CN105153060A - Shikonin carboxylate derivatives, and synthetic method and application thereof - Google Patents
Shikonin carboxylate derivatives, and synthetic method and application thereof Download PDFInfo
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- CN105153060A CN105153060A CN201510416326.7A CN201510416326A CN105153060A CN 105153060 A CN105153060 A CN 105153060A CN 201510416326 A CN201510416326 A CN 201510416326A CN 105153060 A CN105153060 A CN 105153060A
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- 241001071917 Lithospermum Species 0.000 title claims abstract description 29
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 29
- -1 Shikonin carboxylate Chemical class 0.000 title claims abstract description 5
- 238000010189 synthetic method Methods 0.000 title description 2
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 claims abstract description 26
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 15
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract 2
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 230000005918 in vitro anti-tumor Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 6
- 230000005760 tumorsuppression Effects 0.000 description 4
- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 2
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 235000004256 Buglossoides arvense Nutrition 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 241000118841 Lithospermum incisum Species 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 229930192627 Naphthoquinone Natural products 0.000 description 1
- 102100029177 PDZ and LIM domain protein 3 Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
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- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical pharmacy, and concretely relates to phenyloxadiazolyl shikonin carboxylate derivatives, and an application thereof in tumor inhibition. Corresponding carboxylic acid is connected with shikonin through a synthesis means to obtain the corresponding ester derivatives, and a result of in vitro antitumor activity researches shows that the shikonin carboxylate derivatives have very strong inhibition activity on tumor cell strains.
Description
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to the preparation of a class Ben oxadiazole shikonin ramification of carboxylic esters and the application in tumor suppression thereof.
Two: background technology
Shikonin is naphthoquinone compound, is a kind of natural product extracted from Asian puccoon, has the biological activity of wide spectrum, as anti-inflammatory, antitumor, immunomodulatory, sterilization and the effect such as antiviral.Recent study shows, it has very large potentiality as primer in the functional molecular research of Tumor suppression activity.
" Shikoninmodulatescellproliferationbyinhibitingepidermalg rowthfactorreceptorsignalinginhumanepidermoidcarcinomace lls " that Singh etc. deliver finds that Shikonin suppresses human epidermal cell to be bred in the mode of time and dose-dependently, reduce the phosphorylation level of EGFR, ERK1/2 and Tyrosylprotein kinase, and then affecting cytoplasmic MAPK signal path, the phosphorylation level of JNK increases.Have investigator to find Shikonin suppresses human osteosarcoma cell line to be survived with dosage and time-dependent manner mode simultaneously, and the generation of induction ROS, increases the phosphorylation of ERK albumen, reduces the expression of Bcl-2, causes apoptosis.
Kumar, A. etc., suppress the transduction of HIF-1 in EAT cell by research replacement 1,3,4-oxadiazole derivative and study its antiproliferative activity.Result display well suppresses the activity of EAT.With facs analysis and the method reducing ALP activity, replace 1,3,4-oxadiazole derivative and there is effective antiproliferative activity.In addition ， Han oxadiazole rings derivative is due to the effect to nuclear translocation, and the expression of HIF-1 is reduced.
The toxic side effect that shikonin is potential and the shortcoming such as poorly soluble, make it be difficult to as clinical candidates.Based on the shortcoming of above-mentioned shikonin and 1,3,4-oxadiazole derivative, all there is very strong antiproliferative activity.This seminar carries out structural modification to shikonin, by lead compound shikonin Yu oxadiazole rings is tied by intermediate bridging, to obtaining the Shikonin Derivative Formation of high-efficiency low-toxicity.
Three: summary of the invention
The present invention needs problem Ben oxadiazole shikonin ramification of carboxylic esters being to provide a class formation novelty solved and preparation method thereof and the application in tumor suppression.
Ben oxadiazole shikonin ramification of carboxylic esters structural formula of the present invention is such as formula shown in I:
Four: accompanying drawing explanation
Fig. 1 represents the inhibit activities of shikonin ramification of carboxylic esters to tumour cell MCF-7
Fig. 2 represents the inhibit activities of shikonin ramification of carboxylic esters to tumour cell A549
Fig. 3 represents the inhibit activities of shikonin ramification of carboxylic esters to tumour cell HeLa
Five: embodiment
Example one: the preparation of shikonin ramification of carboxylic esters
Under condition of ice bath, in 50mL round-bottomed flask, add shikonin, corresponding carboxylic acid, refining methylene dichloride and catalyzer successively, TLC detection reaction is complete, obtains corresponding shikonin ramification of carboxylic esters through thin plate chromatographic separation.
