CN104530136B - A kind of chiral platinum complex and preparation method thereof - Google Patents
A kind of chiral platinum complex and preparation method thereof Download PDFInfo
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- CN104530136B CN104530136B CN201410784089.5A CN201410784089A CN104530136B CN 104530136 B CN104530136 B CN 104530136B CN 201410784089 A CN201410784089 A CN 201410784089A CN 104530136 B CN104530136 B CN 104530136B
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- phenanthroline
- imidazo
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 121
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000010668 complexation reaction Methods 0.000 title abstract description 4
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 29
- 239000011591 potassium Substances 0.000 claims abstract description 29
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 28
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 201000007270 liver cancer Diseases 0.000 claims abstract description 16
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 12
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- 125000005594 diketone group Chemical group 0.000 claims abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 238000010438 heat treatment Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- MNOPPWUITYVVJC-UHFFFAOYSA-N 1h-imidazo[4,5-f][1,10]phenanthroline Chemical compound C12=CC=CN=C2C2=NC=CC=C2C2=C1NC=N2 MNOPPWUITYVVJC-UHFFFAOYSA-N 0.000 claims description 16
- 229910000474 mercury oxide Inorganic materials 0.000 claims description 16
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 235000019441 ethanol Nutrition 0.000 claims description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 8
- 239000005695 Ammonium acetate Substances 0.000 claims description 8
- 229940043376 ammonium acetate Drugs 0.000 claims description 8
- 235000019257 ammonium acetate Nutrition 0.000 claims description 8
- 150000005045 1,10-phenanthrolines Chemical class 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000003205 fragrance Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000003560 cancer drug Substances 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 19
- 230000000259 anti-tumor effect Effects 0.000 abstract description 12
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 abstract description 11
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 abstract description 10
- 206010017758 gastric cancer Diseases 0.000 abstract description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 201000011549 stomach cancer Diseases 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 58
- 239000000243 solution Substances 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 26
- 229940125782 compound 2 Drugs 0.000 description 18
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 13
- 230000000118 anti-neoplastic effect Effects 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 201000005296 lung carcinoma Diseases 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 6
- 208000010749 gastric carcinoma Diseases 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 201000000498 stomach carcinoma Diseases 0.000 description 6
- 206010005003 Bladder cancer Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- VQLYBLABXAHUDN-UHFFFAOYSA-N bis(4-fluorophenyl)-methyl-(1,2,4-triazol-1-ylmethyl)silane;methyl n-(1h-benzimidazol-2-yl)carbamate Chemical compound C1=CC=C2NC(NC(=O)OC)=NC2=C1.C=1C=C(F)C=CC=1[Si](C=1C=CC(F)=CC=1)(C)CN1C=NC=N1 VQLYBLABXAHUDN-UHFFFAOYSA-N 0.000 description 5
- 201000001531 bladder carcinoma Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 210000003411 telomere Anatomy 0.000 description 5
- 102000055501 telomere Human genes 0.000 description 5
- 108091035539 telomere Proteins 0.000 description 5
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 5
- ZRSNZINYAWTAHE-UHFFFAOYSA-N Anisaldehyde Natural products COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 150000004696 coordination complex Chemical class 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 150000003057 platinum Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ACOJCCLIDPZYJC-UHFFFAOYSA-M thiazole orange Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1=CC=C2C(C=C3N(C4=CC=CC=C4S3)C)=CC=[N+](C)C2=C1 ACOJCCLIDPZYJC-UHFFFAOYSA-M 0.000 description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 description 3
- 230000005291 magnetic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 241001062009 Indigofera Species 0.000 description 1
- OYCDTPQIKJZGBS-UHFFFAOYSA-N P(O)(O)(O)=O.[O] Chemical compound P(O)(O)(O)=O.[O] OYCDTPQIKJZGBS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000013522 chelant 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
- ZYZCZCHRQQZTHI-UHFFFAOYSA-N cyclohexane-1,1-diamine;platinum Chemical compound [Pt].NC1(N)CCCCC1 ZYZCZCHRQQZTHI-UHFFFAOYSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of chiral platinum complex and preparation method thereof, the complex:Dichloride 2 [2（Hydroxyl）‑4‑（Methoxyl group）Phenyl] imidazo [4,5 f] [1,10] phenanthroline S, S cyclohexanediamine conjunction platinum（Ⅱ）, there is chirality.It, for raw material, prepares 2 [2 with the diketone of 1,10 phenanthroline 5,6 and the methoxybenzaldehyde of 2 hydroxyl 4（Hydroxyl）‑4‑（Methoxyl group）Phenyl] imidazo [4,5 f] [1,10] phenanthroline, add potassium chloroplatinite and prepare 2 [2（Hydroxyl）‑4‑（Methoxyl group）Phenyl] imidazo [4,5 f] [1,10] phenanthroline dichloro conjunction platinum（Ⅱ）, cyclohexanediamine is finally added, obtains the product chirality platinum complex of the present invention.The complex has excellent antitumor activity, can be applied in anti-liver cancer and anti-, lung cancer and gastric cancer medicament.
