CN109893523A - A kind of ATP- citrate lyase inhibitor of broad-spectrum anti-tumor cell Proliferation - Google Patents
A kind of ATP- citrate lyase inhibitor of broad-spectrum anti-tumor cell Proliferation Download PDFInfo
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- CN109893523A CN109893523A CN201910156682.8A CN201910156682A CN109893523A CN 109893523 A CN109893523 A CN 109893523A CN 201910156682 A CN201910156682 A CN 201910156682A CN 109893523 A CN109893523 A CN 109893523A
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- citrate lyase
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Abstract
The invention discloses a kind of dehydrogenation curvularins, and are used for the ATP- citrate lyase inhibitor of broad-spectrum anti-tumor cell Proliferation.With molecular probe and chemical proteomics technology, confirm that the action target spot of the compound is ATP- citrate lyase, IC50Value is 930nM.Through Cytotoxic evaluation, which has broad-spectrum anti-tumor cell-proliferation activity, can be used as ATP- citrate lyase inhibitor and deeply develop anti-tumor drug.
Description
Technical field
The invention belongs to drug design and synthesis field, be related to a kind of Novel ATP-citrate lyase inhibitor and its
Application in anti-tumor drug.
Technical background
ATP- citrate lyase (ATP citrate lyase, abbreviation ACLY) is that connection glucose metabolism is closed to lipid
At an important enzyme, can catalytic citric acid and CoA converting at oxaloacetic acid and acetyl coenzyme A.Studies have shown that ACLY is big
Expression with higher and activity in most tumors cell inhibit ACLY activity can obvious blocks tumor cells proliferation.ACLY at
For a potential treatment target spot for inhibiting tumor cell proliferation.
It is less as the discovery research of the inhibitor of target spot using ACLY albumen, 25 kinds of compounds are reported altogether, source and structure are single,
Mostly quinones and alkane compound, and derived from only 10 compounds of natural products.Currently, only Bempedoic acid conduct
ATP- citrate lyase inhibitor completes phase III clinical trial.Structures of Natural Products and function have diversity, are guideizations
The main source of conjunction object discovery, ACLY inhibitor is screened from natural products library can pharmacological property elder generation to expansion compound library and discovery
Compound is led with realistic meaning.
Dehydrogenation curvularin is natural DAL12 class benzenediol lactone compound, document report and previous experiments
Confirmation has broad spectrum anticancer activity, and to HSP90, p97 and TGF-β have inhibitory activity, currently inhibit proliferative activity o f tumor
Mechanism and target spot are indefinite.
Summary of the invention
The purpose of the present invention is to provide a kind of compound, entitled dehydrogenation curvularin, structural formula is such as
Under:
Further, above compound or pharmaceutically acceptable other forms prodrug are as ATP- lemon acid cleavage
Application in the drug of enzyme inhibitor.
Further, above compound or pharmaceutically acceptable other forms prodrug are in preparation inhibition tumour cell
Application on the drug of proliferation.
The tumour cell includes t cell lymphoma cell strain Jurkat, cervical cancer cell lines HeLa, colon cancer cell
The former white blood cell strain K562 of HCT116, chronic marrow.
Technical solution of the present invention uses molecular probe and chemical proteomics technology screening drug target, utilizes
The action target spot of ATP- citrate lyase activity probe " hook fishing " identification cancer cell from cell, further confirms that ATP- lemon
Lemon acid cleavage enzyme is the action target spot of dehydrogenation curvularin.
Detailed description of the invention
Fig. 1 is dehydrogenation curvularin (DCV) and curvularin (CV) ACLY inhibitory activity is evaluated.
Specific embodiment
Test example 1: molecular probe and chemical proteomics confirm ATP- citrate lyase target spot
Dehydrogenation curvularin and curvularin probe molecule DCV-yne and CV-yne synthesis
Thionyl chloride is added dropwise while stirring into anhydrous methylene chloride (10mL) solution of 5- hexynic acid (224mg, 2mmol)
The DMF of (560 μ L, 8mmol) and catalytic amount.Said mixture return stirring is reacted 3 hours, and was removed under vacuum
The thionyl chloride and methylene chloride of amount.Residue is dissolved in methylene chloride (30mL).Under stiring by curvularin
(10mg, 0.0345mmol) and triethylamine (140mL, 1mmol) are added in above-mentioned solution of acid chloride (2mL).Gained reaction is mixed
It closes object to stir under reflux 4 hours, be concentrated in vacuo.Then by residue flash column chromatography, with chloroform/methanol
(60:1) eluant, eluent obtains crude product (4mg), then using C18 chromatographic column (5 μm of YMC-Pack-ODS-A, 4.6 ×
250mm), half is carried out using reversed-phase HPLC to prepare, obtain DCV-yne (2.3mg).
