CN102321012B - Acenaphthene heterocyclic compounds and application thereof - Google Patents

Acenaphthene heterocyclic compounds and application thereof Download PDF

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CN102321012B
CN102321012B CN201110191883.5A CN201110191883A CN102321012B CN 102321012 B CN102321012 B CN 102321012B CN 201110191883 A CN201110191883 A CN 201110191883A CN 102321012 B CN102321012 B CN 102321012B
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acenaphthene
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bcl
nitrile
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CN102321012A (en
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张志超
吴桂叶
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Dalian University of Technology
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Dalian University of Technology
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Abstract

The invention relates to new acenaphthene heterocyclic compounds and application of the compounds in preparation of BH3 analogues Bcl-2 family protein inhibitors. The acenaphthene heterocyclic compounds have the structure of a general formula I as shown in the specification. The acenaphthene heterocyclic compounds are prepared by introducing various oxides, sulfides and carbonyl group, ester group and acyl group compounds on 3, 4 and 6 positions of 8-oxy-8-hydro-acenaphtho[1,2-b]pyrrole-9-nitrile or further replacing 9-nitrile as acid, ester, amido compounds. According to the invention, the acenaphthene heterocyclic compounds can perform in vitro and intracellular competitive bonds and antagonisms with Bcl-2 and Mcl-1 proteins through stimulating a BH3-only protein, thereby inducing apoptosis. The acenaphthene heterocyclic compounds can be used for preparing anticancer compounds.

Description

One class acenaphthene and heterocyclic compound and application thereof
Technical field
The present invention relates to a series of new acenaphthenes and heterocyclic Bcl-2 family protein inhibitor and in vivo, external simulation BH3-only albumen, competitive combination and antagonism Bcl-2 and Mcl-1 albumen, thereby cell death inducing effect and as the application of anticancer compound.
Background technology
Molecular targeted antitumor drug is becoming after the cytotoxic agent series antineoplastic medicament, the product of new generation of the focus of new drug development and the marketization.The Bcl-2 family protein is the most important molecular target of antagonism and reversion of malignant tumour immortality.So the medicine of specificity antagonism Bcl-2 family protein will be by single-minded inducing apoptosis of tumour cell, finally realize highly selective, safety, efficient, anticancer target has no side effect.In Bcl-2 class inhibitor, the most remarkable with the antitumous effect of the special BH3 analogue (BH3mimetics) of height, the pharmacodynamics activity is best, and toxic side effect is minimum.In addition, also must possess the anti-apoptosis member's (comprising Bcl-2 and Mcl-1 albumen at least) of wide spectrum antagonism Bcl-2 family protein ability, could realize the effective and low resistance of single agent.
But up to the present, be that the antitumor drug of target spot does not still have the listing product with Bcl-2, only 19 clinical before in the Bcl-2 inhibitor, what three effect optimums were arranged is in clinical I, II, III phase respectively.Be respectively: by the ABT-737 of Illinoi State, The United States Alpert laboratory research and development, the Obatoclax (GX15-070) of Gemin X company research and development and the AT-101 of U.S. Ascenta company.They all are the BH3 analogues, reach the nM level with the competition binding constant of Bcl-2 albumen, are higher than other 15 congeneric elements far away.But all there is deficiency: Gossypol in they, and the similar degree deficiency of the BH3 of Obatoclax is not absolute BH3 analogue, just has the cytotoxicity that does not rely on BAX/BAK, and the action target spot that has other is described, therefore have toxic side effect.Though the ABT-737 the highest BH3 analogue that is specificity can not antagonism and in conjunction with Mcl-1 albumen, is not the Bcl-2 family protein inhibitor of wide spectrum, thereby has seriously limited its disease kind that is suitable for.
Disclose a series of 8-oxygen-8H-acenaphthene also acenaphthene and the heterocyclic compound of [1,2-b] pyrroles-9-nitrile in the achievement that the inventor previously studies, and this compounds has the activity (CN1304370C) that suppresses tumor growth by cell death inducing.Yet, as the potential antitumor drug based on apoptosis, the same difficult point in the face of this type of drug development of its exploitation: the blindness of the medication that the strong cytotoxicity that the apoptotic signal path is complicated and potential and institute thereof must cause, and this is the major reason that causes the exploitation of such medicine to be failed.Therefore, need to highlight pharmaceutically-active targeting in the research.
