CN109422724B - Indole-substituted isoquinoline compound and synthesis method thereof - Google Patents
Indole-substituted isoquinoline compound and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses an indole-substituted isoquinoline compound and a preparation method and application thereof. The indole-substituted isoquinoline compound is shown as a formula I, wherein R1Is hydrogen, halogen atom, alkyl, R2And R3Is hydrogen, halogen atom, alkyl or alkoxy. The target product is synthesized through 2-step reaction, the synthesis method is simple and rapid, the yield of the target compound is high, and necessary basis is provided for further research on the compound of the formula I or related compounds. The compound of the invention has good inhibition effect on human tumor cells, and has practical application value in the field of biological medicine.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an indole-substituted isoquinoline compound and a preparation method thereof, and application of the compound as a novel antitumor drug lead compound.
Background
Cancer is a malignant tumor originated from epithelial tissues, and although the diagnosis and treatment techniques thereof have made great progress, it is one of three major causes of human fatal diseases and brings great mental and economic stress to the human society. During the last decades, much work has been done in developing first-come compounds of cancer chemotherapeutic agents, and a number of compounds have also been shown to have good therapeutic effects. In 1974, naphthyridinomycin compounds were isolated and showed excellent anticancer effects, and therefore, isoquinoline compounds were used as a class of specific alkaloids in antitumor research and continuously developed as lead compounds to new derivatives.
The isoquinoline compounds are natural products, and have good anticancer activity and special biological pharmacological activities of resisting diabetes, resisting tubulin and the like. It is not only an important intermediate for total synthesis of alkaloids, but also a sub-structural unit of many kinds of natural molecules and synthetic molecules. Therefore, the isoquinoline compounds can be synthesized by a diversity-oriented synthesis method, and the method has great significance to chemical synthesis, pharmacology and biology.
Indole-substituted isoquinoline compounds, which combine two specific structural units of indole and isoquinoline, have unexpected potential biological activity. Indole-substituted isoquinoline hydrazonium salt compounds have been reported, but the naked hydrazonium group has larger cytotoxicity and is not suitable for being applied to drug development. Therefore, the method for simply and efficiently synthesizing the indole-substituted isoquinoline compounds is developed, and the antitumor activity of the compounds is researched, so that the method has important significance for developing the independent intellectual property medicines.
Disclosure of Invention
The invention aims to provide an indole-substituted isoquinoline compound and a synthesis method thereof.
The indole-substituted isoquinoline compound has certain anticancer activity, can be used as a potential antitumor drug or a candidate drug for resisting diabetes, and is shown as a formula I:
I
wherein R is1Is hydrogen, halogen atom or alkyl, R2And R3Is hydrogen, halogen atom, alkyl or alkoxy.
The synthesis method of the indole-substituted isoquinoline compound comprises the following steps:
(1) preparation of intermediate Compound 2
Dissolving a compound 1 and 80% hydrazine hydrate in absolute ethyl alcohol, wherein the mass ratio of the compound 2 to the hydrazine hydrate is 5:1-1:1, stirring for 1-2 hours at a certain temperature, completely separating out a solid, filtering, and recrystallizing a crude product with absolute ethyl alcohol to obtain a white solid compound 2.
(2) Preparation of the target Compound
Dissolving an intermediate 2 and an indole compound 3 in an organic solvent, wherein the mass ratio of the intermediate 2 to the indole compound to the catalyst is 1: 0.3-2: reacting at 0.1-2 ℃ at 20-100 ℃, detecting the reaction process by TLC, stopping the reaction when the reaction is complete, cooling the reactant to room temperature, filtering to obtain filtrate, removing the solvent by rotary evaporation under reduced pressure, and carrying out column chromatography on the residue to obtain a target product shown in formula I;
the above compounds are distinguished by the following numbers of the compounds in the reaction scheme, wherein R1Is hydrogen, halogen atom or alkyl, R2And R3Is hydrogen, halogen atom, alkyl or alkoxy.
Further, R1Preferably H, Cl, Br, I, F, NO2CN or Me.
Further, R2Preferably H, Cl or Me.
Further, R3Preferably H, Cl, F or Me.
Further, in the step (2), the organic solvent is preferably dimethyl sulfoxide (DMSO).
Further, in the step (2), the catalyst is preferably AgNO3。
Further, in the step (2), the reaction temperature is preferably 80 ℃.
