CN102552227A - Application of shikonin derivatives to preparation of pyruvate kinase inhibitors - Google Patents
Application of shikonin derivatives to preparation of pyruvate kinase inhibitors Download PDFInfo
- Publication number
- CN102552227A CN102552227A CN2010106160010A CN201010616001A CN102552227A CN 102552227 A CN102552227 A CN 102552227A CN 2010106160010 A CN2010106160010 A CN 2010106160010A CN 201010616001 A CN201010616001 A CN 201010616001A CN 102552227 A CN102552227 A CN 102552227A
- Authority
- CN
- China
- Prior art keywords
- shikonin
- pyruvate kinase
- pkm2
- compound
- kinase inhibitors
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- LBDOGIZEEBHJSE-UHFFFAOYSA-N Cc1ccc(C)[n]1-c(cc1C(O)=O)ccc1O Chemical compound Cc1ccc(C)[n]1-c(cc1C(O)=O)ccc1O LBDOGIZEEBHJSE-UHFFFAOYSA-N 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N Nc(cc1)cc(C(O)=O)c1O Chemical compound Nc(cc1)cc(C(O)=O)c1O KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention mainly relates to application of five shikonin derivatives to preparation of pyruvate kinase inhibitors. The shikonin derivatives are one of deoxyshikonin, isobutyryl shikonin, beta,beta-dimethylacrylshikonin, Isovalerylshikonin and [(2-methyl-n-butyl)shikonin. A currently reported M2 pyruvate kinase (PKM2) inhibitor is Compound 3. According to the invention, natural shikonin derivatives have higher inhibiting effects on the PKM2 compared with the Compound 3. The natural shikonin derivatives serving as pyruvate kinase inhibitors have important application value. The invention has the advantages that: the five new pyruvate kinase inhibitors, namely natural shikonin derivatives, provide bases for screening of new medicines and have important application prospects.
Description
(1) technical field
The present invention relates generally to the application of five kinds of alkannin derivants in preparation pyruvate kinase inhibitor.
(2) background technology
Five kinds of alkannin derivants that the present invention relates to are naturally occurring naphthoquinone compound, and its general formula is following:
Wherein R is a substituted radical.
Pyruvate kinase is a crucial rate-limiting enzyme in the glycolysis, in energy metabolism, plays pivotal role.The M2 type pyruvate kinase that the present invention relates to (being called for short PKM2) mainly is present in individual early development and the tumor tissues.The PKM2 inhibitor of having reported at present seldom, micromolecular compound inhibitor compound 3 one examples (Vander Heiden MG, Christofk HR only wherein; Schuman E, Subtelny AO, Sharfi H; Harlow EE et al.Biochem Pharmacol2010; 79,1118.), its amount (being IC50) that suppresses the work of 50% enzyme is 50 μ M.
Up to the present, also do not have the shikonin natural derivative to have pyruvate kinase and suppress active report.
(3) summary of the invention
The purpose of this invention is to provide the new application of five kinds of alkannin derivants in preparation pyruvate kinase inhibitor.
The technical scheme that the present invention adopts is: under the room temperature condition; The PKM2 of chemical compound and reorganization is hatched half an hour, through detecting the effect that matched group (only adding drug solvent DMSO) and the active difference of each experimental group (interpolation medicine) PKM2 can confirm that the medicine inhibitory enzyme is lived.
Said alkannin derivant is one of following: deoxyshikonin, isobutyryl shikonin, β, beta-dimethyl-acryloyl shikonin, isovaleryl shikonin, 2-methyl-positive butyryl shikonin.
The substituted radical of described five kinds of shikonin natural derivative and the numbering as follows:
Title | Numbering | R |
Deoxyshikonin | DS | H |
Isobutyryl shikonin | IBS | OCOCH(CH 3) 2 |
β, beta-dimethyl-acryloyl shikonin | DMS | OCOCH=C(CH 3) 2 |
The isovaleryl shikonin | IVS | OCOCH 2CH(CH 3) 2 |
Alpha-Methyl-positive butyryl shikonin | MBS | OCOCH(CH 3)CH 2CH 3 |
Said pyruvate kinase is PKM2.
The PKM2 inhibitor of report has Compound 3 (molecular structure is following) at present, and the present invention finds that the effect of shikonin natural derivative inhibition PKM2 is than Compound the last 3.Therefore, the shikonin natural derivative itself has important use to be worth as the inhibitor of pyruvate kinase.
Beneficial effect of the present invention is mainly reflected in: five kinds of new pyruvate kinase inhibitor---shikonin natural derivative is provided, for new medicament screen provides the foundation, has had the important application prospect.
(4) description of drawings
Fig. 1 is embodiment 1 synthetic Compound 3 Mass Spectrometer Method results.
(5) specific embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1:
Experiment material:
The standard substance of 5 kinds of alkannin derivants are available from Japanese Wako company.