Description
Technical field
The present invention relates to antibumor molecules compound field, and in particular to chiral platinum complex and preparation method thereof and is making
Application in standby antineoplastic.
Background technology
Since it is found that the serobila DNA of G- tetra- are potential anti-tumor targets is marked with, people are can stable G- tetra- serobila DNA
Organic molecule in terms of done substantial amounts of research work.But up to the present most stable serobila DNA's of G- tetra- is small
Molecule is organic compound, and only sub-fraction is metal complex.Because metal complex has many organic molecules difficult
The advantages of to compare, the geometry change such as tempered toughness with gentleness and abundant electrochemical properties, at the same also have optics, magnetics with
And the multiple performance such as catalysis.In terms of binding pattern, metal complex with the serobila DNA of G- tetra- by pi-pi accumulation except can be acted on
Outside, moreover it is possible to the stable stranded structures of G- tetra- by way of forming covalent bond with base or phosphate radical skeleton, and then it is anti-swollen
The effect of knurl.This causes people constantly to find suitable antineoplastic in metal complex.
Platinum complexes start from nineteen sixties as the research of antineoplastic, the platinum class on the basis of cis-platinum
Design synthesis and antitumor activity screening like thing are always the focus of antineoplastic research field.Chiral platinum complexes
Its antitumor activity also has point of height, and causing the lipophilicity of this active difference and complex structure has important relationship.
The content of the invention
It is an object of the invention to provide chiral platinum complex with antitumor activity and its preparation method and application.Should
Complex molecule Stability Analysis of Structures, synthetic method is simple, while has very strong antitumor activity, can be the research and development of antineoplastic
Theoretical direction is provided.
Technical scheme：
A kind of chiral platinum complex, its structural formula are：
The chiral platinum complex chemical name is：Dichloride -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,
5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes platinum (II) complex, and it has chirality, belongs to chiral Δ type, Δ-
[Pt(chda)(o-HO-p-MOPIP)]2+(Δ-Pt)。
Pt is divalent metal in the chiral platinum complex of the present invention.
The preparation method of the chiral platinum complex of the present invention, comprises the following steps：
(1) it is by the mol ratio of 1,10- phenanthrolines -5,6- diketone (compound 1) and 2- hydroxyls -4-methoxybenzaldehyde
1:1~2 weighs raw material, and 8~10mL glacial acetic acid is added by every mole of 1,10- phenanthrolines -5,6- diketone, then by 1,10-
The mol ratio of phenanthroline -5,6- diketone and ammonium acetate is 1:25~30 add ammonium acetate, under 120~130 DEG C of oil baths, heating
Flow back 5~7h, is cooled to room temperature；Under condition of ice bath, concentrated ammonia liquor is slowly added dropwise to neutrality in stirring, obtains 2- [2- (hydroxyl) -4-
(methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline yellow mercury oxide (compound 2)；
(2) every mole 2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-luxuriant and rich with fragrance hello of neighbour is pressed again
4~5L dimethyl sulfoxide (DMSO) is added in the yellow mercury oxide of quinoline, oil bath heating dissolves yellow mercury oxide to 140~150 DEG C, obtained
To yellow solution；Chloroplatinous acid potassium solution well prepared in advance is slowly dropped into yellow solution again, separates out yellow mercury oxide, after
1.5~2h of continuous return stirring, makes reaction complete, filters while hot, removes unreacted reactant, washs, and filters, drying, obtains the 2- of yellow
[2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline dichloro closes platinum (II) (complex
3)；
(3) every mole 2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline
Dichloro closes the absolute ethyl alcohol that 60~70L is added in platinum (II) (complex 3), after being reacted 20~30 minutes at 70~80 DEG C, adds
1, the 2- cyclohexanediamine (compound 4) of 6~8 times of mol ratios of complex 3, fully dissolved is back under constant temperature, is filtered to remove insoluble
Thing, filtrate are slowly volatilized, and separate out red precipitate, with ethyl alcohol recrystallization, produce chiral platinum complex (complex 5).
As the further preferred of technical scheme, concentrated ammonia liquor volume fraction is 25-28% in above-mentioned steps (1), addition
8~10mL concentrated ammonia liquors are added dropwise for every mole of 1,10- phenanthrolines -5,6- diketone.
As the further preferred of technical scheme, potassium chloroplatinite is prepared as in above-mentioned steps (2)：First by chloroplatinous acid
Potassium adds water, is dissolved by heating at 50~60 DEG C, then adds 0.8~1L dimethyl sulfoxide, heating stirring 5 by every mole of potassium chloroplatinite
~10min is i.e. available.
As the further preferred of technical scheme, the amount of water of potassium chloroplatinite is every mole of chlorine Asia in above-mentioned steps (2)
Add 300~400mL water in potassium platinate.
