CN102659849A - Platinum (II) complex with antitumor activity and preparation method thereof - Google Patents
Platinum (II) complex with antitumor activity and preparation method thereof Download PDFInfo
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- CN102659849A CN102659849A CN2012101508252A CN201210150825A CN102659849A CN 102659849 A CN102659849 A CN 102659849A CN 2012101508252 A CN2012101508252 A CN 2012101508252A CN 201210150825 A CN201210150825 A CN 201210150825A CN 102659849 A CN102659849 A CN 102659849A
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Abstract
The invention provides a platinum complex with a chemical name of cis-gallate cyclopentylamine, methylamine platinum (II), molecular formula of Pt(CNH5)(C5NH11)(C7H4O5) and molecular weight of 479. The compound has excellent antitumor activity. The structure of the complex is shown in the specification.
Description
Technical field
The present invention relates to medical technical field, relate to a kind of platinum complex, this title complex has anti-tumor activity.
Background technology
Cancer is the disease of a kind of serious threat human health and life, is the dead disease of the world's second largest after cardiovascular and cerebrovascular diseases.In recent years, because the influence of factors such as environmental degradation, bad life habits and aging population, the cancer morbidity of China constantly increases.Cancer has become one of difficult medical problem that the mankind demand urgently capturing.
In the sixties in 20th century; The state college professor Rosenberg of Michigan, United States finds that cis-platinum has antitumour activity at the researching DC electric field during to the influencing of intestinal bacteria growths; And through clinical verification; Cis-platinum all has good therapeutic action to kinds of tumors, thereby has opened up the frontier of metal platinum complex compound antitumous effect research.Platinum-containing anticancer drug has become indispensable medicine in the cancer chemotherapy at present, existing cis-platinum, carboplatin, oxaliplatin, S 254, the granted listings such as platinum, Lip river platinum of relaxing.But at present also there are many self inherent shortcomings in the medicine of listing: toxic side effect is big, can cause feeling sick, vomiting, bone marrow depression etc., exists cross resistance and anticancer spectrum narrow etc. each other, these drawbacks limit they use widely.Seek low toxicity, efficient, wide spectrum and lack the important directions that cross resistance becomes the platinum family drug research.
Discovering that the biological activity of the metal complexes of the effective constituent in some natural drug obviously is better than single effective constituent, is that leavings group and platinum coordinate new type anticancer medicine release one after another with Cantharidic acid, Quercetin.
Gallic acid is also claimed gallic acid or gallate, is a kind of organic acid, is found in
Turkey-galls,
Lacquer tree,
TeaIn plant, chemical formula C
6H
2(OH)
3COOH.It is external that streptococcus aureus, sarcina, α-type streptococcus, Neisseria gonorrhoeae, Pseudomonas aeruginosa, bacterium flexneri, Corynebacterium diphtheriae Hd, paratyphosum Bacterium A etc. are had restraining effect, its Mlc is 5mg/ml.External, under 3% concentration, 17 kinds of fungies there is bacteriostatic action, influenza virus also there is certain restraining effect.The mouse lung adenoma that morpholine is added due to the sodium nitrite has strong restraining effect.The present invention is according to these characteristics of gallic acid, with itself and platinum coordination.
Summary of the invention
The purpose of this invention is to provide a kind of platinum complex with anti-tumor activity.
The said platinum complex of the object of the invention is a leavings group with the gallate, and with NSC 32389, methylamine is for following group, and structure is following:
。
Platinum complex chinesization formal name used at school of the present invention is called cis-gallate-NSC 32389, methylamine closes platinum (II), and molecular formula is Pt (CNH
5) (C
5NH
11) (C
7H
4O
5), molecular weight is 479.
Inoculating cell: the nutrient solution (DMEM or RMPI1640) with containing 10% foetal calf serum is made into the individual cells suspension, with every hole 5000-10000 cell inoculation to 96 orifice plates, every pore volume 100 μ L, attached cell shifts to an earlier date 12 hours inoculation culture.Add testing compound solution (fixed concentration 40 μ mol/L primary dcreening operations are suppressed near 50% compound in this concentration to growth of tumour cell and establish 5 concentration and get into gradients and sieve again), every hole final volume 200 μ L, every kind of processing is all established 3 and is answered holes.Colour developing: cultivate after 48 hours for 37 degrees centigrade, every hole adds MTT solution 20 μ L.Continued to hatch 4 hours, and stopped cultivating, inhale and abandon culture supernatant liquid in the hole, every hole adds the SDS solution (10%) of 200 μ L, and night incubation (37 ℃ of temperature) is fully melted crystallisate.Colorimetric: select the 595nm wavelength; Enzyme-linked immunosorbent assay instrument (Bio-Rad 680) reads each hole absorbance value; The record result; With concentration is X-coordinate, and cell survival rate is that ordinate zou is drawn cell growth curve, uses IC50 (μ m) value of two-point method (Reed and Muench method) computerized compound.
The result sees the following form:
Can find out that from the result compound has certain external tumor growth and suppresses active, to white blood disease HL-60, the IC of mammary cancer MCF-7
50<10 μ m.
