CN101177435A - Cyanidenon ammino platinum anti-cancer drugs and method for making same - Google Patents
Cyanidenon ammino platinum anti-cancer drugs and method for making same Download PDFInfo
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- CN101177435A CN101177435A CNA2007101794164A CN200710179416A CN101177435A CN 101177435 A CN101177435 A CN 101177435A CN A2007101794164 A CNA2007101794164 A CN A2007101794164A CN 200710179416 A CN200710179416 A CN 200710179416A CN 101177435 A CN101177435 A CN 101177435A
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- luteolin
- ammino platinum
- platinum
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- diiodo
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Abstract
The invention discloses a cyanidenon compound ammino platinum with antitumor activity, belonging to medical technical field. The chemical structure is as follows: the cyanidenon and the platinum type antitumor drug are made into a complex compound by the invention. The invention has the advantages of cooperative antitumor function, lowered side effect of platinum type antitumor drug and avoidance for drug-resistant. The invention also discloses the preparation method for cyanidenon compound ammino platinum type anticancer drug.
Description
Technical field
The present invention relates to medical technical field, it is that a kind of luteolin with anti-tumor activity closes ammino platinum, comprises its preparation method in definite saying.
Background technology
Malignant tumour is one of topmost disease that threatens at present the human life.According to statistics, in the whole world 5,800,000,000 populations in 1996, because of tumour dead have 630 surplus ten thousand people, wherein nearly 60% dies from lung cancer, cancer of the stomach, mammary cancer, colorectal carcinoma, oral carcinoma, liver cancer, cervical cancer, die from tumour person and account for more than 12% of death toll, for being only second to the second largest cause of the death of cardiovascular disorder.In China, cancer also is the second largest cause of the death of population.China human mortality's who announced in 1997 reason, the sample survey result shows, China's the nineties population tumor mortality rate is 124.4610 ten thousand, its percentage that accounts for total cause of the death rises to 17.64% from 12.57% of the seventies, wherein the mortality ratio of cancer of the stomach, liver cancer, lung cancer, these four kinds of cancers of the esophageal carcinoma is 92.06/10 ten thousand, accounts for 73.97% of whole cancer mortalities.This year, along with the deterioration of environment and a large amount of uses of hormone, the trend that cancer morbidity more becomes to rise.Therefore, the exploitation cancer therapy drug, the spectrum anticarcinogen that especially can treat the high cancer of the stomach of sickness rate (accounting for cancer general mortality rate 21.76%), liver cancer (17.83%), lung cancer (11.19%), the esophageal carcinoma (15.02%) has good society and economic benefit undoubtedly.
Since it is found that cis-platinum had antitumour activity in 1967, the application of platinum metals cancer therapy drug and research have obtained rapidly development, today, cis-platinum, carboplatin and heptan platinum-containing anticancer drug such as platinum become indispensable medicine in the cancer chemotherapy.In the cancer therapy choice drug of the U.S. and Canada's recommendation, cis-platinum is proposed as choice drug for 18 kinds at esophagus cancer, nonsmall-cell lung cancer etc.Heptan, platinum was the platinum-containing anticancer drug of new generation that pharmaceutical industry Co., Ltd. of Korea S SK registers first, and in granted patent right in 1998, publication number CN1038590C, this patent according to China before 93 years the patent system approval be preparation technology's patent.
The mechanism of action of platinum series antineoplastic medicament, the significant feature target spot is positioned at DNA, can be crosslinked in the DNA chain, interchain linkage, DNA-protein cross by forming, destroy duplicating and suppressing the growth that cell fission etc. is used for suppressing tumour cell of DNA.But there is self inherent shortcoming in this class medicine: toxic side effect is big, can cause pernicious, vomiting, alopecia, bone marrow depression etc., and paper spare exists cross resistance and anticancer spectrum narrow etc. each other.In order to reduce the toxic side effect of this class medicine, be the complex compound (license number be CN1039588C) of leavings group as the complex compound that carries group (license number be CN1039588C), demethyl spot huge legendary turtle acid group or selenate radical and release one after another with the antitumor drug of salicylate for the ylidene ligands (patent publication No. is CN1557822A) of dissociating with diamino or cyclohexanediamine.
