CN106117234B - Morusin skeleton splices convolutamydine A skeleton class compound and preparation method and application - Google Patents

Morusin skeleton splices convolutamydine A skeleton class compound and preparation method and application Download PDF

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CN106117234B
CN106117234B CN201610484485.5A CN201610484485A CN106117234B CN 106117234 B CN106117234 B CN 106117234B CN 201610484485 A CN201610484485 A CN 201610484485A CN 106117234 B CN106117234 B CN 106117234B
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skeleton
morusin
convolutamydine
compound
class compound
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CN106117234A (en
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刘雄利
周英
陆毅
黄俊飞
俸婷婷
林冰
田民义
彭礼军
余章彪
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Guizhou University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of Morusin skeletons to splice convolutamydine A skeleton class compound, the present invention is with the butanone of the various substituted skeletons containing Morusin, various substituted isatin are in molar ratio the ratio of 3:4, reaction temperature is 40 DEG C in ethanol, reaction time is 15 hours, Aldol addition reaction is carried out, Morusin skeleton is obtained and splices convolutamydine A skeleton class compound.Such skeleton includes the active Morusin skeleton of multi-biological and convolutamydine A skeleton, and chemical combination material resource can be provided for bioactivity screening, and the screening and pharmaceutical industry to multiple target point multipurpose medicine have important application value.Operation of the present invention is simple and easy, and Material synthesis is cheap and easily-available, can carry out in various polar organic solvents, also there is preferable air stability, applicability is wide, has good compatibility for various substituent groups, and these compounds have the potentiality for being developed into anti-tumor drug.

Description

Morusin skeleton splices convolutamydine A skeleton class compound and its preparation Method and application
Technical field
The present invention relates to technical field of chemistry, especially a kind of Morusin skeleton splices convolutamydine A skeleton Class compound and preparation method and application.
Background technique
With bioactive natural products skeleton be spliced to in other natural products skeletons of bioactivity organic It is extremely important research field in chemistry and medical chemistry.(1), lavonoid backbone class compound Morusignin L and its Sang Xin Plain (Morusignin L I and Morusin II) is the two kinds of active components separated from Cortex Mori, in Huang Ketone occupies an important position in field, that is, having significant bioactivity, (anti-inflammatory, diuresis, expectorant and anti-Type B are B-mode Hepatitis activity).(2), the alkaloid of the skeleton of A containing Convolutamydine exists in some biologically active compounds Or in natural products, selective representative example includes: Convolutamydine A III, anticonvulsion ingredient IV- VI, anti-aging disease ingredient VII.Have in view of Morusin framework compound and Convolutamydine A framework compound There is multi-biological active.Therefore, Morusin framework compound is spliced to Convolutamydine A skeleton, synthesized a series of The compound of new potential more active skeletons, can provide chemical combination material resource, to multiple target point multipurpose drug for bioactivity screening Screening and pharmaceutical industry have important application value (as shown in attached drawing 7 and attached drawing 8).
Special emphasis is that Morusin skeleton synthesized by the present invention splices convolutamydine A skeleton class chemical combination Object, and it is a kind of both containing flavonoids skeleton, also there are also Oxoindole alkaloid framework compounds.In nature, flavones and Oxoindole alkaloid belongs to extremely abundant two big natural products libraries, but in nature and artificial synthesized compound, There is no an example to contain the splicing product of this two big natural products flavonoids skeleton and Oxoindole alkaloid skeleton.Therefore, this hair A series of Morusin skeleton of bright new potential more active skeletons of synthesis splices convolutamydine A skeleton class compound, Chemical combination material resource can be provided for bioactivity screening, the screening and pharmaceutical industry to multiple target point multipurpose drug have important answer With value.
Summary of the invention
The object of the present invention is to provide a kind of Morusin skeleton splicing convolutamydine A skeleton class compound and Preparation method and application, it is a kind of important medicine intermediate analog and drug molecule analog, multi-purpose to multiple target point Way drug screening and pharmaceutical industry have important application value, and the very economical simplicity of its synthetic method.
The present invention is implemented as follows: Morusin skeleton splices convolutamydine A skeleton class compound, the change Close the structure that object has following general formula (I):
In formula, R1For alkyl, alkoxy, halogen or hydrogen；R2For alkyl, aryl or hydrogen；R3For alkyl, halogen or hydrogen.
Morusin skeleton splices the preparation method of convolutamydine A skeleton class compound, and various substituted is contained The butanone of Morusin skeleton and various substituted isatin are the ratio of 3:4 in polar solvent in molar ratio, anti-under the conditions of heating It answers, carries out Aldol addition reaction, obtain Morusin skeleton and splice convolutamydine A skeleton class compound.
The polar solvent is methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran, ether, DMSO Or DMF.
The butanone of the various substituted skeletons containing Morusin is with various substituted isatin reaction temperatures in polar solvent 40-100 DEG C, the reaction time is 5-20 hours.
The Morusin skeleton splicing convolutamydine A skeleton class compound prevents and treats tumor disease in preparation The application of drug.