The chemical equation of the present invention：
Effect of each component of the present invention in chiral platinum complex：
Pt++Effect：Directly chelate, draw with DNA some nucleophilic groups (such as phosphoric acid oxygen site or base nitrogen, oxygen site)
The DNA damage of cancer cell is played, makes DNA among replicating and transcribing by obstacle, so as to prevent the growth of cancer cell and division,
And cause it dead.
Dichloride -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline S, S-
Cyclohexanediamine closes the effect of platinum (II)：Be advantageous to insert among the base-pair of DNA double helix.
The chiral platinum complex of the present invention, it is applied to the preparation prepared in the antineoplastics such as anti-liver cancer and anti-, lung cancer and stomach cancer.
Beneficial effects of the present invention：
The chiral platinum complex molecular structure stabilized of the present invention, synthetic method are simple.Imidazo [4,5-f] in the complex
The introducing of [1,10]-phenanthroline, it greatly strengthen the cell transmembrane ability of complex.Anti-tumor experiment shows simultaneously, such
Complex has very strong antitumor activity, and its rejection ability to NCI-H460 cells propagation is 10 times of cis-platinum, anti-swollen
There to be great application potential in terms of tumor medicine.
Brief description of the drawings
Fig. 1 is the Δ-Pt chirality platinum complex structural formulas of the present invention；
Fig. 2 is the infrared spectrogram of Δ type chirality platinum complex of the present invention, and Δ-Pt infrared spectrum is (KBr, cm–1)：
3303,2934,1613,1586,1457,1361,1327,1292,1208,1163,1082,1 039,1026,809,717. coordinate
ν in thing(C-N)In 1292cm-1Place, it is in 3303cm-1Neighbouring wide absworption peak can be pointed out as ν(O-H)Stretching vibration.In complex
The skeleton stretching vibration of phenyl ring is located at 1586cm-1.It is in 1208cm-1And 1039cm-1The absworption peak at place can point out respectively for
ν(C-O-C)Symmetrical and asymmetric stretching vibration.
Fig. 3 is the product of the embodiment of the present invention 1 to six kinds of human tumor cells BEL -7404 (human liver cancer cell), HepG2 (people
Liver cancer cells), NCI-H460 (human lung carcinoma cell), T -24 (transitional cell bladder carcinoma cell line), MGC -803 (gastric carcinoma cells), A549 (people's lungs
Adenocarcinoma cell) and HL -7702 (normal liver cell) inhibiting rate figure.
Fig. 4 is the product of the embodiment of the present invention 1 to six kinds of human tumor cells BEL -7404 (human liver cancer cell), HepG2 (people
Liver cancer cells), NCI-H460 (human lung carcinoma cell), T -24 (transitional cell bladder carcinoma cell line), MGC -803 (gastric carcinoma cells), A549 (people's lungs
Adenocarcinoma cell) and HL -7702 (normal liver cell) IC50 block diagram.
Fig. 5 is the Δ-Pt chiralitys platinum complex and the serobila Htel-1-DNA compound systems of telomere four of the embodiment of the present invention 1
(concentration of complex is 2.0 × 10 to uv absorption spectra–3Mol/L, [DNA]/[complex]=0-1).
Fig. 6 is purple of the Δ-Pt chiralitys platinum complex with the serobila Htel-DNA compound systems of telomere four of the embodiment of the present invention 1
(concentration of complex is 2.0 × 10 to outer abosrption spectrogram–3Mol/L, [DNA]/[complex]=0-1).
Fig. 7 is that the Δ-Pt chiralitys platinum complex of the embodiment of the present invention 1 is glimmering with the serobila DNA complex system of telomere four respectively
Light competition figure.
Embodiment
Below by embodiment combination accompanying drawing, the invention will be further described.
In following examples, compound 1：Phenanthroline -5,6- diketone；
Compound 2：The Huang of 2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline
Color sediment；
Complex 3：2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline two
Chlorine closes platinum (II)；
Compound 4：1,2- cyclohexanediamine；
Complex 5 (chiral platinum complex)：Product of the present invention, dichloride -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl]
Imidazo [4,5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes platinum (II) complex.
Embodiment 1
First, preparation method of the invention：
(1) preparation of compound 2：Weigh 2mol phenanthroline -5,6- diketone (compound 1) and 2mol 2- hydroxyls -
4-methoxybenzaldehyde, glacial acetic acid 16mL and ammonium acetate 3.1g is added, under 120 DEG C of oil baths, 6h is heated to reflux, is cooled to room
Temperature；Under condition of ice bath, stirring, 16mL concentrated ammonia liquors (25-28%) are slowly added dropwise to neutrality, obtain 2- [2- (hydroxyl) -4- (first
Epoxide)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline yellow mercury oxide (compound 2)；
(2) preparation of complex 3：Previously prepared chloroplatinous acid potassium solution, in 2.4mmol potassium chloroplatinites, adds water
0.8mL, 60 DEG C dissolve by heating, and add 2mL dimethyl sulfoxide, 60 DEG C of heating stirring 5min.
