be prepared.
In above-mentioned preparation method, the molar ratio of compound shown in compound shown in the formula (II) and formula (III) is chemistry
Ratio is measured, in actual operation, compound shown in compound shown in formula (II) or formula (III) can also be relatively excessive, but excessive
It is impure to will cause products therefrom.
In above-mentioned preparation method, the organic solvent be can be selected from methanol, ethyl alcohol, chloroform, methylene chloride, dimethyl
The combination of one or more of sulfoxide (DMSO) and n,N-Dimethylformamide (DMF).When being selected as organic solvent
In above-mentioned selection when two or more mixtures, the proportion between them can be any proportion.The dosage of the organic solvent can
It determines as needed.In specific dissolving step, compound shown in compound shown in formula (II) and formula (III) can be used respectively
Organic solvent dissolution, remixes and reacts together；After compound shown in compound shown in formula (II) and formula (III) can also being mixed
It is dissolved again with organic solvent.
11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complex of the present invention can be adopted in specific preparation
It is prepared with solwution method or solvent-thermal method.
When using solwution method preparation, specifically includes that and compound shown in compound and formula shown in formula (II) (III) is taken to dissolve
In organic solvent, complexation reaction being carried out under the conditions of being heated or not heated, is filtered while hot after reaction, filtrate is cooling, has
Solid is precipitated, and collects solid, as target product.
In above-mentioned solwution method, it whether complete can react by thin-layer chromatography tracing detection.In order to improve the yield of reaction,
Reaction is preferably performed under heating conditions, and is further preferably carried out under conditions of >=40 DEG C, more preferably in 60-80 DEG C of condition
Lower progress, when reaction carries out in this preferred range, the time of reaction is usually 24-48h.In this method, 1mmol's
Compound shown in the formula (III) of compound shown in formula (II) and 1mmol is usually dissolved with the organic solvent of 6-25mL.
When using solvent-thermal method preparation, specifically includes that and take compound shown in compound and formula shown in formula (II) (III) molten
Solution is subsequently placed in container (usually heavy-walled glass pipe or pressure bottle open at one end), in organic solvent through liquid nitrogen frozen
After be evacuated to vacuum, sealing after complexation reaction is carried out under heating condition, it is cooling, have crystal precipitation, collect solid, as target produces
Object.In this method, reaction is preferably carried out under conditions of >=40 DEG C, is more preferably carried out under the conditions of 60-80 DEG C, when reaction exists
When carrying out in this preferred range, the time of reaction is usually 24-48h.When using the method, shown in the formula (II) of 1mmol
Compound shown in the formula (III) of compound and 1mmol is usually dissolved with the organic solvent of 5-20mL.
The target product that above-mentioned solvent-thermal method is precipitated is crystal, and the product that solwution method is precipitated is usually powdered, gained
Powdered target product further can obtain crystal using the method for solvent crystallization, specifically: powdered target product is set
In the in the mixed solvent that one of methanol and ethyl alcohol are formed with one of chloroform and methylene chloride, under the conditions of 60-80 DEG C
24-48h is reacted, the target product of lenticular can be obtained after cooling.
The invention also includes above-mentioned 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complex or its pharmaceutically may be used
The salt application in preparation of anti-tumor drugs of receiving.
The present invention further comprises a kind of pharmaceutical composition, it contains above-mentioned 11, the 12- dichloro-benzenes for treating upper effective dose
And imidazoles -1,8- naphthalimide-platinum complex or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides a kind of 11,12- dichloro benzimidazole -1,8- naphthoyls of structure novel
Imines-platinum complex, short preparation period, yield is high, and quality is stablized；Our experimental result show that the complex is to certain
The inhibitory activity of a little cell strains is significantly higher than tumor Drugs cis-platinum (such as human liver cancer cells Hep G2, human glioma
Cell strain U251), while it is lower than cis-platinum and 5 FU 5 fluorouracil to the toxicity of normal cell, is expected to be used for the system of anti-tumor drug
It is standby.
Detailed description of the invention
Fig. 1 is the crystal structure figure of final product made from the embodiment of the present invention 1；
Fig. 2 is that the compound I and Topo I of various concentration act on agarose gel electrophoresis figure.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but
The present invention is not limited to following embodiments.