Reaction principle of the invention is as follows:
It is various to take with the butanone of the various substituted various substituted skeletons containing Morusin by using above-mentioned technical proposal The isatin in generation is in molar ratio the ratio of 3:4, and reaction temperature is 40 DEG C in ethanol, and the reaction time is 15 hours, is carried out Aldol addition reaction obtains Morusin skeleton and splices convolutamydine A skeleton class compound.Such skeleton includes more The active Morusin skeleton of object of living again and convolutamydine A skeleton, can provide compound for bioactivity screening Source, screening and pharmaceutical industry to multiple target point multipurpose medicine have important application value.Operation of the present invention is simple and easy, raw material It synthesizes cheap and easily-available, can be carried out in various polar organic solvents, it may have preferable air stability, applicability is wide, right There is good compatibility in various substituent groups.
Detailed description of the invention
Attached drawing 1 and attached drawing 2 are the compound 3a spectral data of the embodiment of the present invention 1；
Attached drawing 3 and attached drawing 4 are the compound 3b spectral data of the embodiment of the present invention 1；
Attached drawing 5 and attached drawing 6 are the compound 3c spectral data of the embodiment of the present invention 1.
Attached drawing 7 and attached drawing 8 are flow chart of the invention.
Specific embodiment
The embodiment of the present invention 1: the butanone (0.30 of 117.0 mg skeletons containing Morusin is sequentially added in reaction tube Mmol), 89.2 mgNPhenylisatin (0.40 mmol), 11.0 mg diethylamine (50 mmol%) and 2.0 ml ethyl alcohol are molten Liquid, 40oReact 15 h under C, TLC is detected after completion of the reaction, be spin-dried for ethyl alcohol, direct loading chromatograph through column (eluant, eluent:V(petroleum Ether):V(ethyl acetate)=3:1) purify to obtain 128.7 mg compound 3a, faint yellow solid, fusing point: 80.2-80.5oC；Yield 70%.The results such as nuclear magnetic resonance and high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.72-2.77 (m, 4H), 3.08 (d, J = 13.2 Hz, 1H), 3.28 (d, J = 13.2 Hz, 1H), 5.61 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 6.0 Hz, 1H), 7.03-7.07 (m, 1H), 7.19-7.23 (m, 1H), 7.36-7.53 (m, 13H); 13C NMR (CDCl3, 100 MHz) δ: 19.5, 28.2, 42.5, 48.7, 74.3, 77.9, 94.7, 109.8, 115.5, 123.5, 124.0, 126.5, 128.1, 128.2, 128.5, 128.7, 129.6, 129.9, 130.6, 143.7, 156.2, 157.0, 159.5, 162.6, 175.8, 182.3, 207.9; HRMS (ESI-TOF) m/z: Calcd. for C38H31NNaO7 [M+Na]+: 636.1998; Found: 636.1997.
For the preparation method of compound 3b-3w with compound 3a, feed ratio is identical as compound 3a, and compound 3b- can be obtained 3w, reaction yield is shown in Tables 1 and 2, but it is emphasized that the compound of the present invention is not limited to content represented by Tables 1 and 2.
Table 1 is the chemical structure that a kind of Morusin skeleton splices convolutamydine A skeleton class compound
Table 2 is the chemical structure that a kind of Morusin skeleton splices convolutamydine A skeleton class compound
The present embodiment prepare compound 3b: yellow solid, fusing point: 75.6-76.2oC, yield 62%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.26 (s, 3H), 2.62-2.66 (m, 2H), 2.76-2.79 (m, 2H), 2.93 (d, J = 12.1 Hz, 1H), 3.15 (d, J = 12.5 Hz, 1H), 4.80-4.90 (m, 2H), 5.62 (d, J = 7.8 Hz, 1H), 6.27 (s, 1H), 6.55 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 4.2 Hz, 1H), 7.14 (s, 1H), 7.18-7.29 (m, 8H), 7.39-7.42 (m, 1H), 7.50-7.52 (m, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.8, 21.0, 28.3, 42.1, 43.8, 47.8, 74.5, 78.0, 94.8, 105.5, 109.4, 115.5, 120.3, 124.6, 124.8, 127.2, 127.6, 128.2, 128.8, 129.6, 130.1, 130.6, 132.8, 135.5, 140.1, 156.3, 157.3, 157.4, 158.5, 159.7, 160.5, 176.2, 182.0; HRMS (ESI-TOF) m/z: Calcd. for C40H34FNNaO7 [M+Na]+: 682.2217; Found: 682.2221.
The present embodiment prepare compound 3c: yellow solid, fusing point: 80.9-81.4oC, yield 74%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.45 (s, 6H), 2.57-2.61 (m, 2H), 2.76-2.79 (m, 2H), 2.98 (d, J = 13.6 Hz, 1H), 3.19 (d, J = 13.6 Hz, 1H), 4.80-4.90 (m, 2H), 5.61 (d, J = 8.1 Hz, 1H), 6.27 (s, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 7.18-7.31 (m, 9H), 7.41-7.45 (m, 2H), 7.50-7.52 (m, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.7, 28.2, 41.8, 43.9, 47.9, 74.1, 78.0, 94.8, 104.9, 111.1, 115.4, 115.8, 120.2, 127.1, 127.3, 127.8, 128.1, 128.9, 131.7, 132.6, 134.9, 156.3, 157.2, 157.4, 158.4, 159.6, 160.4, 175.8, 181.9, 208.1; HRMS (ESI-TOF) m/z: Calcd. for C39H31BrFNNaO7 [M+Na]+: 746.1166; Found: 746.1169.