Compound structure information is as follows:
White amorphous powder, HR-ESI-MS m/z385.1645 [M+H]+(calcd for C22H25O6385.1651)
；1H NMR(400MHz,CDCl3): δ 6.75 (1H, d, J=2.0Hz), 6.59 (1H, d, J=2.0Hz), 6.53-6.40 (1H,
M), 6.24 (1H, d, J=16.0Hz), 4.98-4.86 (1H, m), 3.40 (2H, s), 2.59 (2H, t, J=7.4Hz), 2.41-
2.30 (1H, m), 2.27 (2H, td, J=2.6,6.9Hz), 2.24-2.14 (1H, m), 1.99 (1H, t, J=2.6Hz),
1.95-1.78 (4H, m), 1.56-1.39 (2H, m), 1.18 (3H, d, J=6.3Hz)；13C NMR (100MHz,CDCl3):δ
196.4,171.3,170.4,157.9,156.9,148.4,133.5,132.4,125.6, 115.5,109.7,83.0,73.4,
69.4,39.5,34.5,34.2,32.7,24.4,23.4,20.4,17.7.
Curvularin (3.4mg, 0.0116mmol) and triethylamine (50 μ is added while stirring in acyl chlorides solvent (1mL)
L, 0.357mmol), it is concentrated in vacuo after said mixture return stirring is then reacted 4h.Gained residue is utilized into C18 chromatography
Column (5 μm of YMC-Pack-ODS-A, 4.6 × 250mm) inverted HPLC is purified, and product CV-yne (1.1mg) is obtained.
Compound structure information is as follows:
White amorphous powder, HR-ESI-MS m/z387.1801 [M+H]+(calcd for C22H27O6387.1808)
；1H NMR(400MHz,CDCl3): δ 6.68 (1H, d, J=2.2Hz), 6.60 (1H, d, J=2.2Hz), 5.14-5.04 (1H,
M), 3.94 (1H, d, J=16.8Hz), 3.71 (1H, d, J=16.8Hz), 3.06 (1H, dt, J=7.1,15.2Hz), 2.77
(1H, t, J=7.1Hz), 2.71 (2H, t, J=7.4Hz), 2.35 (2H, td, J=2.6,6.9Hz), 2.02 (1H, t, J=
2.6Hz), 1.96 (2H, qui, J=7.1Hz), 1.75-1.43 (6H, m), 1.42-1.31 (2H, m), 1.21 (3H, d, J=
6.4Hz)；13C NMR(100MHz,CDCl3):δ207.9,170.8,170.2,159.1, 153.0,135.4,122.9,
117.7,109.7,82.9,72.4,69.5,42.8,40.6,33.0,32.4,26.9,23.4, 23.0,21.9,20.1,
17.8.
The identification of 2 dehydrogenation curvularin target point protein of embodiment
10 μM of probe solution and t cell lymphoma cell strain Jurkat cell are incubated for, cell is collected by centrifugation, is added
The cracking of HEPES lysate, collects supernatant.500 μ L supernatants are taken, final concentration of 500 μM of Biotin-N is added3, 1mM's
CuSO4, the NaVc of 100 μM of THPTA and 1mM, incubation at room temperature 1 hour, collection precipitating, washing 2 times, 50 μ L of addition
Streptavidin magnetic bead is successively washed 3 times with phosphate buffer, 1 μ g is added, grade trypsase is sequenced, 37 DEG C are digested overnight.
Digestive juice is concatenated mass spectrometric tags reagent and carries out isotope labelling processing, and the albumen after merging is through C18Column desalination is concentrated and dried, and is used
15 μ L, 0.1% formic acid solution ultrasonic dissolution carries out LC-MS/MS analysis.The protein fragments that LC-MS/MS is analyzed and handled
Data are compared with the transcript profile database of corresponding microorganism, identify the albumen being enriched with.Using proteomic techniques,
240 potential target spots of identification identification in t cell lymphoma cell strain Jurkat cell, wherein ACLY is as the curved spore mould of dehydrogenation
Plain first potential target spot.Low table is struck through competitive binding, WesternBlot, recombinant protein label, enzyme activity recycling, siRNA
Up to equal serial experiments, the validity of ACLY target spot is confirmed.Enzyme inhibition activity evaluation, dehydrogenation curvularin pair are carried out to ACLY
ACLY inhibits IC50Value is 930nM, as shown in Figure 1.Fig. 1 is dehydrogenation curvularin (DCV) and curvularin (CV) ACLY
(BMS-303141 is positive control, and evaluation method uses ADP-Glo for inhibitory activity evaluationTMKinase assay kit).Confirm this
The invention compound has ACLY inhibitory activity, can be used as ACLY protein inhibitor for for ACLY inhibitor medicaments
Exploitation.