Summary of the invention
One of purpose of the present invention is to provide class acenaphthene and a heterocyclic compound, has the structure of following general formula I:
In the general formula I:
R 1, R 2And R 3Be selected from XR independently of one another 5And H;
R 4Be selected from CN, COOH, COOR 6And CONHR 6
When described X is O, carbonyl, ester group, amide group or sulfoamido;
Described R 5Be selected from (CH 2) nY and (CH 2) nPh-(o, m, p) Y, described Y is selected from the C of straight or branched 2-C 8The C of the straight or branched of alkyl, replacement 1-C 8Alkyl, described substituting group is selected from halogen, amino, hydroxyl, ester group and carboxyl;
Described R 6Be selected from the C of replacement or unsubstituted straight or branched 1-C 6Alkyl, described substituting group is selected from halogen, amino, hydroxyl, ester group, carboxyl or (CH 2) nPh-(o, m, p) Z, wherein Z is selected from-CH 3,-C 2H 5,-NO 2,-Ph ,-F ,-Cl ,-Br ,-CF 3,-OCH 3,-SCH 3,-NH 2With-N (CH 3) 2
When described X is S;
Described R 5Be selected from (CH 2) nPh-(o, m, p) Y, described Y is selected from the C of straight or branched 2-C 8The C of the straight or branched of alkyl, replacement 1-C 8Alkyl, described substituting group is selected from halogen, amino, hydroxyl, ester group and carboxyl;
Described R 6Be selected from the C of replacement or unsubstituted straight or branched 1-C 6Alkyl, described substituting group is selected from halogen, amino, hydroxyl, ester group, carboxyl or (CH 2) nPh-(o, m, p) Z, wherein Z is selected from-CH 3,-C 2H 5,-NO 2,-Ph ,-F ,-Cl ,-Br ,-CF 3,-OCH 3,-SCH 3,-NH 2With-N (CH 3) 2
Above-mentioned n is 0～4 integer.
In the optimized technical scheme, described R 1And R 2Be respectively XR 5And H.
Again in the optimal technical scheme, described R 4Be CN.
In the another optimized technical scheme, described R 5Be (CH 2) nPh-(o, m, p) Y.Further preferred X is O or S, and Y is the C of straight or branched 3-C 5Alkyl.Most preferably Y is sec.-propyl, isobutyl-or sec-butyl.
More preferably, the compound of the invention described above is selected from:
3-(4-sec-butyl phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
4-(4-sec-butyl phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
3-(4-isobutyl-phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
4-(4-isobutyl-phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
3-(4-sec.-propyl phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
3-(4-isobutyl-benzene sulfenyl)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
4-(4-isobutyl-benzene sulfenyl)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
3-(4-isopropyl benzene sulfenyl)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also;
3-(4-sec-butylbenzene sulfenyl)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile also.
Two of purpose of the present invention is to provide a kind of preparation method of above-claimed cpd, through following a or b approach:
A. with 8-oxygen-8H-acenaphthene also [1,2-b] pyrroles-9-nitrile be raw material, with nucleophilic reagent alcohol, phenol, ester, acid amides reacts, temperature is 20～100 ℃, 0.5～24 hour reaction times steamed solvent after reaction is finished, and column chromatography obtains 3-replacement, 6-replacement or 3, the disubstituted 8-oxygen in 6-position-8H-acenaphthene also [1,2-b] pyrroles-9-nitrile, itrile group passes through hydrolysis again, and esterification or amidation get acenaphthene of the present invention and heterocyclic compound; Reaction formula is as follows:
Figure BSA00000534476600031
B. be raw material with the acenaphthenequinone, add bromine and refluxed 2 hours, obtain the bromo acenaphthenequinone; Again with alcohol, phenol, ester, the acid amides reaction is replaced acenaphthenequinone iii (following reaction formula) accordingly;
Figure BSA00000534476600032
(formula is iii) reacted under the condition of silica gel slightly acidic catalysis with acetonitrile and is obtained the compound that general formula is i or ii, and compound i or ii are at K to replace acenaphthenequinone 2CO 3After catalysis, acetonitrile reflux and to remove partial solvent under reduced pressure after 0.5～6h cooling, filter or 8-oxygen-8H-acenaphthene that column chromatography makes 3 or 4 replacements [1,2-b] pyrroles-9-nitrile also; Pass through hydrolysis again, esterification or amidation get acenaphthene of the present invention and heterocyclic compound, following reaction formula:
Among the preparation method that the invention described above provides, each substituent definition is with aforementioned consistent to substituent definition in the compound, and difference is R the substituent R of addressing enters different the position of substitution in reaction after 1Or R 2
Some are listed as on the basis of acenaphthene of the present invention and heterocyclic compound in the past, and the present inventor reaches test by analysis, filters out above-mentioned a series of new compound.These compounds have with disclosed compound of the past to be compared quite or more excellent BH3 similarity, has suitable application prospect in preparation BH3 analogue Bcl-2 family protein inhibitor.
Based on this, a further object of the present invention is to provide acenaphthene of the present invention and the application of heterocyclic compound in preparation BH3 analogue Bcl-2 family protein inhibitor.Comprise the step that compound of the present invention is cooperated preparation with effective dose and usually optional pharmaceutical excipient, according to the detected result of the embodiment of the invention, of the present invention and compound in this uses required effective dose may be far below prior art in disclosed compound.Further, the present invention also aims to provide acenaphthene of the present invention and the application of heterocyclic compound in the high targeting antineoplastic medicine thing of preparation.