The present embodiment prepare compound 3d: yellow solid, fusing point: 87.4-88.5oC, yield 76%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.50 (s, 6H), 2.59-2.66 (m, 2H), 2.80-2.83 (m, 2H), 3.03 (d, J = 13.6 Hz, 1H), 3.25 (d, J = 13.6 Hz, 1H), 4.85-4.95 (m, 2H), 5.66 (d, J = 7.8 Hz, 1H), 6.31 (s, 1H), 6.62 (d, J = 5.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 7.16-7.17 (m, 1H), 7.18-7.19 (m, 1H), 7.20-7.36 (m, 8H), 7.44-7.47 (m, 1H), 7.55-7.56 (m, 1H), 130.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.7, 28.2, 41.8, 43.9, 47.9, 74.2, 78.0, 94.8, 105.4, 110.6, 115.4, 124.6, 127.1, 127.8, 128.2, 128.6, 128.9, 129.7, 131.3, 134.9, 141.1, 156.3, 157.2, 157.4, 158.4, 159.7, 160.4, 176.0, 181.9, 208.1; HRMS (ESI-TOF) m/z: Calcd. for C39H31ClFNNaO7 [M+Na]+: 702.1671; Found: 702.1670.
The present embodiment prepare compound 3e: yellow solid, fusing point: 78.7-79.1oC, yield 85%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.53 (m, 2H), 2.69 (s, 2H), 3.06 (d, J = 13.6 Hz, 1H), 3.25 (d, J = 13.4 Hz, 1H), 5.62 (d, J = 7.9 Hz, 1H), 6.25 (s, 1H), 6.71-6.73 (m, 1H), 6.76-6.78 (m, 1H), 7.04 (s, 1H), 7.19-7.21 (m, 1H), 7.29-7.53 (m, 11H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.7, 28.2, 41.8, 48.8, 74.2, 78.0, 94.7, 109.8, 115.4, 120.2, 123.5, 124.0, 126.5, 128.1, 128.2, 129.2, 129.6, 129.8, 134.0, 143.7, 156.3, 157.2, 157.4, 158.4, 159.6, 160.4, 175.7, 181.9, 207.8; HRMS (ESI-TOF) m/z: Calcd. for C38H30FNNaO7 [M+Na]+: 654.1904; Found: 654.1904.
The present embodiment prepare compound 3f: yellow solid, fusing point: 94.2-94.8oC, yield 65%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.48-2.56 (m, 2H), 2.69-2.72 (m, 2H), 2.93 (d, J = 13.2 Hz, 1H), 3.15 (d, J = 13.3 Hz, 1H), 4.81-4.92 (m, 2H), 5.61 (d, J = 7.9 Hz, 1H), 6.26 (s, 1H), 6.66-6.73 (m, 2H), 6.96-6.99 (m, 1H), 7.14-7.18 (m, 1H), 7.24-7.42 (m, 10H), 7.68-7.70 (m, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 42.0, 43.8, 47.9, 74.3, 78.0, 94.8, 109.6, 115.4, 123.1, 127.2, 127.6, 127.7, 128.1, 128.8, 129.9, 130.6, 131.8, 133.3, 142.6, 156.3, 157.2, 159.7, 161.4, 176.2, 182.1, 208.4; HRMS (ESI-TOF) m/z: Calcd. for C39H32BrNNaO7 [M+Na]+: 728.1260; Found: 728.1262.
The present embodiment prepare compound 3g: yellow solid, fusing point: 80.2-80.9oC, yield 63%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.30 (s, 3H), 2.49-2.57 (m, 2H), 2.70-2.73 (m, 2H), 2.92 (d, J = 13.2 Hz, 1H), 3.14 (d, J = 13.4 Hz, 1H), 4.79-4.90 (m, 2H), 5.61 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 6.54 (d, J = 6.4 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 6.0 Hz, 1H), 7.13 (s, 1H), 7.24-7.43 (m, 9H), 7.69 (d, J = 6.4 Hz, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 21.0, 28.3, 42.0, 43.8, 47.9, 74.4, 78.0, 94.8, 105.5, 109.4, 115.4, 122.6, 124.7, 127.2, 127.6, 127.7, 128.1, 128.8, 130.1, 130.6, 131.8, 132.8, 133.3, 156.3, 157.2, 159.7, 161.4, 176.2, 182.1, 208.4; HRMS (ESI-TOF) m/z: Calcd. for C40H34BrNNaO7 [M+Na]+: 742.1416; Found: 742.1419.
