CN103588761A - Preparation and application of N-[1-(benzofuran-5-yl)-2-oxoethyl]benzopyran-4-amide - Google Patents
Preparation and application of N-[1-(benzofuran-5-yl)-2-oxoethyl]benzopyran-4-amide Download PDFInfo
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- CN103588761A CN103588761A CN201310498591.5A CN201310498591A CN103588761A CN 103588761 A CN103588761 A CN 103588761A CN 201310498591 A CN201310498591 A CN 201310498591A CN 103588761 A CN103588761 A CN 103588761A
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- 0 **c(cc(C(CCO1)C(O)=*)c1c1*)c1I Chemical compound **c(cc(C(CCO1)C(O)=*)c1c1*)c1I 0.000 description 5
- USXVPNCPOMTABQ-UHFFFAOYSA-N CC(C)(Cc1cc(C(CNC(C2c3cccc(C)c3OCC2)=O)=O)c2)Oc1c2OC Chemical compound CC(C)(Cc1cc(C(CNC(C2c3cccc(C)c3OCC2)=O)=O)c2)Oc1c2OC USXVPNCPOMTABQ-UHFFFAOYSA-N 0.000 description 1
- WCGDLBUUTHJOOK-UHFFFAOYSA-N Cc1c2OCCC(C(O)=O)c2ccc1 Chemical compound Cc1c2OCCC(C(O)=O)c2ccc1 WCGDLBUUTHJOOK-UHFFFAOYSA-N 0.000 description 1
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to N-[1-(benzofuran-5-yl)-2-oxoethyl]benzopyran-4-amide as shown in a chemical structural formula I. In the formula I, X1-X4 are selected from H, C1-C2 alkyl groups, C3-C4 straight-chain or branched-chain alkyl groups, C1-C2 alkoxy groups, C3-C4 straight-chain or branched-chain alkoxy groups, fluorine, chlorine, bromine or iodine. The invention also relates to an application of the N-[1-(benzofuran-5-yl)-2-oxoethyl]benzopyran-4-amide in preparation of drugs for treating cervical cancer.
Description
Technical field
The present invention relates to the preparation and application of new compound, specifically N-[1-(cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides and preparation method thereof and as the application of preparing cancer therapy drug.
Background technology
Tubatoxin is the broad-spectrum natural flavonoids of a class, and Mammals is had to lower toxicity, and Recent study shows, tubatoxin all has good restraining effect to mammary cancer and liver cancer cell, its IC
50value is in 0.008～0.010 μ g/mL[J.Natural Products, 2005,69 (3): 397-399], be applicable to take it as primer exploitation low toxicity, efficient antitumor drug.Tubatoxin molecule is mainly comprised of chromene and cumarone building stone, and chromene and benzofuran derivative are the important heterocyclic compounds of two classes.
2009, [the J.Natural Products of Yu Dequan seminar, 2009,72 (5): 966-968] from the limb skin of hair mulberry, separation obtains two kinds of compounds 4 and 5 with anti-tumor activity, 4 couples of A549 of compound are found in research, Bel7402, it is active that tetra-kinds of tumor cell lines of BGC-823 and HCT-8 have nonselective inhibition; Compound 5 optionally suppresses A2780, the propagation of Bel7402 and HCT-8 cell strain.
2009, Nguyen etc. [Bioorganic & Medicinal Chemistry Letters, 2009,19 (23): 6745-6749] separation from the stem skin of E.abyssinica obtained compound 6; 6 couples of MCF7 of compound, MCF/TAMR, tetra-kinds of breast cancer cells of MCF/ADR and MDA-MB-231 all have growth-inhibiting effect, its IC
50value is 12.0～28.0 μ mol/L.Atta etc. [European J Medicinal Chemistry, 2010,45 (11): 4920-4927] have described the synthetic of a series of compounds containing cumarone and benzopyrone structure; Bioactivity research shows that this compounds all has good cytotoxicity to human breast cancer cell MCF-7; Wherein compound 7 activity are higher.