Description of drawings
Accompanying drawing 9 width of cloth of the present invention, wherein:
Accompanying drawing 1 is fluorescence polarization method detection compound 1 and the kinetic curve of FAM-Bid peptide section competition in conjunction with Bcl-2 albumen;
Accompanying drawing 2 is fluorescence polarization method detection compound 1 and the kinetic curve of FAM-Bid peptide section competition in conjunction with Mcl-1 albumen;
Accompanying drawing 3 is that the compound 1 of different concns disturbs interaction result diagram between the Bcl-2/Bax at cell levels;
Accompanying drawing 4 are compounds 1 on the cell levels to disturb interaction result diagram between the Bcl-2/Bax different action time;
Accompanying drawing 5 is cytotoxicity experiment results that compound 1 relies on BAX/BAK, and wherein Gossypol is non-specific contrast;
Accompanying drawing 6 is that 1 pair of Mcl-1 restraining effect of compound Western marking detects electrophorogram;
Accompanying drawing 7 is that 1 pair of Bcl-2 restraining effect of compound Western marking detects electrophorogram;
Accompanying drawing 8 is that compound 1 suppresses Mcl-1 albumen effect sxemiquantitative curve;
Accompanying drawing 9 is that compound 1 suppresses Bcl-2 albumen effect sxemiquantitative curve.
Embodiment
Following non-limiting example can make those of ordinary skill in the art more fully understand the present invention, but does not limit the present invention in any way.
First part: acenaphthene and heterocyclic compound preparation and sign embodiment thereof;
Embodiment 1:3-(4-sec-butyl phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile (compound 1) and 4-(4-sec-butyl phenoxy group) phenoxy group-8-oxygen-8H-acenaphthene [1,2-b] pyrroles-9-nitrile (compound 2) synthetic and characterizing also also
Figure BSA00000534476600051
Take by weighing 0.99g 5-(4-sec-butyl phenoxy group) acenaphthenequinone, the 0.33g propane dinitrile adds in the silicagel column with after the methylene dichloride dissolving, drip washing fast, cross post be spin-dried for after finishing red solid.The 1.07g that weighs, productive rate 94%.Get 0.77g gained red solid, add 0.05g K 2CO 3, 20ml acetonitrile reflux 3 hours is spin-dried for reaction solution after reaction finishes.Chromatography column separates (CH 2Cl 2: sherwood oil=1: 1) obtain two kinds of isomerss.
Compound 1:M.p.219-220 ℃. 1H NMR (400M, CDCl 3): δ 8.92 (d, J=8.0Hz, 1H), 8.65 (d, J=8.8Hz, 1H), 8.46 (d, J=8.0Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.33 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 7.04 (d, J=8.0Hz, 1H), 2.70 (m, 1H), 1.65 (m, 2H), 1.30 (d, J=8.0Hz, 3H), 0.88 (t, J=8.0Hz, 3H) .TOF MS (EI +): C 25H 18N 2O 2, (m/z): calcd for 378.1368, found 378.1376.
Compound 2:M.p.278-279 ℃. 1H NMR (400M, CDCl 3): δ 8.76 (d, J=7.6Hz, 1H), 8.60 (d, J=8.0Hz, 1H), 8.42 (d, J=7.6Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 7.40 (d, J=8.0Hz, 2H), 7.09 (d, J=8.0Hz, 2H), 6.95 (d, J=8.0Hz, 1H), 2.70 (m, 1H), 1.65 (m, 2H), 1.30 (d, J=8.0Hz, 3H), 0.88 (t, J=8.0Hz, 3H) .TOF MS EI +: C 25H 18N 2O 2, (m/z): calcd for 378.1368, found 378.1362.
Embodiment 2:3-(4-isobutyl-phenoxy group)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile (compound 3) and 4-(4-isobutyl-phenoxy group) phenoxy group-8-oxygen-8H-acenaphthene [1,2-b] pyrroles-9-nitrile (compound 4) synthetic and characterizing also also
Figure BSA00000534476600061
Take by weighing 0.99g 5-(4-isobutyl-phenoxy group) acenaphthenequinone, the 0.33g propane dinitrile adds in the silicagel column with after the methylene dichloride dissolving, drip washing fast, cross post be spin-dried for after finishing red solid.The 1.07g that weighs, productive rate 94%.Get 0.77g gained red solid, add 0.05g K 2CO 3, 20ml acetonitrile reflux 3 hours is spin-dried for reaction solution after reaction finishes.Chromatography column separates (CH 2Cl 2: sherwood oil=1: 1) obtain two kinds of isomerss.
Compound 3:M.p.214-215 ℃. 1H NMR (400M, CDCl 3): δ 8.78 (d, J=7.6Hz, 1H), 8.60 (d, J=8.0Hz, 1H), 8.43 (d, J=7.6Hz, 1H), 7.67 (t, J=8.0Hz, 1H), 7.29 (d, J=8.0Hz, 2H), 7.12 (d, J=8.0Hz, 2H), 6.95 (d, J=8.0Hz, 1H), 2.42 (d, J=8.0Hz, 2H), 1.75 (m, 1H), 0.75 (d, J=8.0Hz, 6H) .TOF MS (EI +): C 25H 18N 2O 2, (m/z): calcd for 378.1368, found 378.1365.