The present embodiment prepare compound 3h: yellow solid, fusing point: 95.4-96.3oC, yield 70%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.51-2.56 (m, 2H), 2.70-2.74 (m, 2H), 2.96 (d, J = 14.0 Hz, 1H), 3.18 (d, J = 13.6 Hz, 1H), 4.79-4.89 (m, 2H), 5.61 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 7.26-7.45 (m, 11H), 7.70 (d, J = 6.4 Hz, 1H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 41.8, 43.9, 47.9, 74.1, 78.0, 94.8, 111.1, 115.4, 115.9, 119.4, 127.1, 127.4, 127.7, 127.8, 128.1, 128.9, 130.6, 131.9, 132.7, 133.3, 156.3, 157.2, 159.7, 161.4, 175.8, 182.1, 208.0; HRMS (ESI-TOF) m/z: Calcd. for C39H31Br2NNaO7 [M+Na]+: 806.0365; Found: 806.0365.
The present embodiment prepare compound 3i: yellow solid, fusing point: 90.5-90.7oC, yield 70%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.51 (m, 2H), 2.65-2.69 (m, 2H), 2.90 (d, J = 13.2 Hz, 1H), 3.09 (d, J = 13.4 Hz, 1H), 3.54 (s, 3H), 5.61 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.91-6.94 (m, 1H), 7.17-7.21 (m, 2H), 7.32-7.34 (m, 2H), 7.39-7.45 (m, 2H), 7.69-7.71 (m, 1H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 41.9, 48.1, 73.6, 78.1, 94.8, 105.1, 105.5, 115.4, 119.3, 122.3, 122.6, 124.0, 127.7, 128.2, 130.6, 131.9, 132.2, 133.3, 156.2, 157.2, 159.7, 161.5, 176.5, 182.1, 208.0; HRMS (ESI-TOF) m/z: Calcd. for C33H27BrClNNaO7 [M+Na]+: 686.0557; Found: 686.0554.
The present embodiment prepare compound 3j: yellow solid, fusing point: 89.7-90.0oC, yield 62%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.45-2.52 (m, 2H), 2.65-2.69 (m, 2H), 2.88 (d, J = 13.6 Hz, 1H), 3.10 (d, J = 13.6 Hz, 1H), 3.17 (s, 3H), 5.61 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 7.00-7.03 (m, 1H), 7.26-7.44 (m, 5H), 7.70 (d, J = 6.4 Hz, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 26.2, 28.3, 41.9, 47.9, 74.2, 78.0, 94.8, 108.5, 115.4, 119.4, 123.1, 123.9, 127.7, 128.1, 129.9, 130.6, 131.8, 133.3, 143.4, 156.2, 157.1, 159.7, 161.4, 176.1, 182.1, 208.3; HRMS (ESI-TOF) m/z: Calcd. for C33H28BrNNaO7 [M+Na]+: 652.0947; Found: 652.0949.
The present embodiment prepare compound 3k: yellow solid, fusing point: 75.1-75.4oC, yield 80%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.53 (m, 2H), 2.69 (s, 2H), 3.07 (d, J = 13.6 Hz, 1H), 3.25 (d, J = 13.2 Hz, 1H), 5.61 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 6.71-6.78 (m, 2H), 7.04-7.06 (m, 1H), 7.19-7.21 (m, 1H), 7.26-7.53 (m, 11H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.5, 28.3, 41.8, 48.9, 74.2, 78.0, 94.8, 109.8, 115.4, 123.5, 124.0, 126.5, 127.1, 128.2, 128.3, 129.6, 129.9, 130.1, 131.7, 143.8, 156.3, 157.2, 159.7, 160.2, 175.8, 182.1, 207.7; HRMS (ESI-TOF) m/z: Calcd. for C38H30BrNNaO7 [M+Na]+: 714.1103; Found: 714.1105.
The present embodiment prepare compound 3l: yellow solid, fusing point: 73.1-74.2oC, yield 74%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.44 (s, 6H), 2.40-2.46 (m, 2H), 2.63-2.67 (m, 2H), 2.95 (d, J = 13.2 Hz, 1H), 3.13 (d, J = 13.2 Hz, 1H), 4.97 (br s, 1 H), 5.59 (d, J = 7.9 Hz, 1H), 6.23 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.72-6.74 (m, 1H), 6.82-6.86 (m, 1H), 6.97-6.99 (m, 1H), 7.31- 7.41 (m, 3H), 7.65 (d, J = 6.4 Hz, 1H), 9.01 (s, 1H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.2, 28.3, 41.7, 48.2, 74.6, 78.0, 94.8, 105.0, 105.4, 115.3, 119.3, 122.5, 127.7, 128.1, 130.5, 131.5, 131.8, 133.2, 133.3, 136.7, 156.1, 157.1, 158.1, 159.6, 160.0, 161.4, 178.9, 182.0, 207.6; HRMS (ESI-TOF) m/z: C32H25BrFNNaO7 [M+Na]+: 656.0696; Found: 656.0694.