The physicochemical data of respective compound is as follows:
Compound 1:
1hNMR (300MHz, CDCl
3) δ 12.55 (s, 1H ,-OH), 12.38 (s, 1H,-OH), 7.87 (t, J=8.2Hz, 4H, Ar-H), 7.31 (s, 1H, Ar-H), 7.29 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 5.98 (d, J=1.6Hz, 1H ,-CH=C), 5.30 (s, 1H,-CH), 3.81 (s, 2H ,-CH
2), 2.42 (d, J=2.6Hz, 3H ,-CH
3), 2.35 (t, J=7.5Hz, 2H ,-CH
2), 1.65 (d, J=6.1Hz, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Compound 2:
1hNMR (300MHz, CDCl
3) δ 12.54 (d, J=7.7Hz, 1H ,-OH), 12.38 (s, 1H ,-OH), 7.92 (d, J=7.9Hz, 2H, Ar-H), 7.16 (s, 3H, Ar-H), 7.07 (s, 1H, Ar-H), 6.91 (s, 1H, Ar-H), 6.12 (s, 1H ,-CH=C), 5.14-5.07 (m, 1H,-CH), 4.18 (s, 2H ,-CH
2), 2.36 (t, J=7.5Hz, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 3:
1hNMR (300MHz, CDCl
3) δ 12.58 (s, 1H ,-OH), 12.40 (s, 1H ,-OH), 8.00 (dd, J=7.9,1.7Hz, 2H, Ar-H), 7.58-7.46 (m, 3H, Ar-H), 7.18 (s, 2H, Ar-H), 7.10 (d, J=0.9Hz, 1H, Ar-H), 6.14 (dd, J=6.5,5.2Hz, 1H ,-CH=C), 5.11 (t, J=7.3Hz, 1H ,-CH), 4.20 (s, 2H ,-CH
2), 2.61 (ddd, J=22.2,14.8,7.9Hz, 2H ,-CH
2), 1.68 (s, 3H ,-CH
3), 1.58 (s, 3H ,-CH
3).
Compound 4:
1hNMR (300MHz, CDCl
3) δ 12.55 (d, J=2.3Hz, 1H ,-OH), 12.37 (d, J=2.4Hz, 1H ,-OH), 7.89-7.79 (m, 2H, Ar-H), 7.67-7.58 (m, 2H, Ar-H), 7.16 (s, 2H, Ar-H), 7.06 (d, J=0.9Hz, 1H, Ar-H), 6.18-6.05 (m, 1H ,-CH=C), 5.09 (t, J=7.3Hz, 1H,-CH), 4.15 (d, J=12.6Hz, 2H ,-CH
2), 2.74-2.41 (m, 2H ,-CH
2), 1.64 (d, J=14.2Hz, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 5:
1hNMR (300MHz, CDCl
3) δ 12.55 (d, J=3.3Hz, 1H ,-OH), 12.39 (s, 1H ,-OH), 7.92 (dd, J=11.6,6.1Hz, 6H, Ar-H), 7.06 (d, J=9.0Hz, 1H, Ar-H), 6.16=6.06 (m, 1H,-CH=C), 5.09 (s, 1H ,-CH), 4.26 (q, J=7.1Hz, 2H ,-CH
2), 2.71-2.45 (m, 3H ,-CH
3), 2.40-2.26 (m, 2H ,-CH
2), 1.66 (s, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Compound 6:
1hNMR (300MHz, CDCl
3) δ 12.56 (s, 1H ,-OH), 12.39 (d, J=2.3Hz, 1H ,-OH), 7.88 (dd, J=7.7,1.8Hz, 1H, Ar-H), 7.73 (dd, J=7.9,1.2Hz, 1H, Ar-H), 7.48-7.36 (m, 2H, Ar-H), 7.17 (s, 2H, Ar-H), 7.08 (d, J=0.8Hz, 1H, Ar-H), 6.13 (dd, J=6.5,5.3Hz, 1H ,-CH=C), 5.10 (t, J=7.3Hz, 1H ,-CH), 4.19 (d, J=0.6Hz, 2H ,-CH
2), 2.60 (ddd, J=22.7,15.0,8.3Hz, 2H ,-CH
2), 1.68 (s, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 7:
1hNMR (300MHz, CDCl
3) δ 12.56 (s, 1H ,-OH), 12.38 (s, 1H ,-OH), 7.56 (d, J=1.0Hz, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 7.51-7.48 (m, 1H, Ar-H), 7.44-7.39 (m, 1H, Ar-H), 7.37 (d, J=7.8Hz, 1H, Ar-H), 7.16 (s, 2H, Ar-H), 6.16-6.06 (m, 1H ,-CH=C), 5.09 (t, J=7.3Hz, 1H ,-CH), 4.17 (s, 2H ,-CH
2), 3.87 (d, J=2.7Hz, 3H ,-CH
