Application of indeno triazine compounds as substrate of quinone oxidoreductase depending on NAD (P) H

An indenotriazine and compound technology, applied in the field of quinone oxidoreductase substrates, can solve the problems of high affinity, inability to detect changes in NAD+ levels, poor folding, etc.

Inactive Publication Date: 2014-01-22
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, they have some disadvantages such as pH sensitivity, poor folding or too high affinity, and cannot detect NAD + Level changes, such shortcomings make it urgent to use a new type of NADH probe for high-throughput drug screening

Method used

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  • Application of indeno triazine compounds as substrate of quinone oxidoreductase depending on NAD (P) H
  • Application of indeno triazine compounds as substrate of quinone oxidoreductase depending on NAD (P) H
  • Application of indeno triazine compounds as substrate of quinone oxidoreductase depending on NAD (P) H

Examples

Experimental program
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Embodiment 1

[0046] Example 1 The level of NADH in the cytoplasm of cancer cells is significantly higher

[0047] In the 1930s, German biochemist Otto Warburg discovered that tumor cells and normal cells have metabolic differences. They produce energy through glycolysis and produce a large amount of by-products-lactic acid (Warburg, O., etc., Science) .1956, V.123(3191), pp.309-314.). This metabolic property makes tumor cells consume sugar much faster than normal cells. This phenomenon of increased dependence of tumor cells on the production of glycolytic pathways is called the "Waberg effect", which will promote cell proliferation and tumor growth extremely quickly (Clower, CV, etc., Proc Natl Acad Sci USA. 2010, V .107(5), pp.1894-1899.). Previously, using NADH autofluorescence method, it was found that the level of NADH in tumor cells was relatively high (Villette, S. et al. Photochem Photobiol Sci. 2006, 5(5), pp.483-492. Uppal, A. et al., Biotechnol Appl Biochem. 2003, 37 (Pt1), pp. 4...

Embodiment 2

[0048] Example 2 KP372-1 significantly reduces NADH levels in cancer cells

[0049] We used NADH probes for high-throughput screening and found that a compound known as PDK1 / AKT / Flt3 dual pathway inhibitor-KP372-1 (Table 1) can significantly reduce the level of NADH in cancer cells ( figure 2 ). Mix the H1299 cell line stably expressing NADH probe with KP372-1 of different concentrations (0μM, 0.01μM, 0.02μM, 0.05μM, 0.1μM, 0.2μM, 0.5μM, 1.0μM, 2.0μM, 5.0μM, 10μM) , Add it to a black 96-well plate, use a multifunctional microplate reader to measure the fluorescence change of NADH probe at 420nm / 485nm, confirm that KP372-1 at 0.5μM can reduce the intracellular NADH level to the lowest level, and it is more than common Oxidant H 2 O 2 , Aldrithiol-2 and diamide are about 2000 times stronger ( figure 2 ).

Embodiment 3

[0050] Example 3 KP372-1 has a broad-spectrum anti-cancer effect

[0051] In order to further analyze the anti-cancer effect of KP372-1, we tested the effect of KP372-1 on the proliferation of cancer cells from different tissues. These cancer cells include: human liver cancer cell BEL-7404, human brain astrocytes Tumor U87, human high metastatic lung cancer cell 95-D, human non-small cell lung cancer cell NCI-H1299, human lung adenocarcinoma cell SPC-A-1, human lung cancer cell A549, human orthotopic pancreatic adenocarcinoma cell BxPC-3, human Chronic myeloid leukemia cells K562, human breast cancer cells MCF-7, human breast cancer cells MDA-MB-468, human prostate cancer cells PC-3, human oral epidermoid cancer cells KB, human esophageal cancer cells TE-1, human Gastric cancer cells MKN-45, human gastric cancer cells MGC80-3, human colon adenocarcinoma cells LS174T, human nasopharyngeal cancer cells CNE-1 and CNE-2, human renal clear cell cancer cells CaKi-2 and human Hela cervi...

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Abstract

The invention discloses application of indeno triazine compounds as a substrate of quinone oxidoreductase depending on NAD (P) H. The indeno triazine compounds are catalyzed through the quinone oxidoreductase depending on the NAD (P) H to generate an oxidation reduction cycle reaction, a large number of reactive oxide free radicals are generated, strong oxidative stress is induced, and the obvious lethal effect on lung cancer, liver cancer, cervical cancer, pancreatic cancer, breast cancer, prostate cancer, nasopharynx cancer, kidney clear cell carcinoma, oral epidermoid carcinoma, chronic myelogenous leukemia, intestinal cancer, brain cancer, gastric cancer, esophagus cancer and other cancer cells expressed by the quinone oxidoreductase depending on the NAD (P) H is achieved. The indeno triazine compounds used as the substrate of the quinone oxidoreductase depending on the NAD (P) H can also be used as sensitizers for treating the cancer with radiotherapy, and have the obvious anticancer synergistic effect. In addition, the indeno triazine compounds used as the substrate of the quinone oxidoreductase depending on the NAD (P) H have antibacterial and antifungal activity.

Description

Technical field [0001] The present invention belongs to the fields of medicinal chemistry and biochemical pharmacology, and specifically relates to the use of a series of indenotriazine compounds as substrates of NAD(P)H-dependent quinone oxidoreductase. Background technique [0002] Unlike normal tissue-derived cells, the metabolism of cancer cells has undergone significant changes in order to maintain a rapid proliferation rate and resist certain cell death signals, especially those that induce oxidative stress damage. This means that cancer cells need to consume more nutrients and discharge more waste than normal cells. In order to maintain cell division, cells not only need to increase their size but also need to replicate DNA. This creates a huge metabolic demand and consumes a lot of protein, lipids, nucleic acids and energy. The demand for anabolism drives cells to increase the absorption of glucose and amino acids, and synthesize the raw materials needed in the process o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/53A61P35/00A61P31/04A61P31/10C07D487/04
Inventor 杨弋赵玉政呼庆勋苏倪王傲雪
Owner EAST CHINA UNIV OF SCI & TECH
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