Nearly 2 years for the toxic side effect that reduces chemotherapeutics, improve curative effect, reduce tumor recurrence and avoid drug-fast generation, the patent No.: disclose in 200610074209.8 luteolin and platinum compound are made up also appears in the use of uniting of chemotherapeutics in succession.Luteolin belongs to flavonoid compound
That luteolin has is anti-oxidant, antibiotic, anti-inflammatory, anticancer, spasmolysis, eliminate the phlegm, press down the effect of enzyme, diuresis and cholagogic.Utilize these effects successively to use with the platinum-based chemotherapy medicine or work in coordination with to use and obtain effect preferably.
Summary of the invention
(1) technical problem that will solve
Not only toxic side effect is strong for heavy dose of platinum medicine, and is easy to generate resistance.The present invention is subjected to luteolin and platinum series antineoplastic medicament has synergistic enlightenment, only luteolin is being united on the basis of using the treatment tumor disease, luteolin and the synthetic luteolin of a kind of platinum medicine are closed ammino platinum, not only has antineoplastic action, the detoxification that also has the flavonoid medicine, owing to have the toxic side effect that synergy has reduced antitumor drug, avoid drug-fast generation again.
Polar group-the OH of two vicinities among the luteolin phenyl ring B on C3, the C4 is essential for suppressing the tumour enzymic activity; Conjugated double bond between C2 and the C3 causes the B ring and C ring both on same plane, helps near the kinase substrate binding site, and these two kinds of structures are active most important for the luteolin inhibition of cell proliferation.Luteolin mainly by changing the infiltration that the cell signal path suppresses the growth of tumour cell factor or changes kinase activity opposing cancer cells, also can suppress growth of tumour cell by modes such as retardance cell cycles.There is the flavones of hydroxyl that anti-mutagenic activity is all arranged on the phenyl ring, on luteolin phenyl ring A ring and the B ring 2 hydroxyls are arranged respectively, carbonyl on the phenyl ring C ring C4 has vital role (" luteolin Antitumor Effects progress " journal of Zhejiang university, the 5th phase, 2006) to the curative effect that improves chemicotherapy.The present invention is according to these characteristics of luteolin, under the situation of the polar group-OH that keeps inhibitory enzyme activity, utilize the effect of the carbonyl on the phenyl ring C ring C4, inserted platinum ammonia complex with antitumous effect, improve the anticancer property of medicine greatly, reduced the toxic side effect of medicine.
(2) technical scheme
The present invention relates to a kind of luteolin and close ammino platinum medicine with anti-tumor activity.
The present invention relates to the preparation method that a kind of luteolin with anti-tumor activity closes ammino platinum medicine.
Described potassium chloroplatinite can obtain or obtain through commercial sources by technique known is synthetic.
Described luteolin can extract from plants such as Japanese Honeysuckle chrysanthemum and obtain, also can make or obtain or obtain through commercial sources by microbial process by known common synthetic technology, be known about extraction, the synthetic method of luteolin to those of ordinary skills.
The present invention has two kinds of synthesis paths as follows:
(1), closes ammino platinum with the synthetic luteolin of luteolin more earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum.
(2), closing ammino platinum with the synthetic luteolin of luteolin salt earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum.
Embodiment
Further set forth the present invention below in conjunction with specific embodiment.Should be understood that these embodiment only are used to illustrate the present invention, and be not used for limiting the scope of the invention.
Embodiment 1
(1) earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum, concrete synthesis path and chemical equation are as follows:
(2) again synthetic diiodo-two ammino platinum and the synthetic luteolin of luteolin are closed ammino platinum, concrete synthesis path and chemical equation are as follows:
The concrete steps of diiodo-two ammino platinum preparation:
Measure 20ml and contain 20g potassium chloroplatinite (K
2(PtCl
4), the 0.048mmol) aqueous solution mixes with 3.3g KI saturated solution, heating in water bath 5min, reaction soln becomes black, adds 1.5ml (1: 1) aqua ammonia, forms pitch black yellow crystal, solution is colourless solution, filter, use cold water washing, again with ice-cold ethanol and ether washing, dry air obtains diiodo-two ammino platinum (Pt (NH
3)
2I
2) 22g.