The present embodiment prepare compound 3m: yellow solid, fusing point: 74.7-77.1oC, yield 69%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.49-2.56 (m, 2H), 2.69-2.71 (m, 2H), 2.94 (d, J = 13.2 Hz, 1H), 3.16 (d, J = 13.2 Hz, 1H), 4.81-4.92 (m, 2H), 5.61 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 6.66-6.73 (m, 2H), 6.98-7.00 (m, 1H), 7.14-7.18 (m, 1H), 7.25-7.42 (m, 10 H), 7.69 (d, J = 6.4 Hz, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 41.9, 43.8, 48.0, 74.2, 78.0, 94.7, 123.9, 126.9, 127.1, 127.2, 127.3, 127.6, 128.6, 128.7, 128.8, 129.8, 129.9, 130.1, 130.3, 131.6, 156.2, 157.2, 159.6, 160.2, 176.3, 182.0, 208.2; HRMS (ESI-TOF) m/z: C39H32ClNNaO7 [M+Na]+: 684.1765; Found: 684.1767.
The present embodiment prepare compound 3n: yellow solid, fusing point: 80.7-82.4oC, yield 65%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.26 (s, 3H), 2.55-2.67 (m, 2H), 2.76-2.79 (m, 2H), 2.92 (d, J = 12.6 Hz, 1H), 3.15 (d, J = 12.4 Hz, 1H), 4.80-4.90 (m, 2H), 5.62 (d, J = 7.8 Hz, 1H), 6.27 (s, 1H), 6.55 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 7.14-7.29 (m, 9H), 7.39-7.41 (m, 1H), 7.49-7.53 (m, 1H), 12.99 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 21.0, 28.3, 41.9, 43.8, 47.9, 74.3, 78.0, 94.8, 109.4, 115.4, 127.1, 127.2, 127.3, 127.5, 128.1, 128.7, 130.0, 130.1, 130.5, 131.7, 132.8, 135.4, 156.2, 157.2, 159.6, 160.2, 176.3, 182.0, 208.2; HRMS (ESI-TOF) m/z: C40H34ClNNaO7 [M+Na]+: 698.1921; Found: 698.1924.
The present embodiment prepare compound 3o: yellow solid, fusing point: 88.7-89.4oC, yield 74%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.50-2.56 (m, 2H), 2.70-2.74 (m, 2H), 2.96 (d, J = 15.6 Hz, 1H), 3.17 (d, J = 12.7 Hz, 1H), 4.79-4.89 (m, 2H), 5.61 (d, J = 8.1 Hz, 1H), 6.27 (s, 1H), 6.52 (d, J = 4.6 Hz, 1H), 6.71 (s, 1H), 7.26-7.44 (m, 11H), 7.70 (d, J = 8.1 Hz, 1H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 41.8, 43.9, 47.9, 74.1, 78.0, 94.8, 111.1, 115.4, 115.8, 127.1, 127.2, 127.3, 127.8, 128.9, 129.0, 130.1, 130.5, 131.8, 132.6, 134.9, 156.3, 157.2, 159.7, 160.2, 175.8, 182.0, 207.9; HRMS (ESI-TOF) m/z: C39H31BrClNNaO7 [M+Na]+: 762.0870; Found: 762.0868.
The present embodiment prepare compound 3p: yellow solid, fusing point: 83.8-84.2oC, yield 73%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.49-2.57 (m, 2H), 2.70-2.72 (m, 2H), 2.94 (d, J = 13.6 Hz, 1H), 3.17 (d, J = 13.4 Hz, 1H), 4.80-4.90 (m, 2H), 5.61 (d, J = 8.1 Hz, 1H), 6.26 (s, 1H), 6.57 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 7.12-7.13 (m, 1H), 7.14-7.31 (m, 10H), 7.52 (d, J = 6.0 Hz, 1H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 41.9, 43.9, 47.8, 74.2, 78.0, 94.9, 110.7, 115.4, 124.6, 127.1, 127.8, 128.2, 128.6, 128.9, 129.7, 130.2, 130.5, 131.3, 131.8, 134.9, 156.3, 157.2, 159.7, 160.2, 175.8, 182.0, 208.1; HRMS (ESI-TOF) m/z: C39H31Cl2NNaO7 [M+Na]+: 718.1375; Found: 718.1375.
The present embodiment prepare compound 3q: yellow solid, fusing point: 87.4-88.9oC, yield 75%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.38 (s, 6H), 2.41-2.48 (m, 2H), 2.62-2.65 (m, 2H), 2.87 (d, J = 13.6 Hz, 1H), 3.12 (d, J = 13.6 Hz, 1H), 4.72-4.83 (m, 2H), 5.53 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 6.48-6.50 (m, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.76-6.80 (m, 1H), 6.98-7.00 (m, 1H), 7.18- 7.45 (m, 10H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 28.3, 41.9, 44.0, 48.0, 74.3, 78.0, 94.8, 105.0, 115.4, 119.7, 127.1, 127.7, 128.2, 128.9, 130.1, 130.5, 131.4, 131.7, 133.2, 135.0, 156.2, 157.2, 158.4, 159.7, 160.2, 160.3, 176.2, 182.0, 208.0; HRMS (ESI-TOF) m/z: C39H31ClFNNaO7 [M+Na]+: 702.1671; Found: 702.1674.