(i.e. 11,12- dichloro benzimidazole -1,8- naphthoyl is sub- for compound shown in formula involved in following embodiment (II)
Amine) it is prepared as follows to obtain:
Take 1,8- naphthalene anhydride (5g, 25.2mmol, 1.0equiv), 4,5- dichloro o-phenylenediamine (4.43g, 25.2mmol,
It 1.0equiv) is placed in 100ml round-bottomed flask, after 50mL acetic acid is added, reaction is heated to 118 DEG C and is stirred at reflux 7h.Stop anti-
It answers, cooled to room temperature, there is yellow solid precipitation, filter, obtain compound (yellow powdery solid) shown in formula (II)
7.31g, yield 86.11%.1H NMR (400MHz, DMSO) δ 8.63 (dd, J=13.3,5.6Hz, 2H), 8.49 (d, J=
8.2Hz,1H),8.47–8.25(m,2H),8.01–7.73(m,2H),7.65–7.55(m,1H).13C NMR(101MHz,DMSO)
δ160.59,150.81,145.33,136.34,133.17,133.05,132.36,131.95,131.15,128.85,
128.14,128.02,127.74,127.65,127.02,126.98,122.99,122.71,120.26,118.24,
117.23.MS m/z:339.00[M+H]+.
Embodiment 1
Measure 11,12- dichloro benzimidazole -1,8- naphthalimide (100mg, 0.2958mmol), (diformazan is sub- for dichloro two
Sulfone) close platinum (II) (Pt (DMSO)2Cl2) (124.53mg, 0.2958mmol), 5ml methanol and 5ml chloroform, it is placed in round-bottomed flask
In, at being 60 DEG C in temperature, it is stirred to react 48h, is filtered to remove unreacting material while hot after reaction, filtrate is cooled to room
Temperature has yellow solid precipitation, collects solid, dry, obtains product as yellow powder 127.60mg, yield 50.00%.
The characterizations such as mass spectrum, elemental analysis and the analysis of X- single crystal diffraction are carried out to this implementation products therefrom, specific as follows:
(1)MS m/z:716.8864[M+Cl]-.
(2)Anal.Calc.(for C20H14Cl4N2O2PtS)C 35.16；H 2.07；N 4.10%,
Found.C35.14；H 2.09；N 4.12%.
(3) take this implementation of 10mg products therefrom and 5ml methanol/chloroform mixed solution (volume ratio of methanol and chloroform is 1:
1) it is placed in tube sealing, is warming up to 90 DEG C, react 12h, it is cooling, there is crystal precipitation, collects crystal, it is dry, obtain yellow crystals.It will
Gained yellow crystals are parsed through X-Ray single crystal diffraction, and crystallographic data is as described in Table 1, and part bond distance and bond angle are as follows
It states shown in table 2, the crystal structure of products therefrom is as shown in Figure 1.
Table 1: the crystallography and structural modifications data of product
Table 2: the strong length in the part of productWith bond angle [°]
Accordingly, it can be determined that the present embodiment obtained by product as yellow powder be target product 11, dichloro benzimidazole -1 12-,
8- naphthalimide-platinum complex, shown in structural formula such as following formula (I):
Embodiment 2
Take 11,12- dichloro benzimidazole -1,8- naphthalimide (339.17mg, 1mmol), Pt (DMSO)2Cl2
(422.9mg, 1mmol) and 9ml methanol, is placed in heavy wall pressure bottle, at being 70 DEG C in temperature after dissolution, is stirred to react 36h, from
It is so cooled to room temperature, there is yellow solid precipitation, separate, it is dry, obtain yellow powder 413.80mg, yield 54.30%.
Mass spectrum, elemental analysis and the analysis of further X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determined
The present embodiment products therefrom is target compound.
Embodiment 3
Take 11,12- dichloro benzimidazole -1,8- naphthalimide (251.12mg, 0.7404mmol), Pt (DMSO)2Cl2
(311.64mg, 0.7404mmol) and 6ml DMSO, sets in a round bottom flask, at being 80 DEG C in temperature after dissolution, is stirred to react
For 24 hours, cooled to room temperature has yellow solid precipitation, separates, dry, obtains yellow powder 316.05mg, yield 56.15%.
Mass spectrum, elemental analysis and the analysis of further X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determined
The present embodiment products therefrom is target compound.