Luteolin closes the concrete steps of ammino platinum preparation:
Add 12.5g diiodo-two ammino platinum (Pt (NH successively
3)
2I
2, 0.02mmOl), 4.6gAgNO
3, remove by filter AgI.Add the 2.2g luteolin in filtrate, lucifuge stirred 35 hours for 60 ± 5 ℃, and reaction mixture is after silica gel algae soil layer filters, get solution, be evaporated to 150ml, filter and obtain the brownish black solid, a small amount of washing, the lucifuge dry air obtains luteolin and closes ammino platinum.
Embodiment 2
(1) earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum, concrete synthesis path and chemical equation are as follows:
(2) again synthetic diiodo-two ammino platinum and the synthetic luteolin of luteolin sylvite are closed ammino platinum, concrete synthesis path and chemical equation are as follows:
The concrete steps of diiodo-two ammino platinum preparation:
Measure 20ml and contain 20g potassium chloroplatinite (K
2(PtCl
4), the 0.048mmol) aqueous solution mixes with the 3.3gKI saturated solution, heating in water bath 10min, reaction soln becomes black, adds 1.5ml (1: 1) aqua ammonia, forms pitch black yellow crystal, solution is colourless solution, filter, use cold water washing, again with ice-cold ethanol and ether washing, dry air obtains diiodo-two ammino platinum (Pt (NH
3)
2I
2) 22g.
Luteolin closes the concrete steps of ammino platinum preparation:
Add 12.5g diiodo-two ammino platinum (Pt (NH successively
3)
2I
2, 0.02mmol), 4.6gAgNO
3, remove by filter AgI.Add 2.2g luteolin sylvite in filtrate, lucifuge stirred 10 hours for 50 ℃, and reaction mixture is after silica gel algae soil layer filters, get solution, be evaporated to 150ml, filter and obtain the brownish black solid, a small amount of washing, the lucifuge dry air obtains luteolin and closes ammino platinum.
Embodiment 3
(1) earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum, concrete synthesis path and chemical equation are as follows:
(2) again synthetic diiodo-two ammino platinum and the synthetic luteolin of luteolin are closed ammino platinum, concrete synthesis path and chemical equation are as follows:
The concrete steps of diiodo-two ammino platinum preparation:
Measure 20ml and contain 20g potassium chloroplatinite (K
2(PtCl
4), the 0.048mmol) aqueous solution mixes with 3.3g KI saturated solution, heating in water bath 5min, reaction soln becomes black, adds 1.5ml (1: 1) aqua ammonia, forms pitch black yellow crystal, solution is colourless solution, filter, use cold water washing, again with ice-cold ethanol and ether washing, dry air obtains diiodo-two ammino platinum (Pt (NH
3)
2I
2) 22g.
Luteolin closes the concrete steps of ammino platinum preparation:
Add 0.02mmol 12.5g diiodo-two ammino platinum (Pt (NH successively
3)
2I
2), 4.6g Ag
2O removes by filter AgI.Add 2.2g luteolin sylvite in filtrate, lucifuge stirred 35 hours for 60 ± 5 ℃, and reaction mixture is after silica gel algae soil layer filters, get solution, be evaporated to 150ml, filter and obtain the brownish black solid, a small amount of washing, the lucifuge dry air obtains luteolin and closes ammino platinum.
Embodiment 4
(1) earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum, concrete synthesis path and chemical equation are as follows:
(2) again synthetic diiodo-two ammino platinum and the synthetic luteolin of luteolin sylvite are closed ammino platinum, concrete synthesis path and chemical equation are as follows:
The concrete steps of diiodo-two ammino platinum preparation:
Measure 20ml and contain 20g potassium chloroplatinite (K
2(PtCl
4)) aqueous solution, mix with 3.3g KI saturated solution, heating in water bath 5min, reaction soln becomes black, add 1.5ml (1: 1) aqua ammonia, form pitch black yellow crystal, solution is colourless solution, filters, use cold water washing, with ice-cold ethanol and ether washing, dry air obtains diiodo-two ammino platinum (Pt (NH again
3)
2I
2) 22g.
