CN110054652A - A kind of high activity jateorrhizine platinum (II) complex and its synthetic method and application - Google Patents
A kind of high activity jateorrhizine platinum (II) complex and its synthetic method and application Download PDFInfo
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- CN110054652A CN110054652A CN201910495363.XA CN201910495363A CN110054652A CN 110054652 A CN110054652 A CN 110054652A CN 201910495363 A CN201910495363 A CN 201910495363A CN 110054652 A CN110054652 A CN 110054652A
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- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 230000000694 effects Effects 0.000 title claims abstract description 35
- MXTLAHSTUOXGQF-UHFFFAOYSA-O Jatrorrhizine Chemical compound COC1=CC=C2C=C3C(C=C(C(=C4)O)OC)=C4CC[N+]3=CC2=C1OC MXTLAHSTUOXGQF-UHFFFAOYSA-O 0.000 title claims abstract description 34
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000003446 ligand Substances 0.000 claims abstract description 22
- -1 bromo jateorrhizine derivative Chemical class 0.000 claims abstract description 15
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 11
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 10
- 125000003963 dichloro group Chemical group Cl* 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 7
- 239000001103 potassium chloride Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010668 complexation reaction Methods 0.000 claims abstract description 5
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000843 powder Substances 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims abstract description 5
- 239000006227 byproduct Substances 0.000 claims abstract description 3
- 238000001035 drying Methods 0.000 claims abstract description 3
- 238000005406 washing Methods 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 11
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- 230000035484 reaction time Effects 0.000 claims description 2
- 241001597008 Nomeidae Species 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 21
- 229910052697 platinum Inorganic materials 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 230000008685 targeting Effects 0.000 abstract description 3
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- 206010028980 Neoplasm Diseases 0.000 description 23
- 239000000243 solution Substances 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 238000011580 nude mouse model Methods 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 241000699660 Mus musculus Species 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
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- 206010005003 Bladder cancer Diseases 0.000 description 4
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- 235000006508 Nelumbo nucifera Nutrition 0.000 description 4
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 201000005112 urinary bladder cancer Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
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- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229910019032 PtCl2 Inorganic materials 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
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- 230000029087 digestion Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 150000003057 platinum Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
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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 present invention relates to a kind of high activity jateorrhizine platinum (II) complex, synthetic method and the complex application in preparation of anti-tumor drugs.The synthetic method of high activity jateorrhizine platinum (II) complex is the following steps are included: bromo jateorrhizine derivative, potassium chloride and lutidine amine are dissolved in solvent by (1), reaction obtains yellow solid powder at 90 DEG C, is Jat ligand；(2) the Jat ligand of step (1) preparation and dichloro two (dimethyl sulfoxide) are closed into platinum (II), is dissolved in acetonitrile solution, complexation reaction is carried out at 55~65 DEG C；(3) by product washing, drying to get target product.The present invention using novel jateorrhizine derivative Jat as active ligand, synthesizes its platinum complex for the first time, shows superior inside and outside anti-tumor activity and targeting, has potential medical value, is expected to be used for the preparation of various anti-tumor drugs.The structural formula of high activity jateorrhizine platinum (II) complex is as follows:
Description
Technical field
The present invention relates to platinum class high activity complex and synthetic method, in particular to a kind of high activity jateorrhizine platinum (II)
Complex and its synthetic method.The invention further relates to high activity jateorrhizine platinum (II) complex answering in the preparation of antitumor drugs
With.
Background technique
According to incompletely statistics, cancer per year over six million peoples is died of in the whole world at present.Cancer have become seriously affect and
Threaten one of common disease and the frequently-occurring disease of human health (Guo, Z.；et al.Chem.Soc.Rev.,2013,42:202–
224.).For treating cancer, scientific worker has carried out unremitting effort, has synthesized many classical cis-platinums and its derivative etc.
Platinum-containing anticancer drug；But these are easy to produce drug resistance, toxicity height, poorly water-soluble, system along platinum medicine in use
About their curative effect and use.Therefore, novel low toxicity is developed, high efficiency anti-tumor drug is still the heat studied now
Point.
