High efficiency telomerase inhibitor and application of telomerase inhibitor in antitumor drug

A technology of reaction and reaction formula, applied in the field of preparation of trinuclear platinum complexes, can solve the problem of no metal complexes, etc., and achieve the effects of high anticancer activity, high granulase inhibitory ability, and excellent anticancer activity

Inactive Publication Date: 2013-01-30
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the research on selective anticancer drugs targeting G-quadruplexes has only been carried out for more than 10 years, new small molecular compounds have gradually entered clinical trials, but there are no metal complexes in these compounds

Method used

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  • High efficiency telomerase inhibitor and application of telomerase inhibitor in antitumor drug
  • High efficiency telomerase inhibitor and application of telomerase inhibitor in antitumor drug
  • High efficiency telomerase inhibitor and application of telomerase inhibitor in antitumor drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]Synthesis of organic hybrid trinuclear platinum complex (ZD028): Dissolve 0.5 mmol of monodentate platinum ligand [Pt(dien)Cl]Cl·HCl in 6 ml of water, add 1.5 A millimolar amount of silver nitrate was stirred at 45°C for 36 hours. After the reaction was completed, the precipitate was discarded by centrifugation, and the clear night was kept; The reaction was protected from light for 3 days. After the reaction, an appropriate amount of absolute ethanol was added to the reaction solution to precipitate a light yellow solid, which was centrifuged to obtain a light yellow solid, and the product was vacuum-dried. Yield: 83%. Elemental analysis(%),

[0037] Theoretical value: C 30 h 51 N 21 o 18 Pt 3 ·6H 2 O: C, 21.36; H, 3.76; N, 17.43. Experimental values: C, 21.20; H, 3.76; N, 17.52. 195 Pt NMR (D 2 O, δ / ppm): -1222.20, and K 2 PtCl 4 was used as an internal standard (δ=0).

[0038] The structure of the compound is as figure 1 shown.

Embodiment 2

[0040] Fluorescence resonance energy transfer (FRET) experiment: 10 μM human telomere DNA (F21T), promoter DNA (c-kit) or double-stranded DNA (dsDNA) was mixed with 10 μL of complex (ZD028) solution at different concentrations. The resulting 20 μL sample solution was added to a LightCycler capillary and inserted into a Roche LightCycler 2 fluorescent quantitative PCR instrument. The excitation wavelength is fixed at 470nm, and the emission fluorescence intensity at 530nm is monitored. The temperature range is 37 -99 0 C, the heating interval is 1 0 C, sampled after equilibrating for 30 s, T m Value calculations are fitted using Origin. The data results are shown in Table 1. Experimental results show that the trinuclear platinum compound can specifically and efficiently stabilize human telomere G-quadruplex DNA.

[0041] Table 1 The thermal stability of trinuclear platinum complex (ZD028) to different DNA (△ T m ).

[0042]

Embodiment 3

[0044] Telomerase inhibition (TRAP) experiment: the lysate of HeLa cells was collected, added to the TRAP reaction solution containing the corresponding concentration of the complex, and PCR was amplified, and the amplified product was analyzed by 0.8% polyacrylamide gel. The data results are shown in Figure 2. The experimental results show that the complex is an excellent telomerase inhibitor ( Tel IC 50 =30 nM).

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Abstract

The invention discloses a trinuclear platinum complex (ZD028) capable of inhibiting the telomerase activity with high efficiency, a preparation method and an application of the trinuclear platinum as an antitumor drug. The trinuclear platinum complex can specifically inhibit the telomerase activity of the cancer cell, destroy a telomere maintenance mechanism which is pivotal to the cancer cell, accelerate the shortening of the telomere of the cancer cell, induce the aging of the cancer cell, and lead to death of the cancer cell to reach a purpose for treating malignant tumor, and the toxicity on normal cell is low. The conventional antitumor drug comprises doxorubicin, cisplatin and paclitaxel but not the limitation. Compared with the conventional antitumor drugs, the trinuclear platinum complex (ZD028) reduces the toxic and side effect on other organs or systems due to low toxicity on normal cells. The preparation method has the advantages of simple and easy operation and low cost, can be competed in a common chemical laboratory, and has no environmental pollution during the production process, thereby the trinuclear platinum complex (ZD028) can be used as a novel latent antitumor drug.

Description

technical field [0001] The invention relates to a trinuclear platinum complex (ZD028) capable of efficiently inhibiting telomerase activity, a preparation method thereof and an application as an antitumor drug. It specifically relates to a preparation method of a trinuclear platinum complex (ZD028) capable of efficiently inhibiting telomerase activity and its application as an antitumor drug. Background technique [0002] At present, malignant tumor is a major disease that endangers human health and life, but the research and development of new anti-tumor drugs is constantly updated, including traditional Chinese medicine and western medicine. A large number of long-term clinical evidences show that antineoplastic drugs have a common problem of high toxicity and side effects. Surgery is suitable for early and mid-term treatment of some local tumors, but most patients cannot prevent tumor recurrence and distant metastasis by surgical treatment. Although radiotherapy and che...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61K31/555A61P35/00
CPCC07F15/00A61K31/555A61P35/00C07F15/0093
Inventor 毛宗万郑小辉钟毅芳黄华珍计亮年
Owner SUN YAT SEN UNIV
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