Compound 4:M.p.273-274 ℃. 1H NMR (400M, CDCl 3): δ 8.72 (d, J=7.6Hz, 1H), 8.53 (d, J=8.0Hz, 1H), 8.38 (d, J=7.6Hz, 1H), 7.98 (t, J=8.0Hz, 1H), 7.31 (d, J=8.0Hz, 2H), 7.02 (d, J=8.0Hz, 2H), 6.80 (d, J=8.0Hz, 1H), 2.43 (d, J=8.0Hz, 2H), 1.75 (m, 1H), 0.75 (d, J=8.0Hz, 6H) .TOF MS EI +: C 25H 18N 2O 2, (m/z): calcd for 378.1368, found 378.1363.
Embodiment 3:3-(4-sec.-propyl phenoxy group)-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-nitrile (compound 5) also
Figure BSA00000534476600071
Add also [1,2-b] pyrroles-9-nitrile of 1g8-oxygen-8H acenaphthene in 50 milliliters of acetonitriles, the 0.54g australol refluxed 3 hours, steamed solvent, chromatography column separate compound 5, yield 30%.
Compound 5:M.p.272-274 ℃; 1H NMR (400M, CDCl 3): δ 8.92 (d, J=8.0Hz, 1H), 8.25 (d, J=8.8Hz, 2H), 8.44 (d, J=8.0Hz, 1H), 7.86 (t, J=8.0Hz, 1H), 7.38 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 7.04 (d, J=8.8Hz, 1H), 3.01 (m, 1H), 1.32 (d, J=8.0Hz, 6H); TOF MS EI +(m/z): C 24H 16N 2O 2, calculated value: 364.1212, measured value: 364.1215.
Embodiment 4:3-(4-isobutyl-benzene sulfenyl)-8-oxygen-8H-acenaphthene is [1,2-b] pyrroles-9-nitrile (compound 6) and 4-(4-isobutyl-benzene sulfenyl) phenoxy group-8-oxygen-8H-acenaphthene [1,2-b] pyrroles-9-nitrile (compound 7) synthetic and characterizing also also
Take by weighing the tertiary amyl phenoxy group of 1.04g acenaphthenequinone, the 0.33g propane dinitrile adds in the silicagel column with after the methylene dichloride dissolving, drip washing fast, cross post be spin-dried for after finishing red solid.The 0.99g that weighs, productive rate 84%.Get 0.79g gained red solid, add 0.05g K 2CO 3, 20ml acetonitrile reflux 3 hours is spin-dried for reaction solution after reaction finishes.Chromatography column separates (CH 2Cl 2: sherwood oil=1: 1) obtain two kinds of isomerss.
Compound 6:M.p.234-235 ℃. 1H NMR (400M, CDCl 3): δ 8.58 (d, J=7.6Hz, 1H), 8.41 (d, J=8.0Hz, 1H), 8.30 (d, J=7.6Hz, 1H), 7.53 (t, J=8.0Hz, 1H), 7.31 (d, J=8.0Hz, 2H), 7.02 (d, J=8.0Hz, 2H), 6.95 (d, J=8.0Hz, 1H), 2.75 (m, 1H), 1.69 (m, 2H), 1.29 (d, J=8.0Hz, 3H), 0.92 (t, J=8.0Hz, 3H) .TOF MS (EI +): C 25H 18N 2OS, (m/z): calcd for 394.1140, found 394.1142.
Compound 7:M.p.282-283 ℃. 1H NMR (400M, CDCl 3): δ 8.55 (d, J=7.6Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.15 (d, J=7.6Hz, 1H), 7.92 (t, J=8.0Hz, 1H), 7.45 (d, J=8.0Hz, 2H), 7.13 (d, J=8.0Hz, 2H), 7.02 (d, J=8.0Hz, 1H), 2.75 (m, 1H), 1.69 (m, 2H), 1.29 (d, J=8.0Hz, 3H), 0.92 (t, J=8.0Hz, 3H) .TOF MS EI +: C 25H 18N 2OS, (m/z): calcd for 394.1140, found 394.1137.
Embodiment 5:3-(4-isopropyl benzene sulfenyl)-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-nitrile (compound 8) also
Figure BSA00000534476600081
Add also [1,2-b] pyrroles-9-nitrile of 0.69g 8-oxygen-8H-acenaphthene in the 50mL acetonitrile, the propylbenzene thiophenol of 1.82g, normal-temperature reaction 3 hours steams solvent, chromatography column separate compound 8, yield 50%.
Structural characterization: mp:214-215 ℃. 1H NMR (400MHz, CDCl 3): δ 8.57 (d, J=8.4Hz, 1H), 8.47 (d, J=8.4Hz, 2H), 7.92 (d, J=8.0Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.61 (t, J=8.0Hz, 1H), 7.31 (t, J=9.2Hz, 2H), 7.22 (d, J=8.4Hz, 1H), 2.87 (m, 1H), 1.2 (d, J=8.0Hz, 6H) .TOF MS (EI +): C 24H 16N 2OS, (m/z): calcd for 380.0983, found 380.0985.
Embodiment 6:3-(4-sec-butylbenzene sulfenyl)-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-nitrile (compound 9) also
Figure BSA00000534476600082
Add also [1,2-b] pyrroles-9-nitrile of 0.69g 8-oxygen-8H-acenaphthene in the 50mL acetonitrile, the sec-butylbenzene thiophenol of 1.99g, normal-temperature reaction 3 hours steams solvent, chromatography column separate compound 9, yield 42%.