The present embodiment prepare compound 3r: yellow solid, fusing point: 84.8-85.0oC, yield 71%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.50 (m, 2H), 2.64-2.68 (m, 2H), 2.93 (d, J = 13.2 Hz, 1H), 3.10 (d, J = 13.2 Hz, 1H), 3.53 (s, 3H), 5.61 (d, J = 8.1 Hz, 1H), 6.25 (s, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.90-6.93 (m, 1H), 7.16-7.20 (m, 3H), 7.33-7.40 (m, 2H), 7.45-7.52 (m, 2H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.1, 28.3, 30.5, 41.8, 48.3, 73.5, 78.0, 94.8, 105.0, 105.4, 115.4, 115.9, 122.3, 123.9, 127.1, 128.2, 130.1, 130.6, 131.7, 132.2, 132.3, 156.2, 157.2, 159.7, 160.2, 176.6, 182.0, 207.8; HRMS (ESI-TOF) m/z: C33H27Cl2NNaO7 [M+Na]+: 642.1062; Found: 642.1067.
The present embodiment prepare compound 3s: yellow solid, fusing point: 80.3-81.5oC, yield 74%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.51 (m, 2H), 2.66-2.68 (m, 2H), 2.91 (d, J = 14.0 Hz, 1H), 3.09 (d, J = 13.6 Hz, 1H), 3.54 (s, 3H), 5.62 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.91-6.94 (m, 1H), 7.16-7.20 (m, 4H), 7.39-7.45 (m, 2H), 7.70 (d, J = 6.1 Hz, 1H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 26.4, 28.3, 41.8, 47.8, 74.0, 78.0, 94.8, 110.0, 115.4, 115.7, 127.1, 127.3, 128.2, 128.6, 130.2, 130.5, 131.8, 132.7, 142.5, 156.2, 157.2, 159.7, 160.2, 175.6, 182.0, 208.1; HRMS (ESI-TOF) m/z: C33H27BrClNNaO7 [M+Na]+: 686.0557; Found: 686.0557.
The present embodiment prepare compound 3t: yellow solid, fusing point: 87.9-88.3oC, yield 80%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.53 (m, 2H), 2.69 (s, 2H), 3.06 (d, J = 16.5 Hz, 1H), 3.25 (d, J = 13.6 Hz, 1H), 5.62 (d, J = 8.1 Hz, 1H), 6.25 (s, 1H), 6.71-6.78 (m, 2H), 7.03-7.06 (m, 1H), 7.18-7.22 (m, 1H), 7.33-7.53 (m, 11H), 13.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.5, 28.3, 41.8, 48.9, 74.2, 78.0, 94.8, 109.8, 115.4, 123.5, 124.0, 126.5, 127.1, 128.2, 128.3, 129.6, 129.9, 130.1, 131.7, 143.8, 156.3, 157.2, 159.7, 160.2, 175.8, 182.1, 207.7; HRMS (ESI-TOF) m/z: C38H30ClNNaO7 [M+Na]+: 670.1608; Found: 670.1610.
The present embodiment prepare compound 3u: yellow solid, fusing point: 78.9-79.7oC, yield 64%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CD3OD, 400 MHz) δ: 1.32 (s, 6H), 2.27 (s, 3H), 2.42-2.45 (m, 2H), 2.55-2.58 (m, 2H), 3.13 (d, J = 13.6 Hz, 1H), 3.35 (d, J = 13.2 Hz, 1H), 5.56 (d, J = 7.8 Hz, 1H), 6.09 (s, 1H), 6.53-6.56 (m, 2H), 6.88-6.91 (m, 1H), 7.04-7.08 (m, 1H), 7.11 (d, J = 6.4 Hz, 2H), 7.19 (d,J = 6.5 Hz, 2H), 7.24 (d, J = 6.0 Hz, 1H), 7.33-7.37 (m, 3H), 7.43-7.46 (m, 2H); 13C NMR (CD3OD, 100 MHz) δ: 21.5, 28.6, 42.7, 51.1, 66.7, 74.5, 79.1, 95.6, 110.5, 116.2, 119.1, 124.4, 124.7, 128.1, 129.4, 129.5, 129.7, 130.3, 130.7, 131.0, 135.9, 142.2, 157.1, 158.3, 160.8, 164.3, 178.8, 183.5, 207.8; HRMS (ESI-TOF) m/z: C39H33NNaO7 [M+Na]+: 650.2155; Found: 650.2158.
The present embodiment prepare compound 3v: yellow solid, fusing point: 100.4-100.8oC, yield 62%;Nuclear magnetic resonance With high resolution mass spectrum test etc. results it is as follows:1H NMR (CDCl3, 400 MHz) δ: 1.46 (s, 6H), 2.46-2.52 (m, 2H), 2.68-2.71 (m, 2H), 2.89-2.93 (m, 1H), 3.09-3.21 (m, 4H), 5.62 (d, J = 8.0 Hz, 1H), 6.25 (s, 1H), 6.86-6.72 (m, 2H), 7.31-7.33 (m, 1H), 7.39-7.44 (m, 4H), 7.55 (s, 1H), 12.9 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.4, 26.4, 28.3, 41.7, 47.9, 74.0, 78.1, 94.8, 105.0, 105.5, 110.0, 115.4, 115.8, 120.0, 127.3, 127.6, 128.2, 130.1, 131.5, 132.8, 134.3, 137.3, 156.2, 157.2, 159.1, 159.8, 175.6, 181.9, 207.9; HRMS (ESI-TOF) m/z: C33H26BrCl2NNaO7 [M+Na]+: 720.0167; Found: 720.0167.
