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
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- 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
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- shikonin
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- 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
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Abstract
本发明主要涉及五种紫草素衍生物在制备丙酮酸激酶抑制剂中的应用，所述紫草素衍生物为下列之一：去氧紫草素、异丁酰紫草素、β，β-二甲基丙烯酰紫草素、异戊酰紫草素、2-甲基-正丁酰紫草素。目前报道的M2型丙酮酸激酶(简称PKM2)抑制剂有Compound 3，而本发明发现紫草素天然衍生物抑制PKM2的作用比Compound 3强。因此，紫草素天然衍生物作为丙酮酸的抑制剂其本身有重要的应用价值。本发明的有益效果主要体现在：提供了五种新的丙酮酸激酶抑制剂——紫草素天然衍生物，为新药筛选提供了基础，具有重要应用前景。The present invention mainly relates to the application of five shikonin derivatives in the preparation of pyruvate kinase inhibitors. The shikonin derivatives are one of the following: deoxyshikonin, isobutyrylshikonin, β, β -Dimethacrylshikonin, isovalerylshikonin, 2-methyl-n-butyrylshikonin. Currently reported M2-type pyruvate kinase (abbreviated as PKM2) inhibitor is Compound 3, but the present invention finds that the shikonin natural derivative has a stronger inhibitory effect on PKM2 than Compound 3. Therefore, shikonin natural derivatives have important application value as inhibitors of pyruvate. The beneficial effects of the present invention are mainly reflected in that five new pyruvate kinase inhibitors-shikonin natural derivatives are provided, which provide a basis for new drug screening 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 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546450A (en) * | 2003-12-04 | 2004-11-17 | 上海交通大学 | Shikonin derivatives and their metal complexes as immunosuppressants |
| 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 naphthoquinones |
| 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 pharmacy |
-
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 | Shikonin derivatives and their metal complexes as immunosuppressants |
| 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 naphthoquinones |
| CN101721401A (en) * | 2008-10-10 | 2010-06-09 | 上海交通大学医学院 | Application of beta hydroxyisovaleryl shikonin in pharmacy |
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Application publication date: 20120711 |