Zhou Zhongzhen etc. described the synthetic and desinsection of 2,3a-dihydro-chromene [4,3-c] pyrazoles-3-ketones derivant and fungicidal activity (organic chemistry, 2009,29:1774).China's invention granted patent has been described the preparation and application of tubatoxin derivative and analogue thereof; The structure of its relevant Chinese invention patent and compound thereof is as follows:
Summary of the invention
The object of the present invention is to provide the N-[1-shown in chemical structural formula I (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
The present invention also provides N-[1-(cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] chromene-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-8-methyl chromene-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-7-methyl chromene-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-6-methyl chromene-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-7-methoxyl group benzo pyrans-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-6-methoxyl group benzo pyrans-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-6-chlorine chromene-4-acid amides, N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] benzo [h] chromene-4-acid amides or N-[2-(2, 2-dimethyl-7-methoxyl group-2, 3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] benzo [g] chromene-4-acid amides.
The present invention also provides N-[1-(cumarone-5-yl)-2-oxoethyl] preparation method of chromene-4-acid amides, it is characterized in that N-[1-(cumarone-5-yl)-2-oxoethyl] preparation method of chromene-4-acid amides is as follows:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
The object of the present invention is to provide the N-[1-shown in chemical structural formula I (cumarone-5-yl)-2-oxoethyl] application of chromene-4-acid amides in the anti-human cervical cancer medicine of preparation:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
The present invention compared with prior art tool has the following advantages: the present invention designs first and prepared N-[1-(cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides, it is active that it has higher anti-human cervical cancer.
Embodiment
Following examples are intended to illustrate the present invention rather than limitation of the invention further.
Embodiment 1
The preparation of compound ii
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
Press document [Sarges R, Schnur R C, Belletire J L, et al.Spiro Hydantoin Aldose Reductase Inhibitors.Journal of Medicinal Chemistry, 1988,31 (1): 230-243; O'Donnell R W H, Reed F P, Robertson is on the synthesis of rotenone and its derivatives.Part IX.Journal of the Chemical Society (Resumed) A.99.Experiments, 1936:419-422] method prepares compound ii.
Embodiment 2
2-amino-1-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl) ethyl ketone hydrobromate (III preparation a)
7.00g urotropine, 60mL trichloromethane, stirring and dissolving at 45 ℃; drip 30ml and be dissolved with 12.00g2,2-dimethyl-7-methoxyl group-5-acetyl bromide-2, the chloroform soln of 3-Dihydrobenzofuranes; in 30min, dropwise; insulation reaction 30min, TLC detection reaction is complete, filters; filter cake washs with trichloromethane; be dried to obtain 15.20g white solid, yield 99.0%, m.p.170～172 ℃.
The above-mentioned white solid of 14.80g (0.04mol), 60mL ethanol, 40.00g36% hydrochloric acid, stirring and refluxing 4.0h, filters, and the cooling solid of separating out of filtrate filters, dry, obtains 7.41g solid III a, yield 58.6%, m.p.157～159 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.45 (s, 6H, 2 * CH
3), 3.09 (s, 2H, 3-H), 3.84 (s, 3H, 7-OCH
3), 4.52 (d, J=5.2Hz, 2H, COCH
2), 7.42 (s, 1H, 4-H), 7.58 (s, 1H, 4-H), 8.18 (s, 2H, NH
2).
Embodiment 3
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] (I preparation a) of chromene-4-acid amides
0.18g compound ii a (1.00mmol), 0.38g compound III a (1.20mmol), 20mL methylene dichloride, 0.20g DCC (1.00mmol), 0.09g DMAP (0.50mmol), room temperature reaction 2.0h, TLC monitoring reacts completely, suction filtration, be spin-dried for, sherwood oil: ethyl acetate=1:1 column chromatography obtains chemical compounds I a, yield 64.5%, m.p.129～131 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.14～2.23 (m, 1H, 3-H), 2.47～2.53 (m, 1H, 3-H), 3.08 (s, 2H, 3 '-H), 3.74 (t, J=4.8Hz, 1H, 4-H), 3.89 (s, 3H, 7 '-OCH
3), 4.12～4.17 (m, 1H, 2-H), 4.28～4.32 (m, 1H, 2-H), 4.61～4.74 (m, 2H, COCH
2), 6.75 (s, 1H, NH), 6.91 (d, J=8.4Hz, 1H, 8-H), 6.96～7.00 (m, 1H, 7-H), 7.20 (d, J=7.6Hz, 1H, 5-H), 7.22～7.27 (m, 1H, 6-H), 7.39 (s, 1H, 4 '-H), 7.42 (s, 1H, 6 '-H).