10mL dimethyl sulfoxide (DMSO) is added in 2.4mmol compounds 2, oil bath heating dissolves compound 2 to 140 DEG C,
Previously prepared chloroplatinous acid potassium solution is slowly dropped into the solution of compound 2, separates out yellow mercury oxide quickly, continues return stirring
1.5h, make reaction complete, filter while hot, remove unreacted part and potassium chloroplatinite, respectively washed with dimethyl sulfoxide, water, ethanol
Wash once, filter while hot, dry, obtain the complex 3 of yellow：2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-
F] [1,10]-phenanthroline dichloro conjunction platinum (II).
(3) preparation of chiral platinum complex：40mL absolute ethyl alcohol, 70 DEG C of reactions 20 are added in 0.6mmol complexs 3
After minute, 8 times mMs of complex 3, i.e. 4.8mmol cyclohexanediamine (compound 4) are added, 70 DEG C are back to fully dissolved,
Insoluble matter is filtered to remove, filtrate is slowly volatilized, and separates out red precipitate, with ethyl alcohol recrystallization, obtains chiral platinum complex：Dichloro
Change -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes platinum
(II) (complex 5) Δ-[Pt (chda) (o-HO-p-MOPIP)]2+, its structural formula is shown in Fig. 1.
2nd, the examination and test of products：
Product carries out structure determination by electrospray ionization mass spectrum, nuclear magnetic resoance spectrum, infrared spectrum and elementary analysis, determines target
Complex is Δ-[Pt (chda) (o-HO-p-MOPIP)]2+：C26H28PtN6O2, specific spectral characteristic is as follows：
Δ-Pt nuclear magnetic resoance spectrums：1H NMR(400MHz,DMSO)δ8.97(d,1H),8.83(s,1H),8.20(d,1H),
7.87(d,1H),7.31(s,1H),6.56–6.41(m,3H),3.95(s,1H),3.81(s,3H),2.15(d,2H),1.55
(d,3H),1.20(s,2H).
Δ-Pt electrospray ionization mass spectrums：m/z 651.02[M-2Cl-H]+。
Elementary analysis C26H26PtN6O2Measured value (calculated value)/%：C 48.08(48.06)；H 4.12(4.03)；N
12.90(12.94)；
Accordingly, it can be determined that above-mentioned red precipitate be dichloride -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,
5-f] [1,10]-phenanthroline S, S- cyclohexanediamine conjunction platinum (II) complex.
3rd, properties of product detection method：
In order to absolutely prove dichloride -2- of the present invention [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,
5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes purposes of platinum (II) complex in pharmacy, applicant using cis-platinum as
Positive control, external inhibitory activity experiment is carried out to a variety of human tumor cell lines to the complex of the gained of embodiment 1.
(1) Δ-Pt and cis-platinum are made into 2.0 × 10 respectively with dimethyl sulfoxide (DMSO) (DMSO)-3Mol/L storing solution, buffering
Solution (pH=7.35) is 0.1molL-1Trishydroxymethylaminomethane-hydrochloric acid (Tris-HCl), MTT reagents (3- (4,5-
Dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides) concentration be 5mg/mL.
(2) BEL -7404 (human liver cancer cell), HepG2 (human liver cancer cell), NCI-H460 (human lung carcinoma cell), T -24
(transitional cell bladder carcinoma cell line), MGC -803 (gastric carcinoma cells) and A549 (human lung adenocarcinoma cell) cell line are placed in 37 DEG C, 5%CO2Fill
In incubator under the conditions of point humidifying, it is inoculated in the PPMI1640 nutrient solutions containing 10% inactivation NBCS and cultivates.
(3) all compounds are configured to 10 μ g/mL, cosolvent DMSO final concentrations are no more than 1%, test each under the concentration
Inhibiting rate of the compound to cancer cell.
(4) cell in exponential phase is taken, per the μ L of hole 180 (about 4500-5000 cell) celliferous culture medium
96 well culture plates are inoculated in, in 37 DEG C, 5%CO224h is cultivated under the conditions of abundant humidifying.
(5) after cell attachment, sample is added by every μ L of hole 20 amount, each sample sets 6 multiple holes, concurrently sets corresponding
Blank control.
(6) continue after cultivating 48h, 10 μ L MTT reagents (concentration 5mg/mL) are added per hole, continue after being incubated 4h, suction is abandoned
Supernatant, 150 μ L DMSO are added per hole, slight concussion reaction 5-8min, crystalline particle is fully dissolved.
(7) blank control group is returned to zero, and the absorbance after removing background absorbance value is determined with 490nm wavelength with ELIASA
(Value), calculate cell proliferation inhibition rate.The inhibiting rate of compound can be calculated according to formula：Inhibiting rate=(1- dosing group OD values/
Control group OD values) × 100%.
(8) all experiments are averaged after being repeated 3 times.Δ-Pt of the invention is obtained with it to six kinds of human tumor cells
Inhibiting rate as shown in Figure 3 and Table 1.