Embodiment 4
Take 11,12- dichloro benzimidazole -1,8- naphthalimide (125.56mg, 0.3702mmol), Pt (DMSO)2Cl2
(155.82mg, 0.3702mmol) and 8ml chloroform, sets in a round bottom flask, at being 80 DEG C in temperature after dissolution, is stirred to react,
44h to be reacted, is filtered to remove unreacting material while hot after reaction, cooled to room temperature has yellow solid precipitation, separation,
It is dry, obtain yellow powder 125.21mg, yield 44.50%.
Mass spectrum, elemental analysis and the analysis of further X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determined
The present embodiment products therefrom is target compound.
Embodiment 5
Take 11,12- dichloro benzimidazole -1,8- naphthalimide (125.56mg, 0.3702mmol), Pt (DMSO)2Cl2
(155.82mg, 0.3702mmol), 5ml ethyl alcohol and 5ml methylene chloride are set in a round bottom flask, at being 40 DEG C in temperature, are stirred
48h to be reacted, is filtered to remove unreacting material while hot after reaction, cooled to room temperature has yellow solid precipitation, separation,
It is dry, obtain yellow powder 50.65mg, yield 18.00%.
Mass spectrum, elemental analysis and the analysis of further X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determined
The present embodiment products therefrom is target compound.
Embodiment 6
Embodiment 5 is repeated, unlike, reaction temperature is room temperature.
Finally obtain yellow powder 10.45mg, yield 3.71%.
Mass spectrum, elemental analysis and the analysis of further X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determined
The present embodiment products therefrom is target compound.
Experimental example 1: target compound of the present invention tests the anti tumor activity in vitro of a variety of human tumor cell lines:
The antitumor action of 11,12- dichloro benzimidazole -1, the 8- naphthalimide-platinum complex to illustrate the invention,
Applicant tests (to commonly use anti-tumor drug 5 FU 5 fluorouracil (5-FU) and cis-platinum the anti-tumor activity that complex has carried out
(Cis-platin) it is reference), and to the toxicity carried out by compound made from 1 the method for above-described embodiment to normal cell
Experiment.
1. the inoculation and culture of cell
Selected cell strain is placed in 37 DEG C, 5%CO2In incubator under the conditions of abundant humidifying, it is inoculated in containing 10% inactivation
It is cultivated in the PPMI1640 culture solution of newborn bovine serum.Cell growth status is observed with inverted microscope, replaces 2-3 training weekly
Base is supported, passage in 6-7 days is primary, with the passage of 0.25% trypsin digestion when inoculation, usually takes passage 3-4 time, is in logarithm life
Long-term cell is for testing.
2. the active primary dcreening operation of Compound cellular level
This tests used compound, and (wherein complex of the present invention is by 1 the method system of above-described embodiment
), all compounds are configured to 100 μ g/mL by purity >=95%, and cosolvent DMSO final concentration is no more than 1%, it is dense to test this
For each compound to the inhibiting rate of cancer cell, all inhibiting rates are greater than 50% and meet suppressed (or impaired) form of cell under light microscopic under degree
(such as cell shrinkage, the broken, floating) of variation, and be not very big compound to normal cell toxicity, then preliminary judgement is
The compound primary dcreening operation is effective, that is, enters next step and seek IC50Stage.
3. cell growth inhibition test (mtt assay)
MTT colorimetric method is the method for a kind of detection cell growth and survival.Testing principle: it is different from dead cell, it is exogenous
MTT can be reduced to bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble simultaneously by the succinate dehydrogenase in living cells mitochondria
It is deposited in cell.Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, with enzyme-linked immunosorbent assay instrument in 490nm wavelength
Place measures its absorbance value, can reflect living cells quantity indirectly.Within the scope of certain cell number, MTT crystallizes the amount to be formed and thin
Born of the same parents' number is directly proportional.This method be widely used in the Activity determinations of some bioactie agents, large-scale screening anti-tumor medicine,
Cell toxicity test and tumor radiosensitivity measurement etc., have the characteristics that high sensitivity, economic.