Structural characterization: M.p.245-246 ℃. 1H NMR (400M, CDCl 3): δ 8.85 (d, J=8.0Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.53 (d, J=8.0Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.12 (d, J=8.4Hz, 1H), 2.55 (m, 1H), 1.55 (m, 2H), 1.31 (d, J=8.0Hz, 3H), 0.89 (t, J=8.0Hz, 3H), TOF MS (EI +): C 25H 18N 2OS, (m/z): calcd for 394.1140, found 394.1137.
Embodiment 7:6-(4-propylbenzene sulfenyl)-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-nitrile (compound 10) also
Figure BSA00000534476600091
Add also [1,2-b] pyrroles-9-nitrile of 0.69g 8-oxygen-8H-acenaphthene in the 50mL acetonitrile, the propylbenzene thiophenol of 1.82g, normal-temperature reaction 3 hours steams solvent, chromatography column separate compound 10, yield 32%.
Structural characterization: M.p.257-259 ℃ of .1H NMR (400M, CDCl 3): δ 8.32 (d, J=8.8Hz, 1H), 8.11 (d, J=8.8Hz, 1H), 7.95 (d, J=8.8Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 7.50 (t, J=8.4Hz, 1H), 7.06 (d, J=8.4Hz, 2H), 2.87 (m, 1H), 1.2 (d, J=8.0Hz, 6H) .TOF MS EI +: C 24H 16N 2OS, (m/z) calcd for 380.0983, found 380.0987.
Embodiment 8:3,6-two (4-sec-butylbenzene sulfenyl)-8-oxygen-8H-acenaphthene be the synthetic and sign of [1,2-b] pyrroles-9-nitrile (compound 11) also
Figure BSA00000534476600092
Add also [1,2-b] pyrroles-9-nitrile of 1.0g 8-oxygen-8H-acenaphthene in the 50mL acetonitrile, the sec-butylbenzene thiophenol of 2.9g, normal-temperature reaction 30 hours steams partial solvent, chromatography column separate compound 11, yield 20%.
Structural characterization: M.p.268-269 ℃. 1H NMR (400M, CDCl 3): δ 8.12 (d, J=8.8Hz, 1H), 7.60 (d, J=8.8Hz, 1H), 7.51 (d, J=8.0Hz, 4H), 7.48 (d, J=8.8Hz, 1H), 7.23 (d, J=8.8Hz, 1H), 7.08 (d, J=8.0Hz, 4H), 2.55 (m, 2H), 1.52 (m, 4H), 1.25 (d, J=8.0Hz, 6H), 0.78 (t, J=8.0Hz, 6H) .TOF MSEI +: C 35H 30N 2OS 2, (m/z): calcd for 558.1800, found 558.1803.
Embodiment 9:3-[(4-amine methyl) benzoyl]-8-oxygen-8H-acenaphthene also [1,2-b] pyrroles-9-nitrile (compound 12) and 4-[(4-amine methyl) benzoyl]-8-oxygen-8H-acenaphthene [1,2-b] pyrroles-9-nitrile (compound 13) synthetic and characterizing also
Take by weighing 0.95g 5-[(4-amine methyl) benzoyl] acenaphthenequinone, the 0.33g propane dinitrile adds in the silicagel column with after the methylene dichloride dissolving, drip washing fast, cross post be spin-dried for after finishing dark red solid.The 0.93g that weighs, productive rate 85%.Get 0.73g gained red solid, add 0.08g K 2CO 3, 20mL acetonitrile reflux 3 hours is spin-dried for reaction solution after reaction finishes.Chromatography column separates (CH 2Cl 2: sherwood oil=2: 1) obtain dark red solid, nuclear-magnetism check isomers ratio 1: 0.2.Utilize the preparation liquid phase separation to obtain two kinds of isomerss.
Compound 12:M.p.289-290 ℃. 1H NMR (400M, CDCl 3): δ 8.96 (dd, J=8.8Hz, 1H), 8.73 (d, J=8.8Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 8.08 (t, J=8.8Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 7.69 (d, J=8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 6.32 (br, 2H), 4.36 (s, 2H) .TOF MS EI +: C 23H 13N 3O 2, (m/z): calcd for 363.1008, found 363.1009.
Compound 13:M.p.＞300 ℃; 1H NMR (400M, CDCl 3): δ 8.85 (dd, J=8.8Hz, 1H), 8.70 (d, J=8.8Hz, 1H), 8.10 (d, J=8.4Hz, 1H), 7.98 (t, J=8.8Hz, 1H), 7.86 (d, J=8.4Hz, 1H), 7.59 (d, J=8.4Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 6.08 (br, 2H), 4.36 (s, 2H) .TOF MS EI +: C 23H 13N 3O 2, (m/z): calcd for 363.1008, found 363.1005.
Embodiment 10:3-hexyloxy-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-formic acid (compound 14) also
Figure BSA00000534476600111
In 50mL single port flask, add the 60mL vitriol oil, under 0～5 ℃, 3-hexyloxy-8-oxygen-8H-the acenaphthene that in batches adds 1.15g is [1,2-b] pyrroles-9-nitrile also, adds in 1 hour, add the back and continue reaction 18 hours in room temperature, reaction mixture is the dark brown red of thickness.Carefully slowly it is splashed in the trash ice then, vigorous stirring leaves standstill after dripping off simultaneously, and filter cake is washed with massive laundering, is neutral until filter cake, obtains compound 14 behind the filtration cakes torrefaction, productive rate 90%.