The present embodiment prepare compound 3w: yellow solid, fusing point: 73.2-74.1oC, yield 60%;Nuclear magnetic resonance and The results such as high resolution mass spectrum test are as follows:1H NMR (CDCl3, 400 MHz) δ: 13.01 (s, 1H), 7.60 – 7.53 (m, 1H), 7.50 – 7.43 (m, 1H), 7.36 – 7.25 (m, 8H), 7.20 – 7.16 (m, 1H), 6.79 – 6.59 (m, 2H), 6.31 (s, 1H), 5.70 – 5.60 (m, 1H), 4.97 – 4.83 (m, 2H), 3.31 – 3.02 (m, 2H), 2.92 – 2.79 (m, 2H), 2.71 – 2.50 (m, 2H), 2.09 (s, 1H), 1.50 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ: 207.88, 182.38, 176.35, 162.73, 159.22, 158.00, 156.21, 134.87, 132.83, 131.42, 131.02, 129.57, 129.44, 128.81, 128.78, 127.87, 127.70, 127.67, 127.14, 127.10, 127.05, 124.46, 119.64, 115.52, 110.58, 105.28, 104.96, 98.75, 98.32, 94.69, 65.57, 55.57, 47.35, 44.91, 44.03, 29.48, 28.21, 19.11; HRMS (ESI-TOF) m/z: C41H36ClNNaO9 [M+Na]+: 744.1976; Found: 744.1974.
Formula (1) compound of the invention has important bioactivity, in vitro to human prostate (PC-3) and the white blood of people The cell toxicity test of sick cell (K562) totally two plants of tumour cells shows: the Morusin skeleton of structure shown in such formula (1) It is inhibited to splice the growth of convolutamydine A skeleton class compound on tumor cell, it is possible to develop into new Prevention and treatment tumour medicine.
Pharmacological Examples 1: compound 3b-3w (not including 3l) is to the cytotoxicity of K562 cell
K562(people's chronic myelogenous leukemia cell) culture of DMEM culture medium is used, 10% fetal calf serum is contained in culture medium, The penicillin and 100U/mL streptomysin of 100 U/mL.Cell is added in 96 holes with the concentration of every 4000 cells in hole, at 37 DEG C Containing 5% CO2It is cultivated 24 hours in the incubator of humid air.
The measurement of cell survival rate improvement mtt assay.Cell is after incubation in 24 hours, compound that will newly match respectively The dimethyl sulphoxide solution of 3b-3w (not including 3l) is added in each hole with concentration gradient, makes compound ultimate density in hole Respectively 3 μm of ol/L, 6 μm of ol/L, 13 μm of ol/L, 25 μm of ol/L and 50 μm of ol/L.After 48 hours, every hole is added The phosphate buffer of 10 μ L MTT (5 mg/mL), is further continued for 37oAfter C is cultivated 4 hours, it is centrifuged 5 minutes and removes not 150 μ L dimethyl sulfoxides are added in every hole in the MTT of conversion.With the MTT crystal formazan (formazan) of dissolving and reducing, enzyme is used It marks instrument and measures OD value in 490 nm wavelength.Wherein compound 3b-3w (not including 3l) is to K562 cell 503nhibiting concentration IC50By Spss software (19 version) analysis obtains.IC of the compound 3a to K562 tumour cell50For 21.0 μm of ol/L；3b pairs of compound The IC of K562 tumour cell50For 13.7 μm of ol/L；IC of the compound 3c to K562 tumour cell50For 13.5 μm of ol/L；Chemical combination IC of the object 3d to K562 tumour cell50For 15.7 μm of ol/L；IC of the compound 3e to K562 tumour cell50For 17.4 μm of ol/ L；IC of the compound 3f to K562 tumour cell50For 7.9 μm of ol/L；IC of the compound 3g to K562 tumour cell50For 9.4 μ mol/L；IC of the compound 3h to K562 tumour cell50For 5.7 μm of ol/L；IC of the compound 3i to K562 tumour cell50For 20.7 μmol/L；IC of the compound 3j to K562 tumour cell50For 13.2 μm of ol/L；Compound 3k is to K562 tumour cell IC50For 12.8 μm of ol/L；IC of the compound 3m to K562 tumour cell50For 7.4 μm of ol/L；Compound 3n is to K562 tumour The IC of cell50For 6.2 μm of ol/L；IC of the compound 3o to K562 tumour cell50For 5.3 μm of ol/L；Compound 3p is to K562 The IC of tumour cell50For 13.9 μm of ol/L；IC of the compound 3q to K562 tumour cell50For 14.7 μm of ol/L；Compound 3r To the IC of K562 tumour cell50For 13.7 μm of ol/L；IC of the compound 3s to K562 tumour cell50For 10.4 μm of ol/L；Change Object 3t is closed to the IC of K562 tumour cell50For 8.3 μm of ol/L；IC of the compound 3u to K562 tumour cell50For 21.4 μ mol/L；IC of the compound 3v to K562 tumour cell50For 17.5 μm of ol/L；IC of the compound 3w to K562 tumour cell50For 4.5 μmol/L；And positive control cis-platinum is to the IC of K562 tumour cell50For 24.5 μm of ol/L.