Luteolin closes the concrete steps of ammino platinum preparation:
Add 0.02mmol 12.5g diiodo-two ammino platinum (Pt (NH3) 2I2), 5.2gAg successively
2O removes by filter AgI.Add 2.2g luteolin sylvite in filtrate, lucifuge stirred 10 hours for 50 ℃, and reaction mixture is after silica gel algae soil layer filters, get solution, be evaporated to 150ml, filter and obtain the brownish black solid, a small amount of washing, the lucifuge dry air obtains luteolin and closes ammino platinum.
Experimental example 1
Ultimate analysis (%) result: C 35.82, N 5.54, H2.59, O 18.05, and Pt 39.04.Theoretical value (%): C 35.09, and N 5.46, and H 2.73, and O 18.71, and Pt 38.01.
Experimental example 2
As follows through results of IR:
| Stretching vibration peak | ν Pt-O | ν C＝O | ν C2-C3 | δ COH | δ COH | ν C-O |
| Cm - | 482 VW | 1635 S | 1204 S | 1357 m | 1362 S | 1324 S |
Experimental example 3
The intravenous injection luteolin closes ammino platinum and cis-platinum to the contrast of the anti-tumor activity of murine sarcoma S-180 knurl strain, sees Table 1.
Table 1 intravenous injection luteolin closes ammino platinum, the cis-platinum anti-tumor activity to the strain of murine sarcoma S-180 knurl
| Medicine name | Size of animal (only) | Dosage/(mg/kg) | Tumour inhibiting rate/% |
| Luteolin closes ammino platinum | 15 | 4.5 | 90.4 |
| Cis-platinum | 15 | 4.5 | 45.3 |
Claims (2)
1. the luteolin with anti-tumor activity closes ammino platinum, it is characterized in that its structural formula is:
2. preparation method that the luteolin with anti-tumor activity closes ammino platinum is characterized in that:
(1), closes ammino platinum with the synthetic luteolin of luteolin more earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum.
(2), close ammino platinum with the synthetic luteolin of luteolin salt more earlier with potassium chloroplatinite synthetic intermediate diiodo-two ammino platinum.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101794164A CN101177435A (en) | 2007-12-13 | 2007-12-13 | Cyanidenon ammino platinum anti-cancer drugs and method for making same |
| CN2008101831257A CN101456881B (en) | 2007-12-13 | 2008-12-12 | Luteolin and platinum complexes of derivatives thereof, preparation method and use thereof |
Applications Claiming Priority (1)
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|---|---|---|---|
| CNA2007101794164A CN101177435A (en) | 2007-12-13 | 2007-12-13 | Cyanidenon ammino platinum anti-cancer drugs and method for making same |
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|---|---|
| CN101177435A true CN101177435A (en) | 2008-05-14 |
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ID=39403877
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|---|---|---|---|
| CNA2007101794164A Pending CN101177435A (en) | 2007-12-13 | 2007-12-13 | Cyanidenon ammino platinum anti-cancer drugs and method for making same |
| CN2008101831257A Expired - Fee Related CN101456881B (en) | 2007-12-13 | 2008-12-12 | Luteolin and platinum complexes of derivatives thereof, preparation method and use thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588818B (en) * | 2013-11-26 | 2016-06-01 | 中国科学院长春应用化学研究所 | A kind of compound and its preparation method with antitumour activity |
| CN113041285A (en) * | 2019-12-27 | 2021-06-29 | 国药集团北京华邈药业有限公司 | Method for rapidly processing qualified nux vomica powder product |
| CN114681465A (en) * | 2020-12-25 | 2022-07-01 | 华东理工大学 | Lobaplatin-flavone pharmaceutical co-crystal as well as preparation method and application thereof |
| CN113577053A (en) * | 2021-08-10 | 2021-11-02 | 重庆大学附属肿瘤医院 | Application of luteolin in preparation of medicine for targeted inhibition of ovarian cancer stem cells |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100443081C (en) * | 2005-04-05 | 2008-12-17 | 吴一心 | Combination of sweet-scented osmanthus and plantinum chemotherapeutic medicine |
-
2007
- 2007-12-13 CN CNA2007101794164A patent/CN101177435A/en active Pending
-
2008
- 2008-12-12 CN CN2008101831257A patent/CN101456881B/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101456881A (en) | 2009-06-17 |
| CN101456881B (en) | 2012-10-17 |
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