Take the cell in logarithmic growth phase, the celliferous culture medium inoculated of every 180 μ L of hole (about 4500-5000 cell)
In 96 well culture plates, in 37 DEG C, 5%CO2It is cultivated for 24 hours under the conditions of abundant humidifying.After cell is adherent, add by the amount of every 20 μ L of hole
Enter sample, each sample sets 6 multiple holes, concurrently sets corresponding blank control.Continue after cultivating 48h, 10 μ L are added in every hole
MTT reagent (concentration 5mg/mL) continues after being incubated for 4h, inhales and abandon supernatant, and every hole adds 150 μ L DMSO, and slight concussion is anti-
5-8min is answered, dissolves crystalline particle sufficiently.Blank control group zeroing measures removal bias light with microplate reader with 490nm wavelength
After absorption value absorbance value (Value), calculating cell proliferation inhibition rate, the test-compound good to primary dcreening operation antitumous effect, after
The continuous IC for being continued to do corresponding cell strain with 5 concentration gradients50Value, all experiments are averaged after being repeated 3 times.Experimental result is detailed
It see the table below 3.
From the data in table 3, complex of the present invention is thin to human liver cancer cells Hep G2, human glioma
The inhibitory activity of born of the same parents' strain U251 is superior to common anti-tumor drug cis-platinum, and ligands and complexes are to people's normal cell lines of human liver HL-
7702 toxicity is significantly less than cis-platinum.The above result shows that by by 11,12- dichloro benzimidazole -1,8- naphthalimide mesh core
It introduces in the structure of platinum metals and prepares novel 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum antineoplastic complex
Be it is feasible, the new antitumoral complex of high-efficiency low-toxicity can be filtered out.But complex of the present invention is thin to owner's cancer
The inhibitory activity of born of the same parents is not all better than its ligand, that is to say, that by 11,12- dichloro benzimidazole -1,8- naphthalimide mesh core
Introduce the different cytotoxicity surely improved to tumour cell of platinum metals structure.
Table 3: half-suppressed rate concentration (C of the compound to different tumor cell lines50, μM)
ndaExpression is not tested.
Experimental example 2: the Anticancer Effect and Mechanism of complex of the present invention
The antitumor action of the 11,12- dichloro benzimidazole -1,8- naphthalimide-platinum complex to illustrate the invention
Mechanism, applicant study the Anticancer Effect and Mechanism of the complex based on topoisomerase I target spot.
1. with topoisomerase I repercussion study
It is a common target of naphthoyl imide compounds and cis-platinum based on topoisomerase, we are solidifying using agarose
The interaction of gel electrophoresis and Western blotting research complex and topoisomerase.
Fig. 2 is compound I and Topo I the effect agarose gel electrophoresis figure that various concentration is added.Showing of electrophoresis result
Closing object I in vitro has compared with high inhibition effect TopoI, and urging for the TopoI of 0.1U/L can be completely inhibited under 20 μM of concentration
Change function, compound can completely inhibit topoisomerase I activity at 80 μM.Classical Topo I toxic agent camptothecine is in vitro for topology
The 503nhibiting concentration of isomerase I is about 17 μM, and compound I is suitable with it to the inhibitory activity of topoisomerase I.
Fig. 2 experiment shows that compound I has stronger topoisomerase enzyme inhibition activity, therefore it is presumed that its performance anticancer is living
Property may be by inhibiting the activity of intracellular topoisomerase.
Claims (7)
1. compound shown in following formula (I)s or its pharmaceutically acceptable salt:
2. the preparation method of compound described in claim 1, it is characterised in that: mainly comprise the steps that and take following formula (II)
Compound shown in shown compound and formula (III) is placed in organic solvent, and complexation reaction is carried out under the conditions of being heated or not heated,
Up to target product；
3. the preparation method of compound according to claim 1, it is characterised in that: the organic solvent be selected from methanol,
The combination of one or more of ethyl alcohol, chloroform, methylene chloride, dimethyl sulfoxide and n,N-Dimethylformamide.
4. the preparation method of compound according to claim 1, it is characterised in that: it is described reaction under conditions of >=40 DEG C into
Row.
5. the preparation method of compound according to claim 1, it is characterised in that: it is described reaction under the conditions of 60-80 DEG C into
Row.
6. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
7. a kind of pharmaceutical composition, it is characterised in that: contain compound or its medicine described in the claim 1 for treating upper effective dose
Acceptable salt on.
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