PKM2 is available from U.S. BPS Biosciences company.
β-NADH, ADP and phosphoenolpyruvate (PEP) are available from Roche company;
Tris, HCl, KCl, MgCl are available from sky day company.
Dimethyl sulfoxine (DMSO), lactic acid dehydrogenase (LDH) are available from Sigma company.
Compound 3 is synthetic voluntarily, and synthetic method is following: in the 25ml round-bottomed flask, add 5-aminosalicylic acid (5mmol) successively, and 2,5-acetyl butyryl (6mmol), p-methyl benzenesulfonic acid (0.05mmol), toluene 10ml, reflux 1h.After reaction finished, unnecessary toluene was removed in decompression, the bullion column chromatography, eluent is a petroleum ether: the mixed solvent of ethyl acetate=1: 1, productive rate is about 70%.Product is with petroleum ether and re-crystallizing in ethyl acetate.Reaction equation:
Synthetic Compound 3 character: Orange solid, mp.167-169 ℃,
1H-NMR (CDCl
3) δ 10.45 (s, 1H), 7.83 (d, J=2.4Hz, 1H), 7.42-7.39 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 5.93 (s, 2H), 2.06 (s, 6H) ppm; MS (ESI) m/z 232.0 ([M+H]
+).The synthetic product of Mass Spectrometer Method proof is Compound 3, and the mass spectrum result sees Fig. 1.
Experimental technique:
PKM2 is active in lactic acid dehydrogenase (LDH) coupled reaction system (Vander Heiden MG, Christofk HR, Schuman E; Subtelny AO, Sharfi H, Harlow EE et al.BiochemPharmacol2010; 79,1118.) detect, enzyme reaction solution comprises 50mM Tris-HCl (pH 7.5); 100mM KCl, 10mM MgCl
2, 0.6mM PEP, 0.9mM ADP; 0.12mM β-NADH, 4.8units/ml LDH is in 20 minutes; Judge the vigor of PKM2 catalytic action through detecting the substrate β-minimizing of NADH content; Known substrate β-NADH by ultraviolet excitation after, can launch 340nm fluorescence, the amount that 340nm fluorescence reduces is directly proportional with the amount of the minimizing of β-NADH content.PKM2 catalytic reaction formula is following:
The compound solution that 1 μ l variable concentrations is got in this experiment and 9 μ l concentration are that the PKM2 solution of 50pg/ μ l mixes; After hatching 30 minutes under the room temperature, join in the above-mentioned enzyme reaction solution of 125 μ l, detect 340nm fluorescent absorption amount; Judge under the variable concentrations compound effects catalytic activity of PKM2.When utilizing software SigmaPlot 10.0 calculating inhibition 50% enzyme to live again, the concentration of alkannin derivant, i.e. IC50.This experiment has detected the activity of Compound 3 inhibition PKM2 simultaneously, and under same experiment condition, the effect and the Compound 3 that alkannin derivant are suppressed PKM2 contrast.
Experimental result:
Experimental result is seen table 1, and 5 kinds of shikonin natural derivative suppress the IC50 difference of PKM2, but all is lower than the IC50 (37.4 μ M) of Compound 3 inhibition PKM2 under the same experiment condition.Known IC50 is low more, and the dosage of the required inhibitor of inhibitory enzyme activity is more little, and promptly inhibitor effect is good more.The present invention explains that the effect of these 5 kinds of shikonin natural derivative inhibition PKM2 far above the inhibitor Compound of having reported for work 3, is the inhibitor of very effective PKM2.
Table 1: five kinds of shikonin natural derivative and Compound 3 suppress the IC50 of PKM2
Numbering/title | IC50(μM) |
IVS | 2.03 |
DMS | 2.6 |
IBS | 3.03 |
MBS | 2.2 |
DS | 1.97 |
Compound?3 | 37.4 |
Claims (2)
1. the application of alkannin derivant in preparation pyruvate kinase inhibitor; Said alkannin derivant is one of following: deoxyshikonin, isobutyryl shikonin, β, beta-dimethyl-acryloyl shikonin, isovaleryl shikonin, 2-methyl-positive butyryl shikonin.