Structural characterization: M.p.235-237 ℃. 1H NMR (400M, CDCl 3): δ 11.0 (s, 1H), 8.55 (d, J=8.0Hz, 1H), 8.45 (d, J=8.0Hz, 1H), 8.01 (t, J=8.0Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 6.561 (d, J=8.4Hz, 1H), 4.10 (t, J=7.6Hz, 2H), 1.75 (m, J=7.6Hz, 2H), 1.43 (m, 2H), 1.31 (m, 2H), 1.29 (m, 2H), 0.89 (t, J=7.6Hz, 3H); TOF MS EI +: C 21H 19NO 4, (m/z): calcd for 349.1314, found 349.1316.
Embodiment 11:3-(4-isobutyl-phenoxy group)-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-ethyl formate (compound 15) also
Figure BSA00000534476600112
In 100mL single port flask, add also [1,2-b] pyrroles-9-formic acid of 3.78g 3-(4-isobutyl-phenoxy group)-8-oxygen-8H-acenaphthene successively; the 50mL acetonitrile is made solvent, and the salt of wormwood of 2.76g is done and tied up acid meter, excessive 10 times methyl iodide; under the nitrogen protection, be heated to 42 ℃ of reactions 18 hours.The pressure reducing and steaming acetonitrile adds methylene dichloride reactant is fully dissolved, and is spin-dried for filtrate after filtering, and gets the thick product of yellowish brown.Silica gel column chromatography separates, and obtains compound 15, productive rate 85%.
Structural characterization: M.p.215-216 ℃. 1H NMR (400M, CDCl 3): δ 8.45 (d, J=8.0Hz, 1H), 8.35 (d, J=8.0Hz, 1H), 7.85 (t, J=8.0Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.36 (d, J=8.8Hz, 2H), 7.23 (d, J=8.8Hz, 2H), 6.50 (d, J=8.4Hz, 1H), 2.45 (d, J=8.4Hz, 2H), 1.52 (m, 2H), 1.25 (d, J=8.4Hz, 3H), 0.93 (t, J=8.4Hz, 3H) .TOF MS EI +: C 26H 21NO 3S, (m/z): calcd for 427.1242, found 427.1245.
Embodiment 12:3-(4-isobutyl-phenoxy group)-8-oxygen-8H-acenaphthene is the synthetic and sign of [1,2-b] pyrroles-9-N-tert-butylamides (compound 16) also
Figure BSA00000534476600121
In 100mL single port flask, add 3.97g 3-(4-isobutyl-phenoxy group)-also [1,2-b] pyrroles-9-acid of 8-oxygen-8H-acenaphthene successively, 50mL DMF makees solvent, the triethylamine of 0.15mL, (EtO) of 1.63g 2P (=O) CN, excessive 10 times n-Butyl Amine 99, normal-temperature reaction 1 hour.Reaction finishes and obtains yellow solid, productive rate 35%.
Structural characterization: M.p.247 ℃. 1H NMR (400M, CDCl 3): δ 8.49 (d, J=8.0Hz, 1H), 8.40 (d, J=8.0Hz, 1H), 7.83 (t, J=8.0Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.46 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 6.63 (d, J=8.0Hz, 1H), 5.53 (br, 1H), 3.21 (t, J=8.0Hz, 2H), 2.53 (m, 1H), 1.52-1.50 (m, 7H), 1.25-1.32 (m, 5H), 0.91 (t, J=8.0Hz, 3H) .TOF MS EI +: C 25H 19N 2O 3, (m/z): calcd for395.1396, found 395.1394.
Second section: the physics and chemistry of Bcl-2 family protein inhibitor compound is active to be detected
Embodiment 13: by the similar degree of BH3 of fluorescence polarization assay method detection compound
Synthetic one 21 amino acid whose Bid BH3 peptide sections (amino acid: 79-99:QEDIIRNIARHLAQ VGDSMDR), and on N end mark 6-Fluoresceincarboxylic acid succinimide ester (FAM) as fluorescence labels (FAM-Bid).Competition is that GST-Bcl-2 albumen (40nM) or Mcl-1 albumen and FAM-Bid polypeptide (5nM) are dissolved in (100mM K3PO4, pH 7.5,100 μ g/ml ox γ albumin in the reaction buffer in conjunction with used reaction system in the experiment; 0.02% sodiumazide).In 96 orifice plates, every hole adds 100 μ L reaction systems, adds the mother liquor of the compound to be detected 1 that is dissolved in DMSO of 1 μ L different concns then to the required final concentration of experimental design.Set up control group simultaneously, only contain Bcl-2 or Mcl-1 and FAM-Bid (being equivalent to 0% inhibiting rate) in the reaction system.96 orifice plates carry out detecting on the microplate reader after hatching through 4 hours lucifuge.Fluorescence polarization value (mP) is measured under the 485nm emission wavelength that is excited generation by the 530nm wavelength.Competition binding constant (K i) value root calculation formula derives and to draw.Competition binding constant (the K of this compound and Bcl-2 and Mcl-1 albumen i) value is respectively 158nM and 24nM (accompanying drawing 1 and accompanying drawing 2).