The mtt assay of table 1 analyzes the inhibiting rate (%) of complex and cis-platinum to various kinds of cell
From Fig. 3 and table 1, the product Δ-Pt obtained by the embodiment of the present invention 1, to six kinds of equal tables of human tumor cell line
Reveal significant anti tumor activity in vitro, its inhibiting rate is respectively between 39.87 to 84.81.Platinum medicine cis-platinum is used with clinic
Compare, Δ-Pt is to BEL -7404 (human liver cancer cell), NCI-H460 (human lung carcinoma cell) and MGC -803 (gastric carcinoma cells) three
Kind cell line, shows the in-vitro multiplication inhibitory activity higher than cis-platinum.
Embodiment 2
First, preparation method of the invention：
(1) preparation of compound 2：Weigh 2mol phenanthroline -5,6- diketone (compound 1) and 4mol 2- hydroxyls -
4-methoxybenzaldehyde, glacial acetic acid 20mL and ammonium acetate 3.6g is added, under 130 DEG C of oil baths, 7h is heated to reflux, is cooled to room
Temperature；Under condition of ice bath, stirring, 20mL concentrated ammonia liquors (25-28%) are slowly added dropwise to neutrality, obtain yellow mercury oxide (compound
2)；
(2) preparation of complex 3：Previously prepared chloroplatinous acid potassium solution, in 2.4mmol potassium chloroplatinites, adds water
1mL, 50 DEG C dissolve by heating, and add 3mL dimethyl sulfoxide, 50 DEG C of heating stirring 10min.
12mL dimethyl sulfoxide (DMSO) is added in 2.4mmol compounds 2, oil bath heating dissolves compound 2 to 150 DEG C,
Previously prepared chloroplatinous acid potassium solution is slowly dropped into the solution of compound 2, separates out yellow mercury oxide quickly, continues return stirring
2h, make reaction complete, filter while hot, remove unreacted part and potassium chloroplatinite, respectively washed with dimethyl sulfoxide, water, ethanol
Once, filter, dry while hot, obtain the complex 3 of yellow.
(3) preparation of chiral platinum complex：50mL absolute ethyl alcohol, 80 DEG C of reactions 30 are added in 0.6mmol complexs 3
After minute, 7 times mMs of complex 3 are added, i.e. (compound 4) of 4.2mmol, 80 DEG C are back to fully dissolved, are filtered to remove
Insoluble matter, filtrate are slowly volatilized, and separate out red precipitate, with ethyl alcohol recrystallization, obtain product, chiral platinum complex：Dichloride -2-
[2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes platinum (II)
Complex (complex 5) Δ-[Pt (chda) (o-HO-p-MOPIP)]2+。
2nd, properties of product detection method：
In order to absolutely prove chirality -2- of the present invention [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-
F] [1,10]-phenanthroline-purposes of the cyclohexanediamine platinum complex in pharmacy, applicant is using cis-platinum as positive control, to reality
The complex for applying the gained of example 1 has carried out external inhibitory activity experiment to a variety of human tumor cell lines.
(1) Δ-Pt and cis-platinum are made into 2.0 × 10 respectively with dimethyl sulfoxide (DMSO) (DMSO)-3Mol/L storing solution, buffering
Solution (pH=7.35) is 0.1molL-1Trishydroxymethylaminomethane-hydrochloric acid (Tris-HCl), MTT reagents (3- (4,5-
Dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides) concentration be 5mg/mL.
(2) BEL -7404 (human liver cancer cell), HepG2 (human liver cancer cell), NCI-H460 (human lung carcinoma cell), T -24
(transitional cell bladder carcinoma cell line), MGC -803 (gastric carcinoma cells) and A549 (human lung adenocarcinoma cell) cell line are placed in 37 DEG C, 5%CO2Fill
In incubator under the conditions of point humidifying, it is inoculated in the PPMI1640 nutrient solutions containing 10% inactivation NBCS and cultivates.
(3) all compounds are configured to 10 μ g/mL, cosolvent DMSO final concentrations are no more than 1%, test each under the concentration
Inhibiting rate of the compound to cancer cell.
(4) cell in exponential phase is taken, per the μ L of hole 180 (about 4500-5000 cell) celliferous culture medium
96 well culture plates are inoculated in, in 37 DEG C, 5%CO224h is cultivated under the conditions of abundant humidifying.
(5) after cell attachment, sample is added by every μ L of hole 20 amount, each sample sets 6 multiple holes, concurrently sets corresponding
Blank control.
(6) continue after cultivating 48h, 10 μ L MTT reagents (concentration 5mg/mL) are added per hole, continue after being incubated 4h, suction is abandoned
Supernatant, 150 μ L DMSO are added per hole, slight concussion reaction 5-8min, crystalline particle is fully dissolved.
All experiments are averaged after being repeated 3 times.The test-compound good to primary dcreening operation antitumous effect, continue with 5
Concentration gradient is the IC of corresponding cell line50Value, obtain the Δ-Pt and its IC to six kinds of human tumor cells of the present invention50Value is as schemed
4 and table 2 shown in.
