CN105461641A - Beta-lapachol-monastrol heterozygote and preparation method and medical application thereof - Google Patents
Beta-lapachol-monastrol heterozygote and preparation method and medical application thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 7
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- 238000006243 chemical reaction Methods 0.000 claims description 11
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
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- 238000000746 purification Methods 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
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- 238000010189 synthetic method Methods 0.000 claims 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to beta-lapachol-monastrol heterozygote and a preparation method and medical application thereof and provides a compound of the structure as shown in the formula (I), a preparation method thereof and application to preparation of tumor medicine. The compound is of a heterozygosis structure of beta-lapachol and monastrol, high in antitumor activity and metabolism stability and good in selectivity. In-vitro cellular poison and topoisomerase (I) inhibition tests indicate that the compound has great inhibition effects for both test cancer cells and topoisomerase (I), NQO1 activity tests indicate that the compound is an effective substrate of NQO1 and can generate a great amount of active oxygen under the mediation of NQO1 through redox reaction circulation, oxidative stress is induced, tumor cells are killed selectively, and the compound can serve as an anti-cancer drug or a lead compound for further development. The method has the advantages that greenness and environmental friendliness are achieved, raw materials are easy to obtain, operation is simple, and the yield is high.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of β-lapachol-mono-star element heterozygote, comprise the purposes of this compounds process for production thereof and the medicine as preparation treatment malignant tumour.
Background technology
Malignant tumour is one of important diseases of current harm humans health, is the new millennium mankind first killer, forms the most serious threat to human survival, and exploitation and the novel effective antitumour medicine of research are key subjects and the long-range missions of biological medicine scientific research field.Relying on DPNH (II) quinone oxidoreductase 1 (NQO1) is a ubiquitous class flavin protease in eukaryotic cell, and it can participate in the metabolism of multiple quinones and the bioactivation process of quinones medicine in body by de-electronation reduction reaction.The expression of NQO1 in kinds of tumor cells particularly liver cancer, colorectal carcinoma, breast cancer cell is far above healthy tissues.Due to the high expression level of NQO1 at tumour cell and the characteristic of bioactivation thereof, it is considered to the potential molecular target for the treatment of kinds of tumors.β-lapachol, chemistry 3,4-dihydro-2,2-dimethyl-2 by name
h-naphtho-[1,2-
b]-pyrans-5,6-diketone is a NQO1 targeted drug the most promising, it is effective NQO1 substrate, under NQO1 mediation, can be reacted by oxidation reduction cycle, produce active oxygen radical, induced oxidation stress, kill significantly NQO1 express cancer cells.Another research shows: β-lapachol also has very strong suppression to topoisomerase I, to β-lapachol structure of modification, contributes to the cancer therapy drug found for NQO1 or topoisomerase I.
Dihydropyrimidinones has important pharmacologically active in the field such as antitumor, antiviral, antibacterial and anti-oxidant, is one of synthesis focus of organic heterocyclic molecule in recent years.The microtubule spindle kinesin inhibitor list star element with this basic mother nucleus structure is a new antitumoral lead compound of discovered in recent years, and its feature does not affect microtubule stability and avoids producing neurotoxicity, and correlative study is subject to extensive concern.
In recent years, between pharmacophore or active compound, carry out rational molecular hybridization, as the New Policy of drug discovery, be subject to synthetic chemistry and Pharmaceutical Chemist is paid attention to greatly.Heterozygote compound generally has than the better avidity of parent compound and pharmacological action, is the effective way finding to have independent intellectual property right new chemical entities medicine.Innovation of the present invention is to have synthesized a kind of β-lapachol-mono-star element heterozygote, and this compound not yet has report at present.Cell in vitro poison and topoisomerase I inhibition test show that this compound is to testing cancer cells and topoisomerase I all has stronger restraining effect, to test with the molecular docking of NQO1 and NQO1 activity experiment shows, this compound and NQO1 have higher affinity, can be activated by NQO1, produce active oxygen radical, selectively killing tumour cell, the cancer therapy drug that can be used as target topoisomerase I or NQO1 is developed further.
Summary of the invention
The object of the present invention is to provide a kind of β-lapachol-mono-star element heterozygote.
Another object of the present invention is to preparation method and medicinal use that described β-lapachol-mono-star element heterozygote is provided.
In order to realize the object of the invention, β-lapachol of the present invention-mono-star element heterozygote, it is for having the compound of structure shown in formula I:
I。
Specifically, β-lapachol of the present invention-mono-star element heterozygote is 1,2,3,4 tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone, molecular formula: C
18h
12n
2o
3s, molecular weight: 336.06, outward appearance: orange/yellow solid.