For the resource current from Guangxi, Longzhou, Nanning, Jin Xiu tinosporae be the main plant of jateorrhizine alkaloid
One of object source, jateorrhizine have treatment inflammation, bacterium and virus infection, diabetes, cardiovascular disease, mental disease and resist swollen
Tumor etc. is many-sided to have drug action.From the point of view of current report, the metal complex reported using jateorrhizine as ligand there have been no.
A kind of using jateorrhizine as ligand, the platinum medicine higher than clinical medicine cisplatin active is developed, and anti-to their inside and outside
Tumor promotion and its application carry out research and are of great significance.
Summary of the invention
The first purpose of the invention is to provide a kind of high activity jateorrhizine platinum (II) complexs.
First purpose to realize the present invention, the present invention provides technical solutions below:
A kind of high activity jateorrhizine platinum (II) complex has the following general formula I:
Wherein, m=5 or 7.
A second object of the present invention is to provide a kind of synthetic methods of high activity jateorrhizine platinum (II) complex.
Second purpose to realize the present invention, the present invention provides technical solutions below:
A kind of synthetic method of high activity jateorrhizine platinum (II) complex, comprising the following steps:
(1) bromo jateorrhizine derivative, potassium chloride and lutidine amine are dissolved in solvent, are reacted at 90 DEG C
It is Jat ligand to yellow solid powder；
(2) the Jat ligand of step (1) preparation and dichloro two (dimethyl sulfoxide) are closed into platinum (II), it is molten is dissolved in acetonitrile
In liquid, complexation reaction is carried out at 55~65 DEG C；
(3) by product washing, drying to get target product.
Further, in the step (1), the object of the bromo jateorrhizine derivative, potassium chloride and lutidine amine
The ratio between amount of matter is 1:0.5~0.8:1.5.
Further, solvent is acetonitrile in the step (1).
Further, every 1mol bromo jateorrhizine derivative uses the acetonitrile solution of 4~6mL.
Further, in the step (2) Jat ligand and dichloro two (dimethyl sulfoxide) close platinum (II) substance amount
The ratio between be 1:1.
Further, in the step (1), the reaction time is 3~5 hours.
Further, in the step (2), the dosage of acetonitrile is 5~90mL.
Further, in the step (2), the time of reaction is 3~6h.
Third object of the present invention is to provide a kind of high activity jateorrhizine platinum (II) complex and is preparing antineoplastic
Application in object.
Compared with prior art, the invention has the benefit that
1. the present invention synthesizes its platinum complex [Pt for the first time using novel jateorrhizine derivative Jat as active ligand
(Jat) (TFA-H) Cl] Cl (wherein TFA is trifluoroacetic acid), and also synthetic route is simple, reaction condition is mild, at 55~90 DEG C
Under conditions of reaction can be completed.
2. the present invention has investigated jateorrhizine platinum (II) complex to HeLa, T-24, SK-OV-3/DDP, A549 tumour cell
With the activity and toxicity test of normal HL-7702 cell, experimental result finds that the new complexes have very well human tumor cells
Inhibiting effect, IC50Value is 8.00nM-10.57 μM；It is especially preferable to the inhibiting effect of human cervical carcinoma cell HeLa,
IC50Value is respectively 55.03 ± 1.01nM and 8.00 ± 0.17nM, and anti tumor activity in vitro is far longer than the metal of the classic and clinical
Base anticancer drug cis-platinum (13.42 ± 0.74 μM)；In addition, toxicity very little (IC of the complex to normal cell HL-770250> 150
μM), embody the proliferation of good targeted inhibition human tumor cells.
3. high activity jateorrhizine platinum (II) complex of the invention, shows in the tumor inhibition of tumor bearing nude mice, to people
Cervical cancer cell HeLa nude mice model has good tumor killing effect, inhibiting rate 48.8%, significantly larger than clinical medicine cis-platinum
35.5%.