The invention has the beneficial effects that:
(1) the invention provides a novel indole-substituted isoquinoline compound which has good anticancer activity and can be used as a potential antitumor drug or an antidiabetic candidate drug.
(2) The synthesis method is simple and quick, the catalyst is cheap and easy to obtain, the conditions are easy to control, and the yield of the target compound is high, thereby providing a necessary basis for further researching the compound of the formula I or related compounds.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The instruments and reagents used in the invention:
nuclear magnetic resonance apparatus: bruker AV-II 500 MHz NMR, TMS as internal standard, DMSO-d 6 Is a solvent; an infrared spectrometer: TFS-40 type, KBr pellet, melting point apparatus: model XT-4 melting point tester.
The reagents used were either commercially available, chemically pure or analytically pure.
Example 1
Synthesis of Compounds of the invention
The preparation route of the compound of the invention is as follows:
(1) synthesis of intermediate compound 2 a:
taking compound 1a (R)2And R3All H) 2.0 mmol, 1.0 mmol of hydrazine hydrate with the mass fraction of 80 percent are dissolved in 5 mL of absolute ethyl alcohol, the mixture is stirred for 1 hour at room temperature, the solid is completely separated out, the mixture is filtered, and the crude product is recrystallized by the absolute ethyl alcohol to obtain a white solid compound 2 a.
(2) Synthesis and characterization of target compound 4:
dissolving 0.225 mmol of the intermediate 2 and 0.3mmol of the indole compound 3 in 2 mL of dimethyl sulfoxide, reacting at 80 ℃, detecting the reaction process by TLC, stopping the reaction when the reaction is complete, cooling the reactant to room temperature, filtering to obtain filtrate, removing the solvent by rotary evaporation under reduced pressure, and carrying out column chromatography on the residue to obtain a target product shown in the formula I;
1- (1H-3-indole) -3-phenylisoquinoline (4a), pale yellow solid, melting point 234-oC. IR (KBr)ν/cm-1: 3162, 1619, 1551, 1492, 1400, 1242, 1135.1H NMR (DMSO-d 6 , 500 MHz):11.74 (s, 1H), 8.46 (d,J= 8.5 Hz,1H), 8.32 – 8.20 (m, 3H), 8.09 – 7.92 (m,3H), 8.01 (s, 1H), 7.79 (t,J= 7.5 Hz,1H), 7.66 (t,J= 7.5 Hz,1H), 7.58 –7.54 (m, 3H), 7.45 (t,J= 7.5 Hz,1H), 7.24 (t,J= 7.5 Hz,1H), 7.17 (t,J=7.5 Hz,1H),.13C NMR (DMSO-d 6 , 125 MHz): 155.1, 148.8, 139.1, 137.7, 136.5,130.2, 128.8, 128.5, 127.9, 127.7, 127.3, 127.1, 126.8, 126.5, 125.4, 121.9,120.6, 120.0, 113.6, 111.8. HRMS (ESI) calcd for C23H17N2, 321.1392 (M+H)+;Found, 321.1396.
1- (5-chloro-1H-3-indole) -3-phenylisoquinoline (4b), as an orange solid, mp 220-oC. IR(KBr) cm-13129, 1619, 1554, 1400, 1137, 956, 873.1H NMR (DMSO-d 6 , 500 MHz)11.84 (s, 1H), 8.40 – 8.31 (m, 1H), 8.26 – 8.15 (m, 3H), 8.04 (d,J= 7.5 Hz,2H), 7.96 (d,J= 8.0 Hz, 1H), 7.67 (t,J= 7.5 Hz, 1H), 7.59 – 7.41 (m, 4H),7.34 (t,J= 7.5 Hz, 1H), 7.20 – 7.11 (m, 1H).13C NMR (DMSO-d 6 , 125 MHz)154.4, 148.6, 139.1, 137.6, 134.9, 130.1 , 129.4, 128.7, 128.5, 127.9, 127.7,127.4, 126.7, 126.3, 125.2, 124.7, 121.9, 120.0, 113.8, 113.7, 113.41. HRMS(ESI) calcd for C23H16ClN2, 355.1002 (M+H)+; Found, 355.1008.