The present invention also provides the preparation method of above-mentioned β-lapachol-mono-star element heterozygote, is dissolved into by the p-methyl benzenesulfonic acid of 2 hydroxy 1,4 naphthoquinone (lawsone), m-hydroxybenzaldehyde, thiocarbamide and catalyst levels in appropriate acetic acid, heating reflux reaction 8-10 hour, after reaction, by reaction mixture cool to room temperature, steam acetic acid, crude product uses suitable quantity of water successively, washing with alcohol, column chromatography purification, obtain target compound 1,2,3,4-tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone.
The reaction formula of preparation method of the present invention is:
Above-mentioned β-lapachol provided by the invention-mono-star element heterozygote is effective substrate of topoisomerase I inhibitor and bielectron oxydo-reductase NQO1, can be used for the targeted drug preparing treatment malignant tumour.
Advantage of the present invention and beneficial effect are:
1. heterozygote of the present invention has the structure of β-lapachol and single star element, and novel structure has the selectivity that stronger antitumour activity is become reconciled;
2. the anti-tumor activity of the compounds of this invention and druggability are better than β-lapachol;
3. show that this compound all has stronger restraining effect to topoisomerase I with topoisomerase I inhibition test;
4. test with the molecular docking of NQO1 and NQO1 activity experiment shows, this compound and NQO1 have higher affinity, can be activated by NQO1, generation active oxygen radical, selectively killing tumour cell, and the cancer therapy drug that can be used as target NQO1 is developed further;
5. preparation method of the present invention has environmental protection, and raw material is easy to get and feature simple to operate.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
The synthesis of embodiment 1 compound
By 1.74g2-hydroxyl-1,4-naphthoquinone, 1.22g3-hydroxy benzaldehyde, 1.52g thiocarbamide, 0.2g p-methyl benzenesulfonic acid and 20mL acetic acid join in the 50mL flask with reflux condensing tube, after stirring and refluxing 8-10 hour, cool to room temperature, steams solvent, uses water successively, washing with alcohol, column chromatography purification, obtains corresponding orange product 1,2,3,4-tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone 168mg, productive rate is 4.8%.
1HNMR(400MHz,DMSO-
d 6)
δ:9.97(s,2H),9.52(s,1H),8.05-7.84(m,4H),7.15(t,1H,
J=8.0Hz),6.80-6.76(m,2H),6.69-6.67(m,1H),5.44(s,1H);
13CNMR(100MHz,DMSO-
d 6)
δ:181.5,178.6,174.9,158.1,143.5,136.1,135.3,134.2,132.0,130.8,130.3,126.6,126.2,118.0,116.5,115.6,114.2,52.9；ESI-HRMSm/z[M-H]
+:335.0489。
Embodiment 2 anti tumor activity in vitro is tested
Adopt the anti-tumor activity of mtt assay test target compound.With human liver cancer cell HepG2 and colon cancer cell HCT116 for test cell strain, select the attached tumor cells of logarithmic phase, after trysinization, the cell suspension of 5000/mL is made into the RPMIl640 substratum containing 10% calf serum, be seeded in 96 well culture plates, 200 μ L are inoculated in every hole, 37 DEG C, 5%CO
2cultivate 24 hours.Set up negative control group, positive controls and administration group.The substratum containing different concns sample that experimental group renews, control group then changes the substratum containing equal-volume solvent, and positive controls gives positive control drug Zorubicin, and (being diluted to concentration with perfect medium is 10 μm of olL
-1), often group establishes 3-5 parallel hole, 37 DEG C, 5%CO
2cultivate 4-5 days.Abandoning supernatant, every hole adds the freshly prepared serum free medium containing 0.2mg/mLMTT of 200 μ L.37 DEG C are continued cultivation 4 hours.Carefully abandoning supernatant, and add 200 μ LDMSO, after the mixing of miniature ultrasonic vibrator, microplate reader is 570nm with tested wavelength, and reference wavelength is that 450nm measures optical density value.Be calculated as follows the inhibiting rate of drug on tumor Growth of Cells: growth of tumour cell inhibiting rate %=(1-OD experiment/OD contrasts) × 100%.With 1,2,3,4-tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone different concns to growth of tumour cell inhibiting rate mapping can obtain dose response curve, therefrom obtain the half casualty-producing concentrations IC of sample
50.Its IC
50value is 3.18 μMs (HepG2), 3.29 μMs (HCT116).