The mtt assay of table 2 analyzes the cytotoxicity of complex and cis-platinum to six kinds of man―machine systems
From the point of view of in-vitro multiplication inhibitory activity test result, the product Δ-Pt obtained by the embodiment of the present invention 1, to six kinds
Human tumor cell line shows significant anti tumor activity in vitro, its IC50Value is between 1.91 to 19.59, with clinic platinum
Class drugs Cisplatin is compared, Δ-Pt except to human liver cancer cell HepG2 antitumor activities compared with cis-platinum it is slightly weak in addition to, it is to BEL -7404 (people
Liver cancer cells), NCI-H460 (human lung carcinoma cell), T -24 (transitional cell bladder carcinoma cell line), MGC -803 (gastric carcinoma cells) and A549 (people
Lung adenocarcinoma cell) five kinds of cell lines, the in-vitro multiplication inhibitory activity higher than cis-platinum is shown, wherein, Δ-Pt is to NCI-H460
The activity of (human lung carcinoma cell) is 10 times of cis-platinum.
Data above shows that the product obtained by embodiment 1 of the present invention has very in terms of antineoplastic
Wide application prospect, it is expected to be used for preparing the antineoplastic of liver cancer, lung cancer and stomach cancer.
Embodiment 3
First, preparation method of the invention：
(1) preparation of compound 2：Weigh 2mol phenanthroline -5,6- diketone (compound 1) and 4mol 2- hydroxyls -
4-methoxybenzaldehyde, glacial acetic acid 18mL and ammonium acetate 3.6g is added, under 125 DEG C of oil baths, 5h is heated to reflux, is cooled to room
Temperature；Under condition of ice bath, stirring, 18mL concentrated ammonia liquors (25-28%) are slowly added dropwise to neutrality, obtain yellow mercury oxide (compound
2)；
(2) preparation of complex 3：Previously prepared chloroplatinous acid potassium solution, in 2.4mmol potassium chloroplatinites, adds water
1mL, 55 DEG C dissolve by heating, and add 2.5mL dimethyl sulfoxide, 55 DEG C of heating stirring 8min.
11mL dimethyl sulfoxide (DMSO) is added in 2.4mmol compounds 2, oil bath heating dissolves compound 2 to 145 DEG C,
Previously prepared chloroplatinous acid potassium solution is slowly dropped into the solution of compound 2, separates out yellow mercury oxide quickly, continues return stirring
1.5h, make reaction complete, filter while hot, remove unreacted part and potassium chloroplatinite, respectively washed with dimethyl sulfoxide, water, ethanol
Wash once, filter while hot, dry, obtain the complex 3 of yellow.
(3) preparation of chiral platinum complex：45mL absolute ethyl alcohol, 75 DEG C of reactions 25 are added in 0.6mmol complexs 3
After minute, 6 times mMs of complex 3, i.e. 3.6mmol cyclohexanediamine (compound 4) are added, 75 DEG C are back to fully dissolved,
Insoluble matter is filtered to remove, filtrate is slowly volatilized, and separates out red precipitate, with ethyl alcohol recrystallization, obtains product, chiral platinum complex：
Dichloride -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline S, S- cyclohexanediamine
Close platinum (II) complex (complex 5) Δ-[Pt (chda) (o-HO-p-MOPIP)]2+。
2nd, properties of product detection method：
(1) Λ-Pt and Δ-Pt are made into 2.0 × 10 with 10% dimethyl sulfoxide (DMSO) (DMSO)-3Mol/L solution.
(2) Tris-HCl buffer solutions：Tris 5mmol/L, with HCl titration regulations to pH=7.35, constant volume is in 1L volumetric flasks
In, it is standby.
(3) the serobila DNA of telomere four is made into 2.0 with trishydroxymethylaminomethane-hydrochloric acid (Tris-HCl) cushioning liquid ×
10-4Mol/L solution.
(4) 3mL is added in cuvette, 2.0 × 10-3Mol/L complex solution, gradually adds 1 μ L, and 2.0 × 10- 4The mol/L serobila DNA solution of telomere four.
(5) after each mixed liquor shakes up placement 5min, it is placed on uv-visible absorption spectra instrument and scans, as a result such as
Shown in Fig. 5-6.
From Fig. 5-6, with the increase of htel-1, htel concentration, the UV absorption of Δ-Pt-DNA compound systems subtracts
Few, its red shift and the rate of losing lustre are shown in Table 3.