3), 2.74-2.50 (m, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 8:
1hNMR (300MHz, CDCl
3) δ 12.56 (s, 1H ,-OH), 12.39 (s, 1H,-OH), 7.94 (ddd, J=7.8,3.9,1.9Hz, 1H, Ar-H), 7.57-7.34 (m, 4H, Ar-H), 7.16 (s, 2H, Ar-H), 6.12 (dd, J=6.6,5.3Hz, 1H ,-CH=C), 5.10 (t, J=7.2Hz, 1H ,-CH), 4.19 (s, 2H ,-CH
2), 2.73-2.54 (m, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 9:
1hNMR (300MHz, CDCl
3) δ 12.56 (s, 1H ,-OH), 12.39 (s, 1H,-OH), 8.00 (ddd, J=9.0,6.4,2.6Hz, 1H, Ar-H), 7.53 (tdd, J=8.4,5.0,1.8Hz, 1H, Ar-H), 7.32=7.27 (m, 1H, Ar-H), 7.24-7.18 (m, 1H, Ar-H), 7.16 (s, 2H, Ar-H), 7.07 (d, J=0.8Hz, 1H, Ar-H), 6.12 (dd, J=6.4,5.0Hz, 1H,-CH=C), 5.09 (t, J=7.3Hz, 1H,-CH), 4.18 (s, 2H ,-CH
2), 2.71-2.50 (m, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 10:
1hNMR (300MHz, CDCl
3) δ 12.55 (s, 1H ,-OH), 12.36 (s, 1H,-OH), 7.17-7.11 (m, 3H, Ar-H), 7.09 (d, J=2.3Hz, 2H, Ar-H), 7.06 (d, J=0.9Hz, 1H, Ar-H), 6.17-6.06 (m, 1H ,-CH=C), 5.15-5.02 (m, 1H,-CH), 4.16 (s, 2H ,-CH
2), 3.84 (s, 6H ,-CH
3), 2.72-2.50 (m, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Compound 11:
1hNMR (300MHz, CDCl
3) δ 12.58 (d, J=15.1Hz, 1H ,-OH), 12.38 (s, 1H,-OH), 7.91 (d, J=8.6Hz, 2H, Ar-H), 7.51-7.40 (m, 2H, Ar-H), 7.16 (s, 2H, Ar-H), 7.05 (d, J=9.9Hz, 1H, Ar-H), 6.11 (dd, J=6.5,5.1Hz, 1H ,-CH=C), 5.09 (t, J=7.2Hz, 1H ,-CH), 4.17 (s, 2H ,-CH
2), 2.71-2.50 (m, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.58 (d, J=8.3Hz, 3H ,-CH
3).
Compound 12:
1hNMR (300MHz, CDCl
3) δ 12.55 (s, 1H ,-OH), 12.37 (d, J=2.3Hz, 1H ,-OH), 7.98 (ddd, J=9.7,5.1,2.5Hz, 2H, Ar-H), 7.20 (td, J=4.3,1.6Hz, 1H, Ar-H), 7.17 (q, J=1.6Hz, 1H, Ar-H), 7.15 (d, J=3.2Hz, 2H, Ar-H), 7.07 (d, J=0.9Hz, 1H, Ar-H), 6.16-6.05 (m, 1H,-CH=C), 5.16-5.03 (m, 1H ,-CH), 4.17 (s, 2H ,-CH
2), 2.74-2.50 (m, 2H ,-CH
2), 1.66 (s, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Compound 13:
1hNMR (300MHz, CDCl
3) δ 12.55 (s, 1H ,-OH), 12.37 (d, J=2.3Hz, 1H ,-OH), 7.80-7.74 (m, 1H, Ar-H), 7.71-7.64 (m, 1H, Ar-H), 7.52-7.42 (m, 1H, Ar-H), 7.24-7.18 (m, 1H, Ar-H), 7.18-7.14 (m, 2H, Ar-H), 7.07 (d, J=0.9Hz, 1H, Ar-H), 6.17-6.07 (m, 1H ,-CH=C), 5.14-5.03 (m, 1H ,-CH), 4.18 (s, 2H ,-CH
2), 2.72-2.51 (m, 2H ,-CH
2), 1.66 (d, J=4.0Hz, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 14:
1hNMR (300MHz, CDCl
3) δ 12.55 (s, 1H ,-OH), 12.37 (s, 1H ,-OH), 7.97 (dt, J=7.3,1.6Hz, 1H, Ar-H), 7.90-7.83 (m, 1H, Ar-H), 7.53-7.36 (m, 2H, Ar-H), 7.15 (s, 2H, Ar-H), 7.06 (d, J=0.8Hz, 1H, Ar-H), 6.16-6.06 (m, 1H ,-CH=C), 5.14-5.03 (m, 1H ,-CH), 4.18 (s, 2H ,-CH
2), 2.71-2.45 (m, 2H ,-CH
2), 1.65 (d, J=8.7Hz, 3H ,-CH
3), 1.57 (s, 3H ,-CH
3).