4. high activity jateorrhizine platinum (II) complex of the invention shows superior inside and outside anti-tumor activity and targeting
Property, there is potential medical value, be expected to be used for the preparation of various anti-tumor drugs.
Detailed description of the invention
Specific embodiment in reference to the accompanying drawing is described in further detail technical solution of the present invention, but not structure
At any limitation of the invention.
Fig. 1 is the electrospray ionization mass spectrum figure of Jat1 made from the embodiment of the present invention 1；
Fig. 2 is Jat1 hydrogen nuclear magnetic resonance spectrogram made from the embodiment of the present invention 1；
Fig. 3 is Jat1 Enantiomeric excess figure made from the embodiment of the present invention 1；
Fig. 4 is the electrospray ionization mass spectrum figure of Jat2 made from the embodiment of the present invention 2；
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of Jat2 made from the embodiment of the present invention 2；
Fig. 6 is the Enantiomeric excess figure of Jat2 made from the embodiment of the present invention 2；
Fig. 7 is the electrospray ionization mass spectrum figure of complex Pt1 made from the embodiment of the present invention 1；
Fig. 8 is the hydrogen nuclear magnetic resonance spectrogram of Pt1 made from the embodiment of the present invention 1；
Fig. 9 is the carbon-13 nmr spectra figure of Pt1 made from the embodiment of the present invention 1；
Figure 10 is Pt1 Enantiomeric excess figure made from the embodiment of the present invention 1；
Figure 11 is the electrospray ionization mass spectrum figure of complex Pt2 made from the embodiment of the present invention 2；
Figure 12 is the hydrogen nuclear magnetic resonance spectrogram of Pt2 made from the embodiment of the present invention 2；
Figure 13 is the carbon-13 nmr spectra figure of Pt2 made from the embodiment of the present invention 2；
Figure 14 is Pt2 Enantiomeric excess figure made from the embodiment of the present invention 2.
Specific embodiment
Existing literature (Song, D. are examined in 1 and 2 reference of raw material bromo jateorrhizine derivative involved in the embodiment of the present invention；et
Al.Eur.J.Med.Chem., 2018,143:1858-1868.) it is prepared；In addition, dichloro two (dimethyl sulfoxide) closes platinum
(II) existing literature (Al-Allaf, T.A.K. be can refer to；et al.Transit.Met.Chem.,1998,23:403-406.)
It is prepared, is abbreviated as cis-PtCl2(DMSO)2。
The structural formula of bromo jateorrhizine derivative 1 and 2 is as follows:
It wherein, is derivative 1 when m=5, the ligand of synthesis is Jat1, complex Pt1；It is derivative 2 when m=7,
The ligand of synthesis is Jat2, complex Pt2.
Embodiment 1
In the round-bottomed flask of 50mL, the derivative 1 and 0.8mol potassium chloride, 1.50mol diformazan of 1.0mol are weighed respectively
Yl pyridines amine is dissolved in containing in 5.0 milliliters of acetonitrile solutions, after reacting 4 hours at 90 DEG C, obtains yellow solid powder Jat1
Ligand, yield 86.0%.Reaction temperature is 90 DEG C, and temperature is higher than 90 DEG C of product sticky ends and carbochain chain rupture occurs, and temperature is lower than
90 DEG C, which hardly happens.
Two (the dimethyl of dichloro of 1.0mol ligand Jat1 with the amount of equal substances are weighed in the high voltage bottle of 100.0mL
Sulfoxide) close platinum (II), be dissolved in 10.0mL acetonitrile solution, at 60 DEG C carry out complexation reaction 4.0h, after being washed with acetonitrile
It is dried in vacuo at a temperature of 40 DEG C to get the target product Pt1 of yellowish-brown is arrived.Yield is 95.3%.
Embodiment 2
In the round-bottomed flask of 50mL, the derivative 2 and 0.8mol potassium chloride, 1.50mol diformazan of 1.0mol are weighed respectively
Yl pyridines amine is dissolved in containing in 5.0 milliliters of acetonitrile solutions, after reacting 4 hours at 90 DEG C, obtains yellow solid powder Jat2
Ligand, yield 81.0%.