Embodiment 4
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of-8-methyl chromene-4-acid amides (I b)
Press the preparation method of embodiment 3,1.00mmol compound ii b, 1.20mmol compound III a, reaction 2.0h, obtains white solid I b, yield 55.0%, m.p.138～140 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.12～2.19 (m, 1H, 3-H), 2.21 (s, 3H, 8-CH
3), 2.47～2.52 (m, 1H, 3-H), 3.07 (s, 2H, 3 '-H), 3.72 (t, J=5.6Hz, 1H, 4-H), 3.89 (s, 3H, 7 '-OCH
3), 4.11～4.17 (m, 1H, 2-H), 4.29～4.32 (m, 1H, 2-H), 4.65～4.69 (m, 2H, COCH
2), 6.78 (s, 1H, NH), 6.88 (t, J=7.6Hz, 1H, 6-H), 7.04 (d, J=7.6Hz, 1H, 5-H), 7.10 (d, J=7.6Hz, 1H, 7-H), 7.39 (s, 1H, 4 '-H), 7.42 (s, 1H, 6 '-H).
Embodiment 5
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of-7-methyl chromene-4-acid amides (I c)
Press the preparation method of embodiment 3,1.00mmol compound ii c, 1.20mmol compound III a, reaction 2.0h, obtains white solid I c, yield 67.5%, m.p.155～157 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.11～2.21 (m, 1H, 3-H), 2.32 (s, 3H, 7-CH
3), 2.44～2.50 (m, 1H, 3-H), 3.07 (s, 2H, 3 '-H), 3.69 (t, J=5.6Hz, 1H, 4-H), 3.89 (s, 3H, 7 '-OCH
3), 4.06～4.13 (m, 1H, 2-H), 4.23～4.29 (m, 1H, 2-H), 4.61～4.74 (m, 2H, COCH
2), 6.72 (s, 1H, 8-H), 6.78 (s, 1H, NH), 6.80 (d, J=7.6Hz, 1H, 6-H), 7.08 (d, J=7.6Hz, 1H, 5-H), 7.39 (s, 1H, 4 '-H), 7.42 (s, 1H, 6 '-H).
Embodiment 6
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of-6-methyl chromene-4-acid amides (I d)
Press the preparation method of embodiment 3,1.00mmol compound ii d, 1.20mmol compound III a, reaction 2.0h, obtains white solid I d, yield 57.5%, m.p.120～121.5 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.12～2.21 (m, 1H, 3-H), 2.31 (s, 3H, 6-CH
3), 2.43～2.49 (m, 1H, 3-H), 3.08 (s, 2H, 3 '-H), 3.69 (t, J=4.8Hz, 1H, 4-H), 3.90 (s, 3H, 7 '-OCH
3), 4.09～4.16 (m, 1H, 2-H), 4.23～4.28 (m, 1H, 2-H), 4.68 (d, J=4.4Hz, 2H, COCH
2), 6.76 (s, 1H, NH), 6.80 (d, J=8.4Hz, 1H, 8-H), 6.98 (d, J=2.0Hz, 1H, 5-H), 7.04 (dd, J=2.0,8.4Hz, 1H, 7-H), 7.39 (s, 1H, 4 '-H), 7.43 (s, 1H, 6 '-H).
Embodiment 7
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of-7-methoxyl group benzo pyrans-4-acid amides (I f)
Press the preparation method of embodiment 3,1.00mmol compound ii f, 1.20mmol compound III a, reaction 2.0h, obtains white solid I f, yield 51.2%, m.p.156～158 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.11～2.21 (m, 1H, 3-H), 2.44～2.49 (m, 1H, 3-H), 3.08 (s, 2H, 3 '-H), 3.67 (t, J=5.6Hz, 1H, 4-H), 3.79 (s, 3H, 7-OCH
3), 3.89 (s, 3H, 7 '-OCH
3), 4.07～4.13 (m, 1H, 2-H), 4.23～4.29 (m, 1H, 2-H), 4.61～4.74 (m, 2H, COCH
2), 6.45 (d, J=2.4Hz, 1H, 8-H), 6.58 (dd, J=2.4,8.4Hz, 1H, 6-H), 6.77 (s, 1H, NH), 7.08 (d, J=8.4Hz, 1H, 5-H), 7.39 (s, 1H, 4 '-H), 7.42 (s, 1H, 6 '-H).