Embodiment 3: inhibit proliferative activity o f tumor
Select common Cell line, including t cell lymphoma cell strain Jurkat, cervical cancer cell lines
Former white blood cell strain K562 of HeLa, colon cancer cell HCT116, chronic marrow etc., passes through CellTiter-Luminescence method is thin
Born of the same parents' viability detection kit evaluate dehydrogenation curvularin (DCV), curvularin (CV) and its molecular probe (DCV-yne and
CV-yne) to the influence of tumor cell proliferation.
1. compound of table inhibits tumor cell proliferation IC50It is worth (μM)
| Tumor cell line | DCV | CV | DCV-yne | CV-yne |
| HeLa | 3.86±0.66 | >100 | 6.89±0.81 | >100 |
| Jurkat | 1.55±0.24 | >100 | 3.50±0.46 | >100 |
| HCT116 | 4.60±0.82 | >100 | 12.2±1.56 | >100 |
| K562 | 3.66±0.24 | >100 | 7.48±0.88 | >100 |
By upper table, it can be concluded that, dehydrogenation curvularin and its probe DCV-yne have significantly four kinds of tumor cell lines
Antiproliferative activity, IC50Value is 1.5-4.6 μM.And curvularin and its probe CV-yne do not have four kinds of tumor cell lines
There is antiproliferative activity.Prove that compound of the present invention can be used for the exploitation of anti-tumor drug.
Claims (3)
1. application of the dehydrogenation curvularin in the drug of the inhibitor as ATP- citrate lyase.
2. application of the dehydrogenation curvularin on the drug that preparation inhibits tumor cell proliferation.
3. application according to claim 1, which is characterized in that the tumour cell includes t cell lymphoma cell strain
The former white blood cell strain K562 of Jurkat, cervical cancer cell lines HeLa, colon cancer cell HCT116, chronic marrow.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110658314A (en) * | 2019-10-12 | 2020-01-07 | 四川大学 | Method for identifying target of compound, method for detecting interaction between compound and target, and method for evaluating drug effect of compound |
| CN115068455A (en) * | 2022-07-14 | 2022-09-20 | 中南大学湘雅三医院 | Application of BMS-303141 in preparation of medicine for treating chronic kidney disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104988193A (en) * | 2015-07-07 | 2015-10-21 | 三峡大学 | Production method for 10, 11-dehydrogenated curvularin and application thereof |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104988193A (en) * | 2015-07-07 | 2015-10-21 | 三峡大学 | Production method for 10, 11-dehydrogenated curvularin and application thereof |
Non-Patent Citations (6)
| Title |
|---|
| ALY,AMAL H等: "NF kappa B inhibitors and antitrypanosomal metabolites from endophytic fungus Penicillium sp. isolated from Limonium tubiflorum", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| HE JIAN等: "Cytotoxic and other metabolites of Aspergillus inhabiting the rhizosphere of Sonoran desert plants", 《JOURNAL OF NATURAL PRODUCTS》 * |
| KUMAR,CG等: "Metabolite profiling and biological activities of bioactive compounds produced by Chrysosporium lobatum strain BK-3 isolated from Kaziranga National Park, Assam, India", 《SPRINGERPLUS》 * |
| MENG,LING-HONG等: "Sulfur-Containing Cytotoxic Curvularin Macrolides from Penicillium sumatrense MA-92, a Fungus Obtained from the Rhizosphere of the Mangrove Lumnitzera racemosa", 《JOURNAL OF NATURAL PRODUCTS》 * |
| TILLOTSON JOSEPH等: "Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| 李丹: "两株滨海植物内生菌次级代谢产物及其抗肿瘤活性研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110658314A (en) * | 2019-10-12 | 2020-01-07 | 四川大学 | Method for identifying target of compound, method for detecting interaction between compound and target, and method for evaluating drug effect of compound |
| CN115068455A (en) * | 2022-07-14 | 2022-09-20 | 中南大学湘雅三医院 | Application of BMS-303141 in preparation of medicine for treating chronic kidney disease |
| CN115068455B (en) * | 2022-07-14 | 2023-11-07 | 中南大学湘雅三医院 | Application of BMS-303141 in preparation of medicine for treating chronic kidney disease |
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