Embodiment
Platinum complex preparation of the present invention:
Agents useful for same: purity is not less than cis-diiodo--NSC 32389 of 98%, and methylamine closes platinum (II), commercially available analytical pure Silver Nitrate, the single hydration gallic acid of commercially available analysis, commercially available analytical pure absolute ethyl alcohol.
The preparation process:
Cis-diiodo--NSC 32389, methylamine close platinum (II) and adopt the preparation of document (US4533502) reported method; With cis-diiodo--two NSC 32389 close platinum (II) in perchloric acid solution, react change brown solid fully into to yellow solid till, brown solid is reacted in methylamine solution till become yellow solid fully.
Taking by weighing 5.7g (0.01mmol) cis-diiodo--NSC 32389, methylamine closes platinum (II) and adds a small amount of purified water and stir into suspension liquid; Take by weighing to join after 3.4g (0.02mmol) Silver Nitrate dissolves with purified water and encircle in the platinum suspension liquid, replenish purified water and after 55 ~ 60 ℃ of about 3.5h of reaction filter AgI, obtain light yellow hydrating solution to about 100ml.Take by weighing 1.9g (0.01mmol) gallic acid,, under the lucifuge stirring condition, join in the hydrating solution, 55 ℃ of reaction 6h with the dissolving of 250ml ethanol solution.With the solid filtering that obtains, successively water, absolute ethyl alcohol are respectively washed 2 after drying and are obtained the 2.7g light yellow solid.Ultimate analysis: molecular formula PtC
13H
20N
2O
5, the calculated value of C, H, N, Pt is C 32.57% respectively, H4.17%, and N5.84%, Pt 40.71%; Actual detected value C 32.52%, H4.05%, N5.79%, Pt 40.64%.Main infrared peak and ownership: O-H (3429.10cm
-1St), and N-H (3213.00,1586.00cm
-1St), C-H (2940.00cm
-1, 2857.23cm
-1St), C=O (1607.00cm
-1St) C=O (1390.00cm
-1δ) FAB
+– MS (m/z): 480 ([M+1]
+, 100%).
1H-NMR:?1.20~1.25?(m,?CH
3?of aminomethane);?1.40~1.42?(d,?CH
2CHHCHHCH
2?of?cyclopentane);?1.51~1.52?(d,?CH
2CHHCHHCH
2?of?cyclopentane);?1.58~1.59?(m,CHHCHCHH?of?cyclopentane)?;?1.80~1.82?(d,?CHHCHCHH?of?cyclopentane);?2.63~2.64?(d,?CH
2CHCH
2?of?cyclopentane);?5.01~5.02?(m,?NH
2?of?aminomethane);?5.11~5.13?(d,?NH
2?of?cyclopentane);?5.29~5.31?(m,?OH?of?Gallic?acid);?7.10~7.12?(m,?CHCCH?of?Gallic?acid)。
Claims (3)
1. platinum (II) title complex with anti-tumor activity is characterized in that: chemistry cis-gallate by name-NSC 32389, methylamine close platinum (II), and its structural formula is:
2. the preparation method of the platinum with anti-tumor activity (II) title complex of claim 1 is characterized in that containing following steps:
(1) closing platinum (II) with cis-diiodo--NSC 32389, methylamine is starting raw material, presses amount of substance than being 1:2 with Silver Nitrate, reacts 3 ~ 5h down at 50 ~ 60 ℃, obtains light yellow hydrating solution;
(2) anionite-exchange resin is joined cis-diiodo--NSC 32389, methylamine and close in the hydrating solution of platinum (II) and Silver Nitrate, stirring reaction 0.5h at room temperature obtains cis-dihydroxyl-NSC 32389, methylamine closes platinum (II) solution;
(3) cis-dihydroxyl-NSC 32389, methylamine are closed the ethanol solution reaction of platinum (II) solution and gallic acid; Volume ratio is 1:2 ~ 3; Temperature of reaction is 50 ~ 60 ℃; Reaction times is 5 ~ 7h, and cis-diiodo--NSC 32389, methylamine close ratio 1:1 ~ 1.2 of platinum (II) and the amount of substance of a hydration gallic acid.
3. the application of the compound in the claim 1 in the preparation anti-tumor activity medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973754A (en) * | 2019-05-21 | 2020-11-24 | 杭州磐田生物技术有限公司 | Drug-containing nano-particles and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557822A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anti-tumor activity |
| CN1923837A (en) * | 2006-09-29 | 2007-03-07 | 昆明贵研药业有限公司 | Lipophilic platinum antineoplastic complex |
| CN101967163A (en) * | 2010-09-07 | 2011-02-09 | 昆明贵金属研究所 | Platinum (II) anti-cancer compound with selectivity for cancer cells |
-
2012
- 2012-05-16 CN CN201210150825.2A patent/CN102659849B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557822A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anti-tumor activity |
| CN1923837A (en) * | 2006-09-29 | 2007-03-07 | 昆明贵研药业有限公司 | Lipophilic platinum antineoplastic complex |
| CN101967163A (en) * | 2010-09-07 | 2011-02-09 | 昆明贵金属研究所 | Platinum (II) anti-cancer compound with selectivity for cancer cells |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973754A (en) * | 2019-05-21 | 2020-11-24 | 杭州磐田生物技术有限公司 | Drug-containing nano-particles and preparation method and application thereof |
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