Embodiment 8
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of-6-methoxyl group benzo pyrans-4-acid amides (I g)
Press the preparation method of embodiment 3,1.00mmol compound ii g, 1.20mmol compound III a, reaction 2.0h, obtains white solid I g, yield 67.4%, m.p.133～135 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.13～2.23 (m, 1H, 3-H), 2.43～2.49 (m, 1H, 3-H), 3.08 (s, 2H, 3 '-H), 3.71 (t, J=6.4Hz, 1H, 4-H), 3.80 (s, 3H, 6-OCH
3), 3.90 (s, 3H, 7 '-OCH
3), 4.08～4.14 (m, 1H, 2-H), 4.22～4.27 (m, 1H, 2-H), 4.63～4.75 (m, 2H, COCH
2), 6.73 (s, 1H, NH), 6.76～6.84 (m, 3H, 5-H, 7-H, 8-H), 7.38 (s, 1H, 4 '-H), 7.43 (s, 1H, 6 '-H).
Embodiment 9
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of-8-chlorine chromene-4-acid amides (I h)
Press the preparation method of embodiment 3,1.00mmol compound ii h, 1.20mmol compound III a, reaction 2.0h, obtains white solid I h, yield 57.1%, m.p.167～169 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.55 (s, 6H, 2 * CH
3), 2.11～2.20 (m, 1H, 3-H), 2.41～2.48 (m, 1H, 3-H), 3.08 (s, 2H, 3 '-H), 3.72 (t, J=4.8Hz, 1H, 4-H), 3.91 (s, 3H, 7 '-OCH
3), 4.17～4.23 (m, 1H, 2-H), 4.25～4.32 (m, 1H, 2-H), 4.62～4.77 (m, 2H, COCH
2), 6.74 (s, 1H, NH), 6.84 (d, J=8.0Hz, 1H, 8-H), 7.16～7.19 (m, 2H, 5-H, 7-H), 7.40 (s, 1H, 4 '-H), 7.44 (s, 1H, 6 '-H).
Embodiment 10
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of benzo [h] chromene-4-acid amides (I i)
Press the preparation method of embodiment 3,1.00mmol compound ii i, 1.20mmol compound III a, reaction 2.0h, obtains white solid chemical compounds I i, yield 66.8%, m.p.161～163 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.54 (s, 6H, 2 * CH
3), 2.25～2.34 (m, 1H, 3-H), 2.55～2.62 (m, 1H, 3-H), 3.06 (s, 2H, 3 '-H), 3.82～3.86 (m, 1H, 4-H), 3.88 (s, 3H, 7 '-OCH
3), 4.29～4.35 (m, 1H, 2-H), 4.51～4.56 (m, 1H, 2-H), 4.62～4.75 (m, 2H, COCH
2), 6.73 (s, 1H, NH), 7.24～7.26 (m, 1H, 5-H), 7.35 (s, 1H, 4 '-H), 7.40 (s, 1H, 6 '-H), 7.45～7.51 (m, 3H, 6-H, 8-H, 9-H), 7.74～7.81 (m, 1H, 7-H), 8.17～8.23 (m, 1H, 10-H).
Embodiment 11
N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] preparation of benzo [g] chromene-4-acid amides (I j)
Press the preparation method of embodiment 3,1.00mmol compound ii j, 1.20mmol compound III a, reaction 2.0h, obtains white solid I j, yield 78.0%, m.p.165～167 ℃;
1h NMR (CDCl
3, 400MHz) δ: 1.54 (s, 6H, 2 * CH
3), 2.23～2.31 (m, 1H, 3-H), 2.56～2.62 (m, 1H, 3-H), 3.06 (s, 2H, 3 '-H), 3.88 (s, 3H, 7 '-OCH
3), 3.99 (t, J=4.8Hz, 1H, 4-H), 4.24～4.31 (m, 1H, 2-H), 4.33～4.37 (m, 1H, 2-H), 4.68 (d, J=4.8Hz, 2H, COCH
2), 6.77 (s, 1H, NH), 7.29 (s, 1H, 10-H), 7.29～7.35 (m, 1H, 7-H), 7.35 (s, 1H, 4 '-H), 7.40 (s, 1H, 6 '-H), 7.40～7.43 (m, 1H, 8-H), 7.70 (d, J=8.4Hz, 2H, 7-H), 7.72 (s, 1H, 5-H), 7.76 (d, J=8.4Hz, 2H, 9-H).