Two (the dimethyl of dichloro of 1.0mol ligand Jat2 with the amount of equal substances are weighed in the high voltage bottle of 100.0mL
Sulfoxide) platinum (II) is closed, it is dissolved in 5.0mL acetonitrile solution, complexation reaction 4.0h is carried out at 60 DEG C, 40 after being washed with acetonitrile
It is dried in vacuo at a temperature of DEG C to get the target product Pt2 of yellowish-brown is arrived.Yield is 90.8%.
Embodiment 3
Difference from example 1 is that weighing 1.0mol ligand Jat1 and equal objects in the high voltage bottle of 100.0mL
The dichloro two (dimethyl sulfoxide) of the amount of matter closes platinum (II), is dissolved in 90.0mL acetonitrile solution, is coordinated at 60 DEG C
React 4.0h, after being washed with acetonitrile 40 DEG C at a temperature of be dried in vacuo to get arrive yellowish-brown target product Pt1.Yield is
70.5%.
Embodiment 4
The difference is that, 1.0mol ligand Jat2 and equal objects are weighed in the high voltage bottle of 100.0mL with embodiment 2
The dichloro two (dimethyl sulfoxide) of the amount of matter closes platinum (II), is dissolved in 30.0mL acetonitrile solution, is coordinated at 60 DEG C
React 4.0h, after being washed with acetonitrile 40 DEG C at a temperature of be dried in vacuo to get arrive yellowish-brown target product Pt2.Yield is
85.1%.
Experimental example 1
To further determine that whether Jat1, Jat2, Pt1 and Pt2 are target compound, to the structure of Examples 1 to 2 product
It is characterized.
1. a couple gained Jat1 is identified
(1) electrospray ionization mass spectrum, spectrogram are as shown in Figure 1.
ESI-MS m/z:604.8[M-(TFA-H)]+, wherein M is the molecular weight of compound Jat1.
(2) hydrogen nuclear magnetic resonance spectrogram, as shown in Figure 2.
1H NMR(400MHz,CH3OH-d4) δ 9.78 (s, 1H), 8.82 (s, 1H), 8.69 (d, J=4.8Hz, 2H),
8.18-8.12 (m, 1H), 8.03 (d, J=9.1Hz, 1H), 7.93 (dt, J=1.6,7.7Hz, 2H), 7.69 (s, 1H), 7.53
(d, J=7.8Hz, 2H), 7.48 (dd, J=5.2,7.3Hz, 2H), 7.05 (s, 1H), 4.95 (br t, J=6.3Hz, 2H),
4.63 (s, 4H), 4.23 (s, 3H), 4.15-4.09 (m, 5H), 4.02 (s, 3H), 3.33 (br s, 2H), 3.29 (s, 2H),
1.92-1.81 (m, 4H), 1.59-1.49 (m, 2H), 1.38 (br s, 8H).
(3) Enantiomeric excess figure, as shown in Figure 3.
19F NMR(471MHz,CHCl3-d)δ-77.316。
(4) elemental analysis is as a result, as shown in table 1.
The elemental analysis result of compound Jat1 and Jat2 in 1 embodiment of table
Hence, it can be determined that gained yellow target product is compound Jat1, structural formula is as follows:
2. a couple gained Jat2 is identified:
(1) electrospray ionization mass spectrum, spectrogram are as shown in Figure 4.
ESI-MS m/z:632.8[M-(TFA-H)]+, wherein M is the molecular weight of compound Jat2.
(2) hydrogen nuclear magnetic resonance spectrogram, as shown in Figure 5.