The bond strength K of Δ-Pt-DNA compound systems and DNAbIt can be determined by following equation：
[DNA]/(εa–εf)=[DNA]/(εb–εf) 1/ [K of ﹢b(εb–εf)]
Herein, εa,εfAnd εbIt is DNA concentration known respectively, is not bonded and has been bonded with compound related to compound
Coefficient, KbIt is compound and DNA binding constants, [DNA] is DNA dense in 0.1mol/L cushioning liquid (pH=7.35)
Degree.By [DNA]/(εA-εf) mapped than [DNA], (ε of slope 1/ can be obtainedb–εf) and [K of intercept 1/b(εb–εf)], slope and cut
Away from the ratio between can be obtained by binding constants Kb, the binding constants of Δ-Pt-DNA compound systems are shown in Table 2.As can be seen here, Δ-Pt-
DNA is inserted among DNA base-pair strongly, and can also be acted on by Groove binding and DNA.
From above-described embodiment, Δ-Pt of the invention has that stability is good, with cancer cell DNA effects it is stronger the characteristics of,
It is expected to be used for preparing the antineoplastic of liver cancer, lung cancer and stomach cancer.
Red (indigo plant) of the compound of table 3 is moved and the rate that loses lustre
| Compound | Blue shift (nm) | The rate that loses lustre (%) | Red shift (nm) | The rate that loses lustre (%) | Blue shift (nm) | The rate that loses lustre (%) | Kb |
| Δ-Pt-Htel-1 | 0 | 24.70 | 1 | 27.45 | 1 | 12.12 | 2.31×106 |
| Δ-Pt-Htel | 0 | 31.00 | 1 | 37.04 | 1 | 25.71 | 1.09×106 |
Embodiment 4
First, preparation method of the invention：
(1) preparation of compound 2：Weigh 2mol phenanthroline -5,6- diketone (compound 1) and 2mol 2- hydroxyls -
4-methoxybenzaldehyde, glacial acetic acid 16mL and ammonium acetate 3.1g is added, under 120 DEG C of oil baths, 6h is heated to reflux, is cooled to room
Temperature；Under condition of ice bath, stirring, 16mL concentrated ammonia liquors (25-28%) are slowly added dropwise to neutrality, obtain yellow mercury oxide (compound
2)；
(2) preparation of complex 3：Previously prepared chloroplatinous acid potassium solution, in 2.4mmol potassium chloroplatinites, adds water
0.8mL, 60 DEG C dissolve by heating, and add 2mL dimethyl sulfoxide, 60 DEG C of heating stirring 5min.
10mL dimethyl sulfoxide (DMSO) is added in 2.4mmol compounds 2, oil bath heating dissolves compound 2 to 140 DEG C,
Previously prepared chloroplatinous acid potassium solution is slowly dropped into the solution of compound 2, separates out yellow mercury oxide quickly, continues return stirring
1.5h, make reaction complete, filter while hot, remove unreacted part and potassium chloroplatinite, respectively washed with dimethyl sulfoxide, water, ethanol
Wash once, filter while hot, dry, obtain the complex 3 of yellow.
(3) preparation of chiral platinum complex：40mL absolute ethyl alcohol, 70 DEG C of reactions 20 are added in 0.6mmol complexs 3
After minute, 8 times mMs of complex 3, i.e. 4.8mmol cyclohexanediamine (compound 4) are added, 70 DEG C are back to fully dissolved,
Insoluble matter is filtered to remove, filtrate is slowly volatilized, and separates out red precipitate, with ethyl alcohol recrystallization, obtains chiral platinum complex：Dichloro
Change -2- [2- (hydroxyl) -4- (methoxyl group)-phenyl] imidazo [4,5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes platinum
(II) complex (complex 5) Δ-[Pt (chda) (o-HO-p-MOPIP)]2+。
2nd, properties of product detection method：
(1) Tris-HCl buffer solutions：Tris 5mmol/L, with HCl titration regulations to pH=7.35, constant volume is in 1L volumetric flasks
In, it is standby.
(2) Λ-Pt and Δ-Pt are made into 2.0 × 10 with 10% dimethyl sulfoxide (DMSO) (DMSO)-3Mol/L solution.
(3) thiazole orange [TO] is made into 1.0 × 10-3Solution, by four kinds of CT-DNA, ds-26, Htel and Htel-1 etc.
G4-DNA is made into 1.0 × 10-4Solution.
(4) 1.0 × 10 are added in cuvette-3Mol/L thiazole orange (TO) 3.0ul, 1.0 × 10-4G4-DNA
7.5ul, 2990ul trishydroxymethylaminomethane-hydrochloric acid (Tris-HCl) cushioning liquid (pH=7.35), gradually add 3uL
Complex solution, complex is gradually stepped up DNA concentration.
(5) shaken up after above-mentioned each mixed liquor being diluted into 5mL with secondary sub-boiling distillation water.Shake up after placing 5min, will
It is placed in scanning (λ on XRFexIt is 501nm, CT-DNA and ds-26 λemFor 526nm, Htel and Htel-1 λem
For 533nm), as a result as shown in Figure 7.
As shown in Figure 7, complex Δ-Pt has very strong combination, Δ-Pt DC from different G-four serobilas DNA50Value exists
Between 0.3-0.6 μm of ol/L, the DC with duplex DNA (ds26) effect50It is worth for 1.0 μm of ol/L.Complex and G-four serobilas DNA
Binding ability is better than duplex DNA.