Compound 15:
1hNMR (300MHz, CDCl
3) δ 12.54 (s, 1H ,-OH), 12.37 (s, 1H ,-OH), 7.54-7.49 (m, 1H, Ar-H), 7.47 (d, J=1.9Hz, 1H, Ar-H), 7.14 (s, 2H, Ar-H), 7.05 (d, J=0.6Hz, 1H, Ar-H), 6.91 (d, J=8.4Hz, 1H, Ar-H), 6.12 (dd, J=6.4,5.2Hz, 1H ,-CH=C), 5.09 (t, J=7.3Hz, 1H ,-CH), 4.15 (s, 2H ,-CH
2), 3.95 (t, J=2.8Hz, 6H ,-CH
3), 2.72-2.42 (m, 2H ,-CH
2), 1.66 (s, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Compound 16:
1hNMR (300MHz, CDCl
3) δ 12.55 (s, 1H ,-OH), 12.38 (s, 1H,-OH), 7.85 (dd, J=7.6,1.7Hz, 1H, Ar-H), 7.48 (ddd, J=9.1,6.4,1.7Hz, 1H, Ar-H), 7.16 (s, 2H, Ar-H), 7.06 (s, 1H, Ar-H), 7.03 (d, J=0.8Hz, 1H, Ar-H), 7.01 (d, J=1.8Hz, 1H, Ar-H), 6.12 (dd, J=6.2,5.0Hz, 1H,-CH=C), 5.09 (t, J=7.3Hz, 1H,-CH), 4.21-4.12 (m, 2H ,-CH
2), 3.94 (d, J=4.7Hz, 3H ,-CH
3), 2.61 (ddd, J=25.1,14.9,6.7Hz, 2H ,-CH
2), 1.66 (s, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Compound 17:
1hNMR (300MHz, CDCl
3) δ 12.56 (s, 1H ,-OH), 12.41 (d, J=2.4Hz, 1H ,-OH), 7.33 (s, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.29 (s, 2H, Ar-H), 7.27 (d, J=3.1Hz, 1H, Ar-H), 7.18 (s, 2H, Ar-H), 7.03 (d, J=0.9Hz, 1H, Ar-H), 6.08 (dd, J=7.1,4.8Hz, 1H ,-CH=C), 5.06 (dd, J=18.8,11.5Hz, 1H,-CH), 4.17 (s, 2H ,-CH
2), 4.09 (d, J=1.1Hz, 2H ,-CH
2), 2.69-2.41 (m, 2H ,-CH
2), 1.67 (s, 3H ,-CH
3), 1.56 (s, 3H ,-CH
3).
Example two: the application of formula I class Ben oxadiazole shikonin ramification of carboxylic esters
Using MCF-7, A549, Hela cell strain as detection strain, MTT colorimetry is detection method, by finding the research of formula I class Ben oxadiazole shikonin ramification of carboxylic esters tumor cell in vitro inhibit activities, such novel structure derivative has obvious tumor cell in vitro inhibit activities.And the tumor-suppression activity of compound 15 is best.The results are shown in accompanying drawing 1,2,3.
Ben oxadiazole shikonin ramification of carboxylic esters of the present invention can be prepared into antitumor drug.
Claims (3)
1. a class Ben oxadiazole shikonin ramification of carboxylic esters, its structural formula is as follows:
2. Ben oxadiazole shikonin ramification of carboxylic esters described in claim 1, it is characterized in that mole shikonin such as grade and corresponding carboxylic acid in methylene dichloride, continue to add catalyzer, TLC tracing detection reacts completely, and obtains corresponding novel structure shikonin carboxylates derivatives through column chromatography for separation.
3. the application in Ben oxadiazole shikonin ramification of carboxylic esters oncotherapy described in claim 1.
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| CN107304193A (en) * | 2016-04-22 | 2017-10-31 | 南京大学 | Shikonin piperazine acid esters analog derivative and its synthetic method and application |
| CN112010791A (en) * | 2020-09-13 | 2020-12-01 | 济宁市第一人民医院 | Novel lithospermine phenylacetate derivative containing benzenesulfonamide structural unit and synthesis method and application thereof |
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