1H NMR(400MHz,CH3OH-d4) δ 9.78 (s, 1H), 8.82 (s, 1H), 8.69 (br s, 2H), 8.14 (d, J=
9.1Hz, 1H), 8.04 (d, J=9.1Hz, 1H), 7.93 (t, J=1.6Hz, 2H), 7.69 (s, 1H), 7.54 (s, 2H), 7.48
(br t, J=2.9Hz, 2H), 7.05 (s, 1H), 4.95 (br t, J=6.3Hz, 2H), 4.64 (s, 4H), 4.23 (s, 3H),
4.15-4.10 (m, 5H), 4.01 (s, 3H), 3.34 (br s, 2H), 3.29-3.27 (m, 2H), 1.87 (br d, J=6.5Hz,
2H), 1.79-1.72 (m, 2H), 1.58-1.52 (m, 2H), 1.44 (br s, 1H), 1.39-1.37 (m, 2H).
(3) Enantiomeric excess figure, as shown in Figure 6.
19F NMR(471MHz,CHCl3-d)δ-77.316。
(4) elemental analysis is as a result, as shown in table 1.
Hence, it can be determined that gained yellow target product is compound Jat2, structural formula is as follows:
3. a couple gained Pt1 is identified
(1) electrospray ionization mass spectrum, spectrogram are as shown in Figure 7.
ESI-MS m/z:947.7[M-Cl]+, wherein M is the molecular weight of compound Pt1.
(2) hydrogen nuclear magnetic resonance spectrogram, as shown in Figure 8.
1H NMR(500MHz,DMSO-d6) δ 9.89 (s, 1H), 9.04 (s, 1H), 8.83-8.73 (m, 2H), 8.28 (td, J
=7.8,1.6Hz, 2H), 8.21 (d, J=9.2Hz, 1H), 8.04 (d, J=9.1Hz, 1H), 7.84-7.77 (m, 2H), 7.69
(s, 1H), 7.66 (tt, J=5.6,1.0Hz, 2H), 7.00 (s, 1H), 5.34 (d, J=15.9Hz, 2H), 4.94 (t, J=
6.3Hz, 2H), 4.85 (d, J=15.9Hz, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 3.93 (t, J=6.3Hz, 2H), 3.90
(s, 3H), 3.20 (t, J=6.4Hz, 2H), 3.13-3.01 (m, 2H), 1.66-1.53 (m, 4H), 1.36 (p, J=7.3,
6.8Hz,2H)。
(2) carbon-13 nmr spectra figure, as shown in Figure 9.
13C NMR(126MHz,DMSO-d6) δ 166.29,161.49,158.82,158.55,158.29,158.02,
151.18,150.71,149.51,149.23,145.93,144.10,141.79,138.17,133.57,129.03,127.27,
125.83,123.92,121.82,120.62,120.34,119.36,118.26,115.90,113.53,112.54,109.33,
68.59,68.34,64.50,62.38,57.52,56.60,55.85,40.50,40.34,40.17,40.00,39.84,
39.67,39.50,28.64,27.14,26.40,23.01.
(3) Enantiomeric excess figure, as shown in Figure 10.
19F NMR(471MHz,DMSO-d6)δ-74.03。
(4) elemental analysis is as a result, as shown in table 2.
The elemental analysis result of complex Pt1 and Pt2 in 2 embodiment of table
Hence, it can be determined that gained yellow target product is complex Pt1, structural formula is as follows:
4. a couple gained Pt2 is identified
(1) electrospray ionization mass spectrum, spectrogram are as shown in figure 11.
ESI-MS m/z:975.9[M-(TFA-H)]+, wherein M is the molecular weight of compound Pt2.
(2) hydrogen nuclear magnetic resonance spectrogram, as shown in figure 12.
1H NMR(500MHz,DMSO-d6) δ 9.89 (s, 1H), 9.06 (s, 1H), 8.81-8.78 (m, 2H), 8.31-8.28
(m, 2H), 8.20 (d, J=9.3Hz, 1H), 8.05 (d, J=9.1Hz, 1H), 7.83-7.80 (m, 2H), 7.71 (s, 1H),
7.66 (td, J=5.4,4.6,2.4Hz, 2H), 7.04 (s, 1H), 5.34 (t, J=7.9Hz, 2H), 4.95 (t, J=6.4Hz,
2H), 4.87-4.82 (m, 2H), 4.11 (s, 3H), 4.08 (s, 3H), 3.98 (t, J=6.5Hz, 2H), 3.93 (s, 3H), 3.21
(t, J=6.4Hz, 2H), 3.05-3.00 (m, 2H), 1.66 (p, J=6.6Hz, 2H), 1.54-1.48 (m, 2H), 1.26-1.15
(m,6H)。
(2) carbon-13 nmr spectra figure, as shown in figure 13.