According to the similar degree of BH3 that above-mentioned identical test method detects other 12 compounds, the binding constant (being called for short binding constant in the table 1) of they and Bcl-2 and Mcl-1 albumen is also in the nM level, and concrete outcome is as shown in table 1.
Table 1
Compound Bcl-2 protein binding constant (nM) Mcl-1 protein binding constant (nM)
1 158 24
3 140 12
4 210 56
5 20 85
6 120 8
7 23 85
8 23 57
9 12 65
10 9 85
11 540 25
13 115 135
14 105 85
15 86 75
Embodiment 14: the fluorescence polarization energy shifts the BH3 similarity of (FRET) detection compound in the viable cell
The method of utilizing coprecipitation of calcium phosphate with 2 μ g Bcl-2-CFP and Bax-YFP plasmid respectively or transfection simultaneously to the Hela cell, transfection is after 24 hours, with cell inoculation in 6 well culture plates (2 * 10 5Individual/hole), the compound to be detected 1 that adding is dissolved in DMSO is to final concentration (2,5,10 and 15 μ M), and drug effect is (as accompanying drawing 3) after 24 hours, and PBS cleans cell 3 times, and (TECAN Swiss) detects fluorescent value with the GENIOS fluorescence microplate reader.In time dependent experiment, the cell inoculation after the transfection adds 40 μ M compounds behind 6 orifice plates, and drug effect 3,6 and 24 hours (accompanying drawing 4) are read plate and detected fluorescence.Record 475nm emission wavelength values in a groups of cells of transfection Bcl-2-CFP plasmid, excitation wavelength is 433nm.Record 527nm emission wavelength values in a groups of cells of transfection Bax-YFP plasmid, excitation wavelength is 505nm.To cell experiment group record 527nm and the 475nm emission wavelength values of cotransfection Bcl-2-CFP and Bax-YFP plasmid, excitation wavelength is 433nm.The 527nm emitting fluorescence is FRET with 475nm emitting fluorescence phase ratio, and the FRET value of independent transfection control group is made as 1.0.In the cell of cotransfection, because the interaction of Bcl-2 albumen and Bax albumen makes FRET value increase to 2.0, and along with the increase of adding consistency and time, to the interference enhancing of two protein-interactings, FRET weakens thereupon.Cell viability is measured by mtt assay.Test-results is shown in accompanying drawing 3 and accompanying drawing 4, and this compound is at 2 μ M, and the interaction that effect can be disturbed between the Bcl-2/Bax in 3 hours is concentration time-dependent trend.
Detect other 12 compounds according to above-mentioned identical test method, these compounds of evidence are under the condition of different activities and action time, all have the effect of simulation BH3-only albumen in the cell, can obviously disturb the interaction between the Bcl-2/Bax.Concrete outcome is as shown in table 2.Wherein concentration and time representation test compounds are in the time of disturbing the interaction generation between the Bcl-2/Bax under this concentration.
Table 2
Compound Concentration (μ M) Time (hour)
1 0.5 4
3 0.5 4
4 0.5 3
5 0.1 2
6 0.5 4
7 0.3 3
8 0.2 2
9 0.2 2
10 0.5 2
11 1.0 2
13 0.6 4
14 0.5 5
15 0.3 3
Embodiment 15: the BH3 similar degree that is total to the detection and localization compound by Bax albumen and plastosome
Utilize the coprecipitation of calcium phosphate method with 5 μ g Bax-YFP plasmid transfections to the MCF-7 cell, transfection is after 24 hours, with cell inoculation in 6 well culture plates (0.2 * 10 6Individual/hole), add 10 μ M compound 1 to be detected, act on after 6 hours, PBS cleans and with 50nM Mito Tracker Red CMXRos (plastosome specific probe; Redness) lucifuge is hatched 10min, after PBS cleans three times, and Radiance2000 laser confocal microscope (Bio-Rad, USA) scanning fluoroscopic image.Carry out two channels scanning simultaneously, the green fluorescence of a passage scanning Bax-YFP, the mitochondrial CMXRos probe red fluorescence of another passage scanning indication, two channel image mutual superposition show the situation of locating altogether.Under this compound effects, the stack picture presents orange fluorescence, and Bax is to the plastosome displacement in expression.
Detect other 12 compounds according to above-mentioned identical test method, the result shows them under the condition of different activities and action time, all has to drive BAX to the effect of plastosome displacement, and the effect with simulation BH3-only albumen in the cell is described.Concrete outcome is as shown in table 3, and wherein concentration and time representation test compounds are simulated BH3-only albumen and driven BAX to the time of the effect generation of plastosome displacement under this concentration.
