CN102603805A - Platinum (II) complex with antineoplastic activity and preparation method of platinum (II) complex - Google Patents

Abstract

The invention relates to a platinum (II) complex with an antineoplastic activity. The chemical name of the platinum complex is cis-gallic acid group-(1R, 2R)-1,2-cyclohexanediamine conjugated platinum (II), the molecular formula is Pt(C6H14N2)(C7H4O5), and the molecular weight is 477. The platinum (II) complex has a good antineoplastic activity. The structure is as follows.

Description

Has platinum (II) title complex of anti-tumor activity and preparation method thereof

Technical field

The present invention relates to medical technical field, particularly relate to a kind of novel platinum complex with 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 tangerine acid, 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.

Another object of the present invention provides the preparation method of said platinum complex.

The said platinum complex of the object of the invention is a leavings group with the gallate, so that (1R, 2R)-1, the 2-cyclohexanediamine is for following group.Structure is following:

Platinum complex chinesization formal name used at school of the present invention be called cis-gallate-(1R, 2R)-1, the 2-cyclohexanediamine closes platinum (II), molecular formula is Pt (C ₆H ₁₄N ₂) (C ₇H ₄O ₅), molecular weight is 477.

The preparation method of the platinum of anti-tumor activity of the present invention (II) title complex is following:

(1) with cis-diiodo--(1R, 2R)-1, it is starting raw material that the 2-cyclohexanediamine closes platinum (II) (ring platinum), with Silver Nitrate be 1: 2 by the amount of substance ratio, at 50～60 ℃ of following reaction 3～5h;

(2) ring platinum is 1: 1～1.2 with the ratio of the amount of substance of gallic acid, and gallic acid is 1: 1 with the amount of substance ratio of sodium hydroxide, and sodium gallate and ring platinum hydrating solution reaction pH value are about between 6～7, react 3～5h under the room temperature.

Embodiment

Further specify the present invention through embodiment below.Should correct understanding be: the method in the embodiments of the invention is only used for explaining the present invention, rather than limitation of the present invention.

Platinum complex of the present invention preparation: agents useful for same: commercially available purity be not less than 98% cis-diiodo--(1R, 2R)-1, the 2-cyclohexanediamine closes platinum (II) (ring platinum), commercially available analytical pure Silver Nitrate, commercially available analytical pure gallic acid, commercially available analytical pure sodium hydroxide.

Preparation process: take by weighing 5.7g (0.01mmol) ring platinum and add a small amount of purified water and stir into suspension liquid; Take by weighing and join in the ring platinum suspension liquid after 3.4g (0.02mmol) Silver Nitrate dissolves with purified water; Replenish purified water and react about 3.5h at 55～60 ℃, obtain pale yellow colour circle platinum hydrating solution after AgI is filtered to about 100ml.Take by weighing 1.7g (0.01mmol) gallic acid; Add a small amount of purified water and stir into suspension liquid, take by weighing to join after 0.4g (0.01mmol) dissolution of sodium hydroxide and be stirred to solid in the gallic acid suspension liquid and dissolve fully, the solution that obtains is joined under the lucifuge agitation condition in the ring platinum hydrating solution; Regulate between pH6～7 with sodium hydroxide solution; At room temperature react about 3h, 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 ₁₈N ₂O ₅, the calculated value of C, H, N, Pt is C 32.70% respectively, and H 3.77%, and N 5.87%, and Pt 40.88%; Actual detected value C 32.48%, H 3.81%, N5.53%, Pt 41.12%.Main infrared peak and ownership: O-H (3424.10cm ^-1St), and N-H (3200.00,1586.00cm ^-1St), C-H (2936.00cm ^-1, 2856.23cm ^-1St), C=O (1601.00cm ^-1St) C=O (1388.35cm ^-1δ) FAB ⁺-MS (m/z): 478 ([M+1] ⁺, 100%).

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 M 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, and the record result is an X-coordinate with concentration; 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, lung cancer A-549, the IC50 of mammary cancer MCF-7＜10 μ m.

Claims (3)

1. platinum (II) title complex with anti-tumor activity, chemistry cis-gallate by name-(1R, 2R)-1, the 2-cyclohexanediamine closes platinum (II), and molecular formula is Pt (C ₆H ₁₄N ₂) (C ₇H ₄O ₅), molecular weight is 477, its structural formula is:

2. preparation method with platinum (II) title complex of anti-tumor activity is characterized in that:

(1) with cis-diiodo--(1R, 2R)-1, it is starting raw material that the 2-cyclohexanediamine closes platinum (II) (ring platinum), with Silver Nitrate be 1: 2 by the amount of substance ratio, at 50～60 ℃ of following reaction 3～5h;

(2) ring platinum is 1: 1～1.2 with the ratio of the amount of substance of gallic acid, and gallic acid is 1: 1 with the amount of substance ratio of sodium hydroxide, and sodium gallate and ring platinum hydrating solution reaction pH value are about between 6～7, react 3～5h under the room temperature.

3. the application of the platinum of claim 1 (II) title complex in the preparation antitumor drug.