13C NMR(126MHz,DMSO-d6) δ 166.34,161.56,158.82,158.56,158.30,158.04,
151.33,150.69,149.49,149.23,145.90,144.08,141.80,138.18,133.59,129.05,127.23,
125.83,123.90,121.82,120.78,120.34,119.27,118.42,116.05,113.68,112.52,109.36,
68.79,68.35,64.67,62.37,57.51,56.66,55.85,40.51,40.34,40.17,40.01,39.84,
39.67,39.51,32.70,32.14,28.90,28.09,26.08,25.72.
(3) Enantiomeric excess figure, as shown in figure 14.
19F NMR(471MHz,DMSO-d6)δ-73.93。
(4) elemental analysis is as a result, as shown in table 2.
Hence, it can be determined that gained yellow target product is complex Pt2, structural formula is as follows:
Experimental example 2
In order to absolutely prove high activity jateorrhizine platinum (II) complex Pt1 and Pt2 of the present invention prepare it is antitumor
Purposes in drug has carried out the experiment of inside and outside anti-tumor activity to the Pt1 and Pt2 of Examples 1 to 2.
One, platinum (II) complex Pt1 and Pt2 tests the proliferation inhibition activity of a variety of human tumor cell lines
1, cell strain and cell culture
HeLa Cells, human ovarian cancer cisplatin resistance SK-OV-3/DDP cell, human bladder cancer T- are selected in this experiment
5 kinds of human cell's strains such as 24 cells, human bladder cancer A549 cell and people's normal hepatocytes HL-7702 cell.
All human archeocyte strains are cultivated in penicillin containing 100U/mL, 10wt% small ox blood, 100U/mL streptomysin
In RPMI-1640 culture solution, 37 DEG C of 5%CO containing volumetric concentration are set2It is cultivated in incubator.
2, the preparation of untested compound
The purity of ligand Jat1, Jat2, Pt1 and Pt2 used are both needed to >=95%, their DMSO liquid storage physiology is delayed
Fliud flushing is diluted to the whole solution (final concentration≤1% of DMSO) of 20 μm of ol/L, tests under the concentration each compound to normal thin
The inhibition level of born of the same parents or selected growth of tumour cell.
3, cell growth inhibition test (mtt assay)
(1) normal cell or tumour cell of logarithmic growth phase, after trypsin digestion, with containing 10% calf serum
Culture solution be configured to concentration be 5000/mL cell suspension, be inoculated in 96 well culture plates, made to be measured with every 190 μ L of hole
Cell density is to 1000~10000 holes (the sterile PBS of edge hole is filled).
(2) 5%CO2, 37 DEG C are incubated for for 24 hours, until cell monolayer is paved with bottom hole, the drug 10 of a certain concentration gradient is added in every hole
μ L, each concentration gradient set 4 multiple holes.
(3) 5%CO2, 37 DEG C are incubated for 48 hours, observe under inverted microscope.
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added in every hole, continues to cultivate 4h.
(5) culture is terminated, culture solution in hole is carefully sucked, the DMSO that 150 μ L are added in every hole sufficiently dissolves first a ceremonial jade-ladle, used in libation precipitating, vibration
It swings after device mixes, with wavelength is 570nm in microplate reader, reference wavelength is the OD value that 450nm measures each hole.
(6) it is arranged zeroing hole (culture medium, MTT, DMSO) simultaneously, control wells (cell, culture solution, MTT, same concentrations
Drug dissolving medium, DMSO).