2. application as claimed in claim 1 is characterized in that said pyruvate kinase is a M2 type pyruvate kinase.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010106160010A CN102552227A (en) | 2010-12-30 | 2010-12-30 | Application of shikonin derivatives to preparation of pyruvate kinase inhibitors |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010106160010A CN102552227A (en) | 2010-12-30 | 2010-12-30 | Application of shikonin derivatives to preparation of pyruvate kinase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102552227A true CN102552227A (en) | 2012-07-11 |
Family
ID=46399692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010106160010A Pending CN102552227A (en) | 2010-12-30 | 2010-12-30 | Application of shikonin derivatives to preparation of pyruvate kinase inhibitors |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102552227A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1546450A (en) * | 2003-12-04 | 2004-11-17 | 上海交通大学 | Alkannin derivatives as immune inhibitors and metal complexes thereof |
CN101194920A (en) * | 2006-09-29 | 2008-06-11 | 杭州贺博生物技术有限公司 | Lithospermum and application of its active ingredient in preparing medicament for treating tumour stem cell |
CN101234100A (en) * | 2008-02-04 | 2008-08-06 | 浙江大学 | Application of naphthoquinone compounds |
CN101310714A (en) * | 2007-05-24 | 2008-11-26 | 中国科学院上海生命科学研究院 | Use of retinol X receptor used for screening alkannin and derivates thereof |
CN101721401A (en) * | 2008-10-10 | 2010-06-09 | 上海交通大学医学院 | Application of beta hydroxyisovaleryl shikonin in medicament production |
-
2010
- 2010-12-30 CN CN2010106160010A patent/CN102552227A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1546450A (en) * | 2003-12-04 | 2004-11-17 | 上海交通大学 | Alkannin derivatives as immune inhibitors and metal complexes thereof |
CN101194920A (en) * | 2006-09-29 | 2008-06-11 | 杭州贺博生物技术有限公司 | Lithospermum and application of its active ingredient in preparing medicament for treating tumour stem cell |
CN101310714A (en) * | 2007-05-24 | 2008-11-26 | 中国科学院上海生命科学研究院 | Use of retinol X receptor used for screening alkannin and derivates thereof |
CN101234100A (en) * | 2008-02-04 | 2008-08-06 | 浙江大学 | Application of naphthoquinone compounds |
CN101721401A (en) * | 2008-10-10 | 2010-06-09 | 上海交通大学医学院 | Application of beta hydroxyisovaleryl shikonin in medicament production |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Belleau et al. | Occupancy of Adrenergic Receptors and Inhibition of Catechol O-Methyl Transferase by Tropolones1, 2 | |
Xiao et al. | Methyl jasmonate dramatically enhances the accumulation of phenolic acids in Salvia miltiorrhiza hairy root cultures | |
Wu et al. | Discovery and evaluation of piperid-4-one-containing mono-carbonyl analogs of curcumin as anti-inflammatory agents | |
Ćilerdžić et al. | Neuroprotective potential and chemical profile of alternatively cultivated Ganoderma lucidum basidiocarps | |
Vanderhoek et al. | The inhibition of the fatty acid oxygenase of sheep vesicular gland by antioxidants | |
Wang et al. | Bacterial neuraminidase inhibitory effects of prenylated isoflavones from roots of Flemingia philippinensis | |
Nikolic et al. | New metabolic pathways for flavanones catalyzed by rat liver microsomes | |
Chen et al. | New bactericide derived from Isatin for treating oilfield reinjection water | |
EP3611170B1 (en) | Deuterated compounds and medical use thereof as antianxiety agents | |
Pedras et al. | The cruciferous phytoalexins rapalexin A, brussalexin A and erucalexin: chemistry and metabolism in Leptosphaeria maculans | |
Krauss et al. | Synthesis and Biological Evaluation of Novel N‐Alkyl Tetra‐and Decahydroisoquinolines: Novel Antifungals that Target Ergosterol Biosynthesis | |
Rezaei et al. | Developmental accumulation of thebaine and some gene transcripts in different organs of Papaver bracteatum | |
EP2977381B1 (en) | Terpenoid derivative | |
Akçok et al. | Synthesis of stilbene-fused 2′-hydroxychalcones and flavanones | |
CN113563409B (en) | Natural triterpene-iridoid glycoside dimer heterocomplex, preparation method thereof and application thereof in preparation of ACL inhibitor | |
Hayes et al. | Effects of rubratoxin B on liver composition and metabolism in the mouse | |
CN108530435B (en) | Quinoxaline-containing 1, 4-pentadiene-3-ketone derivative, preparation method and application | |
CN102552227A (en) | Application of shikonin derivatives to preparation of pyruvate kinase inhibitors | |
CN112457357B (en) | Method for extracting isoquercitrin from sunflower disc and application of isoquercitrin in preparation of xanthine oxidase inhibitor | |
JPH0578299A (en) | Polyhydroxybenzoic acid derivative and method for suppressing leukemia by using same | |
Ali Shah et al. | Metabolic and pharmacological profiling of Penicillium claviforme by a combination of experimental and bioinformatic approaches | |
Zhang et al. | Analysis of Amaryllidaceae alkaloids from Crinum by high‐performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry | |
Krishna Kumari et al. | Synthesis of Dihydropyridine Derivatives under Eco‐friendly Approach and Investigation of Cytotoxic Activity | |
Selvaraj et al. | Larvicidal activity of novel anthraquinone analogues and their molecular docking studies | |
CN112641819B (en) | Application of flos heptadendri chinensis extract in preparation of ATP citrate lyase inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120711 |