Claims (7)
- A kind of 1. chiral platinum complex, it is characterised in that：Its structural formula is：；The chiral platinum complex chemical name is：Dichloride -2- [2-（Hydroxyl）-4-（Methoxyl group）- phenyl] imidazo [4,5-f] [1,10]-phenanthroline S, S- cyclohexanediamine closes platinum（Ⅱ）Complex.
- A kind of 2. preparation method of chiral platinum complex as claimed in claim 1, it is characterised in that：Its preparation method includes Following steps：（1）It is 1 by the mol ratio of 1,10- phenanthrolines -5,6- diketone and 2- hydroxyls -4-methoxybenzaldehyde:1 ~ 2 weighs original Material, 8 ~ 10 mL glacial acetic acid is added by every mole of 1,10- phenanthrolines -5,6- diketone, then by 1,10- phenanthrolines -5,6- The mol ratio of diketone and ammonium acetate is 1:25 ~ 30 add ammonium acetate, under 120 ~ 130 DEG C of oil baths, are heated to reflux 5 ~ 7 h, cool down To room temperature；Under condition of ice bath, concentrated ammonia liquor is slowly added dropwise to neutrality in stirring, obtains 2- [2-（Hydroxyl）-4-（Methoxyl group）- phenyl] The yellow mercury oxide of imidazo [4,5-f] [1,10]-phenanthroline；（2）Every mole of 2- [2- are pressed again（Hydroxyl）-4-（Methoxyl group）- phenyl] imidazo [4,5-f] [1,10]-phenanthroline 4 ~ 5 L dimethyl sulfoxide (DMSO) is added in yellow mercury oxide, oil bath heating dissolves yellow mercury oxide to 140 ~ 150 DEG C, obtains Huang Color solution；Chloroplatinous acid potassium solution well prepared in advance is slowly dropped into yellow solution again, yellow mercury oxide is separated out, continues back Stream 1.5 ~ 2 h of stirring, make reaction complete, filter while hot, remove unreacted reactant, wash, filter, drying, obtain the 2- [2- of yellow （Hydroxyl）-4-（Methoxyl group）- phenyl] imidazo [4,5-f] [1,10]-phenanthroline dichloro conjunction platinum（Ⅱ）；（3）Every mole of dichloride -2- [2-（Hydroxyl）-4-（Methoxyl group）- phenyl] imidazo [4,5-f] [the 1,10]-luxuriant and rich with fragrance hello of neighbour Quinoline closes platinum（Ⅱ）60 ~ 70 L of middle addition absolute ethyl alcohol, after reacting 20 ~ 30 minutes at 70 ~ 80 DEG C, add 2- [2-（Hydroxyl）- 4-（Methoxyl group）- phenyl] imidazo [4,5-f] [1,10]-phenanthroline dichloro conjunction platinum（Ⅱ）6 ~ 8 times of mol ratios 1, 2- cyclohexanediamine, fully dissolved being back under constant temperature, is filtered to remove insoluble matter, filtrate is slowly volatilized, and separates out red precipitate, uses ethanol Recrystallization, produces chiral platinum complex.
- 3. the preparation method of chiral platinum complex according to claim 2, it is characterised in that：The step（1）In dense ammonia Water volume fraction is 25-28%.
- 4. the preparation method of chiral platinum complex according to claim 2, it is characterised in that：The step（1）In dense ammonia 8 ~ 10 mL are added dropwise in 1,10- phenanthrolines -5,6- diketone that the addition of water is every mole.
- 5. the preparation method of chiral platinum complex according to claim 2, it is characterised in that：The step（2）Middle chlorine is sub- Potassium platinate is prepared as：Potassium chloroplatinite is first added into water, dissolved by heating at 50 ~ 60 DEG C, then is added by every mole of potassium chloroplatinite 0.8 ~ 1L dimethyl sulfoxide, 5 ~ 10min of heating stirring are i.e. available.
- 6. the preparation method of chiral platinum complex according to claim 2, it is characterised in that：The step（2）Middle chlorine is sub- The amount of water of potassium platinate is in every mole of potassium chloroplatinite plus 300 ~ 400 mL water.
- 7. the application of chiral platinum complex as claimed in claim 1, it is characterised in that：It is preparing anti-liver cancer and anti-, lung cancer and stomach Application in cancer drug.
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| Platinum Phenanthroimidazole Complexes as G-Quadruplex DNA Selective Binders;Roxanne Kieltyka等，;《Chem. Eur. J.》;20071119;第1145-1154页，尤其是第1146页 * |
| Three platinum(II) complexes of 2-(methoxy-phenyl)-imidazo-[4,5-f]-[1,10] phenanthroline:cell apoptosis induction by sub-G1 phase cell cycle arrest and G-quadruplex binding properties;Xu-Jian Luo等，;《Inorganic Chemistry Communications》;20140528;第176-179页，尤其是第177页图1-2、方案S1 * |
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