Table 3
Compound Concentration (μ M) Time (hour)
1 5.0 4
3 5.0 3
4 4.0 3
5 1.0 1
6 5.0 4
7 3.0 3
8 5.0 3
9 2.0 2
10 5.0 3
11 1.0 3
13 6.0 4
14 5.0 5
15 2.0 3
Embodiment 16: the cytotoxicity experiment of compound dependence BAX/BAK is verified the characteristic of its BH3 analogue
Coprecipitation of calcium phosphate transfection 3 μ g BAX/BAK interference plasmids are to the MCF-7 cell, and transfection is after 24 hours, and collecting cell, Western detect RNA interference back BAX and BAK protein expression situation, and same treatment plasmid-free cells transfected group is made as control group.Cell inoculation after the transfection is in 96 orifice plates (1 * 10 5Individual/hole), the parallel control experiment of carrying out untransfected plasmid cell group, add compound 1 to be detected by the experimental design concentration gradient, act on after 48 hours, MTT detects cell viability, the result as shown in Figure 5, Gossypol is as non-specific BH3 analogue and compound of the present invention contrast parallel processing, visible compound 1 has the cytotoxicity of absolute dependence BAX/BAK.
Detect other 12 compounds by above-mentioned identical test method, by the IC of comparison and detection compound effects in transfectional cell and non-transfected cells 50Value changes, and illustrates that institute's detection compound also all has the effect characteristics of absolute dependence BAX/BAK (seeing Table 4).
Table 4
Compound Non-transfected cells IC 50Value (μ M) Transfectional cell IC 50Value (μ M)
1 7.5 ＞50
3 7.1 ＞50
4 8.5 ＞50
5 2 ＞50
6 6.8 ＞50
7 2.2 ＞50
8 2.1 ＞50
9 1.5 ＞50
10 1.2 ＞50
11 15 ＞50
13 6.5 ＞50
14 6.2 ＞50
15 5.6 ＞50
Embodiment 17:Western marking detection compound is to the restraining effect of Mcl-1 and Bcl-2
Behind the collecting cell sample, with 1 * 10 6/ 50 μ l cell pyrolysis liquid (62.5mM Tris-HCL pH 6.8; 2%SDS; 10% glycine; 50mM DTT; 0.01% tetrabromophenol sulfonphthalein) low temperature pyrolyzer is centrifugal, gets the albumen supernatant, 100 ℃ were boiled sample 5 minutes, the 12%SDS-PAGE electrophoresis also changes film, corresponding antibodies testing goal albumen, and horseradish peroxidase mark two is anti-and in conjunction with the expression amount of ECL development process testing goal albumen in cell.Accompanying drawing 6 and accompanying drawing 7 show the restraining effect of 1 couple of Mcl-1 of compound to be detected and Bcl-2 respectively.As can be seen from the figure, along with testing compound acts on the prolongation of tumour cell time, the protein band of Bcl-2 and Mcl-1 shoals gradually, illustrates that compound has the effect that suppresses these two albumen.Utilize KODAK Gel Logic1500 imaging system software that protein band concentration in the Western picture is carried out semi-quantitative analysis, after the normalized, the concentration of protein band is shown in accompanying drawing 8 and 9.
Through with quadrat method to detecting following 9 compounds, they all have the effect that suppresses Bcl-2 and Mcl-1 albumen, and these compounds comprise: compound 1, compound 3, compound 5, compound 6, compound 8, compound 9, compound 10, compound 11 and compound 15.
The semi-quantitative analysis result of these compound downward modulation Mcl-1 albumen and Bcl-2 albumen is respectively shown in table 5 and table 6:
Table 5
Compound 1 3 5 6 8 9 10 11 15
Contrast 1 1 1 1 1 1 1 1 1
6 hours 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99
12 hours 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99
18 hours 0.42 0.39 0.58 0.36 0.50 0.49 0.60 0.70 0.57
24 hours 0.14 0.12 0.11 0.10 0.23 0.18 0.37 0.41 0.29
Table 6
Compound 1 3 5 6 8 9 10 11 15
Contrast 1 1 1 1 1 1 1 1 1
2 hours 0.79 0.69 0.65 0.66 0.60 0.59 0.68 0.60 0.57
6 hours 0.29 0.42 0.37 0.39 0.29 0.28 0.49 0.59 0.29

Claims (2)

1. class acenaphthene and a heterocyclic compound is selected from: 3-(4-isopropyl benzene sulfenyl)-and 8-oxygen-8H-acenaphthene also [1,2-b] pyrroles-9-nitrile and 3-(4-sec-butylbenzene sulfenyl)-8-oxygen-8H-acenaphthene [1,2-b] pyrroles-9-nitrile also.
2. the described acenaphthene of claim 1 and the heterocyclic compound application in preparation BH3 analogue Bcl-2 family protein inhibitor.
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CN101423491A (en) * 2008-11-11 2009-05-06 大连理工大学 Acenaphtho-heterocycles compounds and application thereof in preparation of BH3 analogue Bcl-2 family protein inhibitor
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CN101423491A (en) * 2008-11-11 2009-05-06 大连理工大学 Acenaphtho-heterocycles compounds and application thereof in preparation of BH3 analogue Bcl-2 family protein inhibitor
CN101633637A (en) * 2009-08-18 2010-01-27 华东理工大学 8-oxo-8H-acenaphtho[1,2-b]pyrrole derivative

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