(7) according to the OD value (OD value) measured, to judge living cells quantity, OD value is bigger, and cell activity is stronger.Benefit
With formula:
The inhibiting rate that each compound grows selected cell is calculated, then each test-compound is calculated separately with Bliss method
To the IC of selected each cell strain50Value.Its result is as shown in the following Table 3.
IC of 3 compound of table to various cell strains50It is worth (μM)
From IC50From the point of view of active ingredients result, complex Pt1 and Pt2 is to 4 kinds of tested human tumor cell line (HeLa, SK-
OV-3/DDP, T-24 and A549 cell) proliferation inhibition activity be apparently higher than metal salt cis-Pt (DMSO)2Cl2, TFA and its match
Body Jat1 and Jat2, embody the synergistic effect of ligand Jat1 and Jat2 Yu platinum central atom.Wherein, complex Pt1 and Pt2 pairs
The inhibiting effect of HeLa Cells is preferable, IC50Value is respectively 55.03 ± 1.01nM and 8.00 ± 0.17nM, body
Outer anti-tumor activity is far longer than the Metal Substrate anticancer drug cis-platinum (13.50 ± 1.18 μM) of the classic and clinical；In addition, complex
Toxicity very little (IC of the Pt1 and Pt2 to normal cell HL-770250150 μM of value >), embody good targeted inhibition cancer cell
Proliferation.In short, complex Pt1 and Pt2 show superior anti tumor activity in vitro and targeting selectivity, there is potential medicine
With value, it is expected to be used for the preparation of various anti-tumor drugs.
Two, the tumor inhibition of tumor bearing nude mice
(1) animal requires:
Strain: BALB/c-nu；Grade: SPF grades；Week old: 5-6w；Weight: 18-20g；Gender: male.
(2) animal origin source:
Beijing HFK Bio-Technology Co., Ltd., credit number: SCXK (capital) 2014-0004.
(3) place of zoopery:
Institute of Radiation Medicine, Chinese Academy of Medical Sciences (Tianjin), experimental unit are numbered using licensing: SYXK (saliva)
2014-0002。
(4) requirement of feeding environment:
SPF grades, IVC independent ventilation systems；Temperature (26 ± 2 DEG C) and humidity (40-70%) are kept constant, turns on light, turn off the light
Each 12h.
(5) feed:
SPF MOUSE REPRODUCTION feed is selected, is pulled together feed corporation,Ltd purchased from Beijing Australia, section.
(6) main agents and instrument that experiment is used:
Reagent: DMSO, 0.9% physiological saline, 75% medicinal alcohol, 4% paraformaldehyde；Instrument: surgical scissors, tweezers,
Trochar, electronic vernier caliper.
(7) basic process and operation tested
1. cell strain and cell culture
HeLa Cells, human ovarian cancer cisplatin resistance SK-OV-3/DDP cell, human bladder cancer T- are selected in this experiment
5 kinds of human cell's strains such as 24 cells, human bladder cancer A549 cell and people's normal hepatocytes HL-7702 cell.
All human archeocyte strains are cultivated in penicillin containing 100U/mL, 10wt% small ox blood, 100U/mL streptomysin
In RPMI-1640 culture solution, 37 DEG C of 5%CO containing volumetric concentration are set2It is cultivated in incubator.
2. the preparation of lotus HeLa Xenografts in nude mice model
The HeLa cell for being in logarithmic growth phase is collected, with serum free medium cell modulation at 5 × 107A/mL is living thin
Born of the same parents' concentration suspension.0.2mL suspension is extracted with 1.0mL syringe, containing about 1 × 107Then a living cells is inoculated in nude mouse right axillary
Nest is subcutaneous, long to about 1cm to subcutaneous tumor3When, as the knurl source of subcutaneous transplantation knurl model production, passed on nude mouse.
HeLa passed for 4 generations after its growth is stablized with nude mice, chose that tumour growth is vigorous and mice with tumor without ulceration, at dislocation of cervical vertebra
Extremely, animal skin is sterilized with 75% medicinal alcohol, cutd open from tissue block, removed downright bad part, tumor tissue is cut into 1.5mm3Left and right
It is subcutaneous to be inoculated in nude mice right axillary nest with trochar for fritter.With electronics vernier caliper measurement transplantable tumor knurl footpath, to tumor volume growth
To 100-300mm3When, animal is grouped at random.