Experiment conclusion: K562 cell is that the effective tool for the cytotoxicity for testing compound on tumor cell and evaluation refer to Mark.This experiment shows that Morusin skeleton shown in such formula (1) splices convolutamydine A skeleton class compound 3b-3w (not including 3l) has stronger cytotoxicity and the same order of magnitude of oncotherapy fiest-tire medication cis-platinum or work to K562 cell Property is more preferable than cis-platinum, it is possible to develop into the new drug with antitumor action.
Pharmacological Examples 2: the cytotoxicity of compound 3b, 3d, 3e, 3j, 3r and 3v to PC-3 cell
PC-3(human prostata cancer) cell RPMI-1640 culture medium culture, 10% fetal calf serum is contained in culture medium, The streptomysin of 100U/mL penicillin and 100U/mL.Cell is added in 96 holes with the concentration of every 5000 cells in hole, 37oC contains 5% CO2It is cultivated 24 hours in the incubator of humid air.
The measurement of cell survival rate improvement mtt assay.Cell is after incubation in 24 hours, compound that will newly match respectively The dimethyl sulphoxide solution of 3b, 3d, 3e, 3j, 3r and 3v are added in each hole with concentration gradient, make in hole compound most Final concentration is respectively 3 μm of ol/L, 6 μm of ol/L, 13 μm of ol/L, 25 μm of ol/L and 50 μm of ol/L.After 48 hours, often The phosphate buffer of 10 μ L MTT (5 mg/mL) is added in hole, is further continued for 37oAfter C is cultivated 4 hours, it is centrifuged 5 minutes Unconverted MTT is removed, 150 μ L dimethyl sulfoxides are added in every hole.With the MTT crystal formazan of dissolving and reducing (formazan), OD value is measured in 490 nm wavelength with microplate reader.Wherein compound 3b, 3d, 3e, 3j, 3r and 3v couple PC-3 cell 503nhibiting concentration IC50It is obtained by spss software (19 version) analysis.IC of the compound 3b to PC-3 tumour cell50 For 22.9 μm of ol/L；IC of the compound 3d to PC-3 tumour cell50For 24.9 μm of ol/L；Compound 3e is to PC-3 tumour cell IC50For 15.8 μm of ol/L；IC of the compound 3j to PC-3 tumour cell50For 15.7 μm of ol/L；Compound 3r is swollen to PC-3 The IC of oncocyte50For 19.4 μm of ol/L；IC of the compound 3v to PC-3 tumour cell50For 9.6 μm of ol/L；And positive control IC of the cis-platinum to PC-3 tumour cell50For 23.8 μm of ol/L.
Experiment conclusion: PC-3 cell is that the effective tool for the cytotoxicity for testing compound on tumor cell and evaluation refer to Mark.This experiment shows that Morusin skeleton shown in such formula (1) splices convolutamydine A skeleton class compound 3b, 3d, 3e, 3j, 3r and 3v have stronger cytotoxicity and the same number of oncotherapy fiest-tire medication cis-platinum to PC-3 cell Magnitude or activity are more preferable than cis-platinum, it is possible to develop into the new drug with antitumor action.
We can see that these compounds all show centainly this two plants of tumour cells from the above Pharmacological Examples Cytotoxicity.It can be seen that these Morusin skeletons splicing convolutamydine A skeleton class compound is anti-with being developed into The potentiality of tumour medicine are worth continuing deeper into research and.

Claims (5)

1. a kind of Morusin skeleton splices convolutamydine A skeleton class compound, it is characterised in that: compound tool Just like structure shown in general formula (I):
Particular compound is as follows:
2. a kind of preparation of Morusin skeleton splicing convolutamydine A skeleton class compound as described in claim 1 Method, it is characterised in that: by the butanone of the various substituted skeletons containing Morusin and various substituted isatin be in molar ratio 3:4 Ratio in polar solvent, reacted under the conditions of heating, carry out Aldol addition reaction, obtain Morusin skeleton splicing Convolutamydine A skeleton class compound.
3. the preparation side of Morusin skeleton splicing convolutamydine A skeleton class compound according to claim 2 Method, it is characterised in that: the polar solvent is methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran, second Ether, DMSO or DMF.
4. the preparation side of Morusin skeleton splicing convolutamydine A skeleton class compound according to claim 2 Method, it is characterised in that: the butanone of the various substituted skeletons containing Morusin reacts temperature with various substituted isatin in polar solvent Degree is 40-100 DEG C, and the reaction time is 5-20 hours.
5. prepared by a kind of Morusin skeleton splicing convolutamydine A skeleton class compound as described in claim 1 The application for preventing and treating human prostata cancer and human leukemia drug.
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CN105566340A (en) * 2016-01-20 2016-05-11 贵州大学 White mulberry root-bark active ingredient Morusin derivative and application and preparation method thereof
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