Embodiment 3NQO1 active testing
Containing 25mMTris/HCl (pH7.4) in the reaction system of 1mL, 0.7mg/mL bovine serum albumin, 0.1%Tween-20,200 μMs of NADH, 77 μMs of Cytochromec, 2 μ g recombinant human NQOl and 1,2,3,4-tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone (25 μMs).Setting determined wavelength 550nnm, at room temperature, adds NADH and starts reaction, calculate rate of reduction from the initial linear portion of response curve, by cytochrome c molar absorptivity conversion (21.1mM
-1cm
-1), result is expressed as a μm ol reduced form cytochrome c/min/ μ gNQOl.Can judge that compound produces the ability of active oxygen from the change of cytochrome c amount, the speed that compound produces active oxygen at enzyme level is 1350 ± 165 μm of ol reduced form cytochrome cs/min/ μ gNQOl.
embodiment 4 molecular docking is tested
ChemBioDrawUltra12.0 is adopted to draw small molecules 1,2,3,4 tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] structure of quinoline azoles beautiful jade-5,6-diketone, then use the MMFF94 field of force to be optimized with ChemBio3DUltra12.0.NQO1 (PDBID:2F1O) and compound all use AutodockTools1.5.6 to be converted into PDBQT form.Autodockvina1.1.2 is adopted to carry out molecular Docking Study.The coordinate of NQO1 is set to: center_x=11.549, center_y=11.875, center_z=-6.018; Size_x=15, size_y=15, size_z=15.Parameter exhaustiveness is set to 20.Except special instruction, other parameters all adopt default value.Finally, choose the highest conformation PyMoL1.7 of marking value and carry out interpretation of result (Fig. 1).Found out by Fig. 1, compound is in parallel state with coenzyme F AD, forms strong pi-pi accumulation effect.In addition, hydrogen bond is the main phase mutual effect between CP2 and NQO1.Detailed analysis can obtain, and the 5-position ketonic oxygen of Compound C P2 can form interaction of hydrogen bond with amino-acid residue Tyr128, and the ketonic oxygen of 6-position can form dual hydrogen bond action with amino-acid residue Tyr126 and Tyr128.The more important thing is, the 4-interdigit hydroxy phenyl part of compound is parallel to the phenyl ring part of residue Tyr128, forms strong pi-pi accumulation effect.
Embodiment 4 topoisomerase I Inhibition test
The activity of TopoI enzyme is judged by the relaxation cases of observation superhelix pBR322DNA, the DNATopoI of 1 unit is defined as 37 DEG C, under standard reaction condition, through the amount of the TopoI needed for 30 minutes completely lax 0.5 μ g negative supercoiling pBR322 DNA.Testing sample first dissolves with DMSO, by the required solution to be measured being diluted to different concns, makes final concentration be respectively 400 μMs, 200 μMs, 100 μMs, 50 μMs, and camptothecine same method dilutes, final concentration 200 μMs.Reaction mixture (10 μ L), comprises H
2o(6.5 μ L), 10 × DNATopoIBuffer(1 μ L), 0.1%BSA(1 μ L), DNATopoI(0.5U), the testing sample (1 μ L) of pBR322DNA (0.25 μ g), different concns.After adding above-mentioned reaction mixture, centrifugation makes various uniform composition mix, and the while of afterwards, constant temperature 30 minutes, adds reaction terminating liquid (10 × LoadingBuffer, 1 μ L) stopped reaction respectively; On the sepharose of 1%, in tbe buffer liquid, electrophoresis 2 hours under 75V constant-pressure conditions, the gel ethidium bromide solution of 1 μ g/mL dyes 30 minutes, finally observes electrophoresis result with gel imaging system and takes a picture.Compound can suppress the activity (Fig. 2) of TopoI enzyme completely at 200 μMs.
Accompanying drawing illustrates: Fig. 1 is 1,2,3,4 tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzos [
h] molecular docking of quinoline azoles beautiful jade-5,6-diketone and NQO1, wherein dotted line is the hydrogen bond formed.Fig. 2 is 1,2,3,4 tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [h] quinoline azoles beautiful jade-5,6-diketone on the impact of topoisomerase I activity, wherein A road: pBR322DNA; B road: pBR322DNA+0.5UTOPOI enzyme; C road: pBR322DNA+0.5UTOPOI enzyme+camptothecine 200 μMs; D, E, F, G road pBR322DNA+0.5UTOPOI enzyme+1,2,3,4 tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone (difference 400,200,100,50 μMs).
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (3)
1. β-lapachol-mono-star element heterozygote, it is characterized in that, it is for having the compound of structure shown in formula I:
I。
2. prepare the synthetic method of heterozygote according to claim 1, it is characterized in that, by 2-hydroxyl-1, the p-methyl benzenesulfonic acid of 4-naphthoquinones, m-hydroxybenzaldehyde, thiocarbamide and catalyst levels is dissolved in appropriate acetic acid, and heating reflux reaction 8-10 hour, after reaction, by reaction mixture cool to room temperature, steam acetic acid, crude product uses suitable quantity of water successively, washing with alcohol, column chromatography purification, obtains target compound 1,2,3,4-tetrahydrochysene-4-(3-hydroxy phenyl)-2-sulfo-benzo [
h] quinoline azoles beautiful jade-5,6-diketone.
3. the compound of claim 1 is for the preparation of the purposes of medicine for the treatment of malignant tumour.
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