Embodiment 12
N-[1-(cumarone-5-yl)-2-oxoethyl] activity of anti-human cervical cancer of chromene-4-acid amides
1. anti-tumor activity principle
Mtt assay biological activity test claims again MTT colorimetry, is a kind of method that detects cell survival and growth.MTT analytical method is with viable cell metabolite reductive agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-phenylbenzene bromination tetrazole; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] be basis.MTT is a kind of dyestuff that can accept hydrogen atom.Desaturase relevant to NADP in viable cell plastosome can change into yellow MTT insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) in cell, and dead cell is without this function.With DMSO, dissolve after formazon, under certain wavelength, by microplate reader, measure optical density value, both can quantitatively measure the survival rate of cell.According to the variation of optical density value, observe the restraining effect of sample to tumour cell.
2. anti-tumor activity experiment
Sample: N-[1-(cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides (I):
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
Clone: human cervical carcinoma Hela cell is (Xiangya Medical College, Zhongnan Univ cell bank provides).
Reagent: tetrazolium bromide (MTT), RPMI1640 nutrient solution, new-born calf serum, microbiotic (U.S. hero Life Technologies, Inc.); Pancreatin (U.S. AMRESCO company); 96 well culture plates (U.S. hero Life Technologies, Inc.); Dimethyl sulfoxide (DMSO) (U.S. Sigma company).
Instrument: HFsafe-1500 type Bechtop, HF151UV type CO
2incubator (Shanghai Lishen Scientific Equipment Co., Ltd.); XSP-15C type inverted microscope (Shanghai rectangular opticinstrument company limited); Multiskan MK3 type microplate reader (U.S. Thermo company); Ultrapure water preparing instrument (U.S. Milli-Q company).
Experimental implementation: sample is for human cervical carcinoma Hela cell's test.In an experimentation, per sample (p.s.) arranges 5 concentration gradients (1.00 μ mol/mL, 0.30 μ mol/mL, 0.10 μ mol/mL, 0.03 μ mol/mL and 0.01 μ mol/mL), four parallel samples of each concentration, test parallel 3 times for every group, and reach a conclusion by the contrast of blank group.Microplate reader detects each hole OD value, detects wavelength 570nm.
3. anti-tumor activity evaluation
1) cell inhibitory rate calculates:
2) IC
50value is calculated
Sample solution concentration logarithmic value and cell inhibitory rate linear regression, utilize the half-inhibition concentration IC of computed in software sample to cell
50value.N-[1-(cumarone-5-yl)-2-oxoethyl] IC of chromene-4-acid amides to human cervical carcinoma Hela cell
50in Table 1.
Table 1N-[1-(cumarone-5-yl)-2-oxoethyl] IC of chromene-4-acid amides to Hela cell strain
50
Active testing result shows, N-[1-(cumarone-5-yl)-2-oxoethyl] to have good inhibition active for chromene-4-acid amides antagonism human cervical carcinoma Hela cell, can be used for preparing anti-human cervical cancer medicine.
Claims (10)
1. the N-[1-shown in chemical structural formula I (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides:
Wherein, X
1be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
2be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
3be selected from: H, C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy; X
4be selected from: H, C
1～C
2alkoxyl group, C
3～C
4straight chain alkoxyl group or branched alkoxy, fluorine, chlorine, bromine or iodine; X
1x
2be selected from :-CH=CH-CH=CH-; X
2x
3be selected from :-CH=CH-CH=CH-.
2. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] chromene-4-acid amides.
3. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-8-methyl chromene-4-acid amides.
4. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-7-methyl chromene-4-acid amides.
5. N-[1-(cumarone-5-yl)-2-oxoethyl described in claim 1] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-6-methyl chromene-4-acid amides.
6. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-7-methoxyl group benzo pyrans-4-acid amides or N-[2-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]]-6-methoxyl group benzo pyrans-4-acid amides.
7. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl]-6-chlorine chromene-4-acid amides.
8. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] chromene-4-acid amides is selected from N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] benzo [h] chromene-4-acid amides or N-[2-(2,2-dimethyl-7-methoxyl group-2,3-Dihydrobenzofuranes-5-yl)-2-oxoethyl] benzo [g] chromene-4-acid amides.
9. N-[1-claimed in claim 1 (cumarone-5-yl)-2-oxoethyl] preparation method of chromene-4-acid amides, it is characterized in that N-[1-(cumarone-5-yl)-2-oxoethyl] preparation feedback of chromene-4-acid amides is as follows:
In formula, X
1～X
4definition as claimed in claim 1.
10. N-[1-(cumarone-5-yl)-2-oxoethyl described in any one in claim 1～8] application of chromene-4-acid amides in preparing medicament for resisting cervical cancer.
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