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Paraterphenyl derivative and application thereof to preparation of antitumor medicaments

An anti-tumor drug, p-terphenyl technology, applied in the direction of anti-tumor drugs, organic compound preparation, drug combination, etc., can solve the problems of terphenyl complex structure, complicated synthesis, high cost, etc., and achieve low cost and high cytotoxic activity , Synthetic convenient effect

Inactive Publication Date: 2011-07-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, looking at the current research status of terphenyl derivatives, due to the complex structure of terphenyl, there are still problems of cumbersome synthesis, low yield and high cost of natural products.

Method used

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  • Paraterphenyl derivative and application thereof to preparation of antitumor medicaments
  • Paraterphenyl derivative and application thereof to preparation of antitumor medicaments
  • Paraterphenyl derivative and application thereof to preparation of antitumor medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Prepare compound [1,1'-Biphenyl]-4'-monol, 4-bromo-2,3-dimethoxy-(structural formula 3, wherein R 1 =OH, R 2 = R 3 =OCH 3 ,)

[0037] Put p-hydroxyphenylboronic acid (1 mole) and 1,4-dibromo-2,3-dimethoxy-benzene (2 moles) into dioxane (10 ml), add KF (3 moles), nitrogen Pd-DPPF (2% mol) was added under protection, heated to reflux for 24 hours, extracted with ethyl acetate, and the extract was purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate = 10:1. Mp117~118℃.

[0038] 1 H NMR (300MHz, DMSO-d6, rt) δ3.57(s, 3H), 3.58(s, 3H), 6.83(d, J=15.0Hz, 2H), 7.01(d, J=15.0Hz, 1H) , 7.32(s, J=15.0Hz, 2H), 7.37(d, J=14.0Hz, 1H), 9.58(s, 1H); 13 C NMR (75MHz, CDCl 3 , rt) δ60.8, 60.9, 115.2, 115.2, 116.2, 126.4, 127.9, 129.7, 130.3, 130.3, 135.6, 150.7, 151.5, 155.1; HRMS (ESI) calcd for C 14 h 13 BrNaO 3 (M+H) +330.9946, found 330.9947.

Embodiment 2

[0040] Prepare compound [1,1':4',1 "-Terphenyl]-4"-monol, 3,4-dimethoxy-(9CI) (structural formula 5, wherein R 1 =OH,R 2 =R 3 = H, R 4 =R 5 =OCH 3 )

[0041] Put 3,4 dimethoxyphenylboronic acid (1.5 moles) and 1,1'-biphenyl-4-hydroxyl, 4'-bromo (1 mole) into dioxane (10ml), add KF (3 mol), Pd-DPPF (2% mol) was added under nitrogen protection, heated to reflux for 24 hours, extracted with ethyl acetate, and the extract was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate=10:1. Mp250~252℃.

[0042] 1 H NMR (300MHz, DMSO-d6, rt) δ3.77(s, 3H), 3.92(s, 3H), 6.87(d, J=14.0Hz, 2H), 7.04(d, J=14.0Hz, 1H) , 7.23(d, J=14.0Hz, 1H), 7.26(s, 1H), 7.54(d, J=14.0Hz, 2H), 7.64(d, J=14.0Hz, 2H), 7.70(d, J= 13.0Hz, 2H), 9.59(s, 1H); 13 C NMR (75MHz, CDCl 3 , rt) δ109.99, 112.0, 115.6, 115.6, 118.4, 126.1, 126.1, 126.6, 126.6, 127.5, 127.5, 130.3, 132.4, 137.9, 138.4, 148.3, 148.9, 157.0; HRMS (ESI) calcdforC 20 h 19 o 3 (M+H) + 307.1334, fo...

Embodiment 3

[0044] Prepare compound [1,1':4',1 "-Terphenyl]-3,4,4"-triol (9CI) (structural formula 6, wherein R 1 =OH,R 2 =R 3 = H, R 4 =R 5 =OH)

[0045] Dissolve [1,1':4',1"-Terphenyl]-4"-monol, 3,4-dimethoxy-(9CI) (1 mole) in dichloromethane, lower the temperature to -45°C, add three Boron bromide (1.5 mol), warmed up, stirred for 24 hours, extracted with ethyl acetate, and the extract was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate=10:3 to obtain the compound. Mp>260°C.

[0046] 1 H NMR (300MHz, DMSO-d6, rt) δ6.82 (d, J = 10.0Hz, 1H), 6.85 (d, J = 10.0Hz, 2H), 6.97 (d, J = 10.0Hz, 1H), 7.10 (s, 1H), 7.51(d, J=10.0Hz, 2H), 7.55(d, J=10.0Hz, 2H), 7.60(d, J=10.0Hz, 2H), 9.02(s, 1H), 9.05 (s, 1H), 9.54(s, 1H); 13 C DEPT (75MHz, (CD 3 ) 2 CO, rt) δ113.7, 113.7, 115.7, 115.7, 118.2, 118.2, 126.5, 126.5, 126.6, 127.7, 127.7, 131.9, 132.7, 138.99, 139.1, 144.9, 145.4, 157.1; HRMS (ESI) cal cd for C 18 h 15 o 3 (M+H) + 279.1021, found...

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Abstract

The invention discloses a paraterphenyl derivative. The paraterphenyl derivative has a compound structural formula shown as a formula (I) in the specification, wherein R1 is hydroxyl or methoxyl; R2 is hydrogen, hydroxyl or methoxyl; R3 is hydrogen, hydroxyl or methoxyl; R4 is hydrogen, hydroxyl or methoxyl; R5 is hydroxyl or methoxyl; and R6 is hydroxyl or methoxyl. The paraterphenyl derivative is obtained by coupling Suzuki with demthylating boron tribromide. A test shows that the paraterphenyl derivative has higher cytotoxin activity and potential of being developed into antitumor medicaments.

Description

technical field [0001] The invention relates to a class of p-terphenyl compounds and applications thereof, in particular to a class of p-terphenyl derivatives and their application in the preparation of antitumor drugs. Background technique [0002] From the initial cytotoxicity to the current inhibitors of various biological targets, small organic molecules have always been one of the research hotspots of anti-tumor drugs. [0003] James J.Li et al. found that a series of terphenyl dimethylsulfonyl derivatives and sulfonamide derivatives have selective cyclooxygenase 2 inhibitory effect and oral anti-inflammatory activity. Junko Ohkanda et al. designed and synthesized some terphenyl compounds and found that they have farnesyltransferase inhibitory effect. Farnesyltransferase inhibitors are a new class of signal transduction inhibitors. Research at home and abroad has shown that they have obvious inhibitory effects on the growth of tumor cells such as thyroid cancer, pancre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/23C07C43/205C07C41/30C07C39/10C07C37/055A61K31/09A61K31/05A61P35/00
CPCA61K31/09C07C41/30C07C37/055A61K31/05A61P35/00C07C39/10C07C43/205C07C43/23
Inventor 沈月毛马玉道邱进鲁春华赵保兵朱敬
Owner SHANDONG UNIV
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