3. effect experiment
Lotus HeLa tumor nude mouse is randomly divided into blank group, dosing group and cis-platinum positive controls, every group of 7 animals.In point
The group same day starts intraperitoneal injection, is administered within dosing group every two days, cis-platinum is administered every other day.It was surveyed every three days with electronic vernier caliper
Knurl footpath weighs sb..It is put to death in dislocation of cervical vertebra in the 13rd day, cuts open from tumour, weighs, takes pictures, calculates tumour inhibiting rate.
Gross tumor volume calculation formula: V=a × b2/ 2, wherein a is major diameter, and b is minor axis.
Relative tumour volume RTV=Vt/V0, wherein VtVolume when to measure every time, V0Volume when to be grouped.
Relative tumor appreciation rate T/C%=(TRTV/CRTV) × 100%.
Inhibition rate of tumor growth (%)=(solvent group average knurl weight-treatment group's average knurl weight)/solvent group group average knurl weight
× 100%.
From the point of view of the tumor inhibition result shown in the upper table 4, this paper complex Pt2 has lotus people HeLa tumor nude mice
Having preferable proliferation inhibition rate is 58.5%, considerably beyond the tumour inhibiting rate (35.2%) of clinical chemotherapy drugs Cisplatin.
Internal tumor suppression result of the 4. complex Pt2 of table to lotus people HeLa nude mice
In conclusion jateorrhizine platinum (II) the complex Pt1 and Pt2 of two kinds of high activities of the present invention show it is excellent
In vitro and in vivo anti-tumor activity and good cytotoxic selectivity, show the present invention be synthesized new antitumoral
The mentality of designing and synthetic method of platinum complex are practicable.Jateorrhizine derivative platinum (II) complex of two kinds of high activities
The anti-tumor activity that Pt1 and Pt2 are shown makes it have good potential medical value, is expected to be used for various antineoplastics
The preparation of object.
The above is some embodiments of the invention, is not restricted to the present invention.It will be understood by those skilled in the art that
The several improvements and modifications made without departing from the principle of the present invention, also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of high activity jateorrhizine platinum (II) complex has the following general formula:
Wherein, m=5 or 7.
2. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 1, which is characterized in that including following step
It is rapid:
(1) bromo jateorrhizine derivative, potassium chloride and lutidine amine are dissolved in solvent, reaction obtains Huang at 90 DEG C
Color solid powder is Jat ligand；
(2) the Jat ligand of step (1) preparation and dichloro two (dimethyl sulfoxide) are closed into platinum (II), are dissolved in acetonitrile solution,
Complexation reaction is carried out at 55~65 DEG C；
(3) by product washing, drying to get target product.
3. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 2, which is characterized in that the step (1)
In, the ratio between the bromo jateorrhizine derivative, amount of substance of potassium chloride and lutidine amine are 1:0.5~0.8:1.5.
4. the synthetic method of high activity jateorrhizine platinum (II) complex described in Claims 2 or 3, which is characterized in that the step
(1) solvent is acetonitrile in.
5. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 4, which is characterized in that every 1mol bromo medicine
Root alkali derivant uses the acetonitrile solution of 4~6mL.
6. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 2, which is characterized in that the step (2)
It is 1:1 that middle Jat ligand and dichloro two (dimethyl sulfoxide), which close the ratio between the amount of substance of platinum (II),.
7. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 2, which is characterized in that the step (1)
In, the reaction time is 3~5 hours.
8. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 2, which is characterized in that the step (2)
In, the dosage of acetonitrile is 5~90mL.
9. the synthetic method of high activity jateorrhizine platinum (II) complex described in claim 2, which is characterized in that the step (2)
In, the time of reaction is 3~6h.
10. high activity jateorrhizine platinum (II) complex application in preparation of anti-tumor drugs described in claim 1.
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