1- (5-iodo-1H-3-indole) -3-phenylisoquinoline (4c), as an orange solid, mp 208-oC. IR(KBr) cm-13127, 1617, 1555, 1493, 1440, 1140, 955, 875.1H NMR (DMSO-d 6 , 500MHz)11.85 (s, 1H), 8.52 (s, 1H), 8.43 – 8.37 (m, 1H), 8.26 (d,J= 6.0 Hz,3H), 8.01 (d,J= 8.5 Hz, 2H), 7.72 (t,J= 7.5 Hz, 1H), 7.60 (t,J= 7.5 Hz,1H), 7.49 (t,J= 7.5 Hz, 2H), 7.44 (d,J= 8.5 Hz, 1H), 7.42 – 7.36 (m, 2H).13C NMR (DMSO-d 6 , 125 MHz)154.3, 148.5, 139.0, 137.6, 135.5, 130.2, 129.8,129.5, 129.4, 128.8, 128.7, 128.6, 127.7, 127.4, 126.7, 126.3, 125.2, 114.3,113.6, 113.3, 84.0. HRMS (ESI) calcd for C23H16IN2, 447.0358 (M+H)+; Found,447.0353.
1- (6-fluoro-1H-3-indole) -3-phenylisoquinoline (3d), orange solid, melting point 240-oC. IR(KBr) cm-13131, 1619, 1542, 1492, 1400, 1291, 1141, 957, 832.1H NMR (DMSO-d 6 ,500 MHz)11.70 (s,1H), 8.38 (d,J= 8.5 Hz, 1H), 8.31 – 8.15 (m, 3H), 8.07– 7.90 (m, 3H), 7.69 (t,J= 7.5 Hz, 1H), 7.56 (t,J= 7.5 Hz, 1H), 7.47 (t,J= 7.5 Hz, 2H), 7.36 (t,J= 7.0 Hz, 1H), 7.31 – 7.23 (m, 1H), 7.01 – 6.86(m, 1H).13C NMR (DMSO-d 6 , 125 MHz)170.7, 160.5, 158.6, 155.2, 149.2,139.6, 138.1, 136.8, 136.7, 130.6, 129.2, 128.9, 128.8, 128.8, 128.1, 127.8,127.3, 126.9, 125.8, 124.1, 122.3, 122.2, 114.6, 114.1, 109.1, 108.9, 98.3,98.1. HRMS (ESI) calcd for C23H16FN2, 339.1298 (M+H)+; Found, 339.1305.
3-phenyl-1- (1H-3-pyrrole [2, 3-b)]Pyridine) isoquinoline (4e), yellow solid, melting point 278-oC.IR (KBr) cm-13415, 3135, 1618, 1556, 1526, 1494, 1400, 1300, 1134.1H NMR(DMSO-d 6 , 500 MHz)12.19 (s, 1H), 8.44-8.35 (m, 2H), 8.29 (d,J= 4.5 Hz,1H), 8.26 – 8.19 (m, 3H), 8.09 (s, 1H), 8.00 (d,J= 8.0 Hz, 1H), 7.71 (t,J= 7.5 Hz, 1H), 7.58 (t,J= 7.5 Hz, 1H), 7.50 -7.44 (m, 2H), 7.36 (t,J= 7.5Hz, 1H), 7.20 -7.13 (m, 1H).13C NMR (DMSO-d 6 , 125 MHz)154.2, 148.7, 148.6,143.4, 139.0, 137.6, 130.3, 129.1, 128.8, 128.5, 128.0, 127.7, 127.5, 126.5,126.4, 125.1, 119.2, 116.7, 113.8, 112.9. HRMS (ESI) calcd for C22H16N3,322.1344 (M+H)+; Found, 322.1338.
1- (5-Nitro-1H-3-indole) -3-phenylisoquinoline (4f), yellow solid, m.p. 255-oC. IR(KBr) cm-13342, 2915, 1623, 1560, 1487, 1326, 1097, 738, 680.1H NMR (DMSO-d 6 ,500 MHz)12.42 (s, 1H), 9.23 (s, 1H), 8.53 (d,J= 10.0 Hz, 1H), 8.40 -8.36(m, 4H), 8.17- 8.12 (m, 2H), 7.83 (t,J= 5.0 Hz, 1H), 7.83 (t,J= 5.0 Hz,1H), 7.74 (d,J= 10.0 Hz, 1H), 7.57 (t,J= 5.0 Hz, 2H), 7.48 (t,J= 5.0Hz, 1H).13C NMR (DMSO-d 6 , 125 MHz)153.6, 148.7, 141.6, 139.6, 138.9,137.7, 131.4, 130.4, 128.8, 128.7, 127.9, 127.7, 126.5, 126.4, 126.3, 118.2,117.3, 116.1, 114.2, 112.4. HRMS (ESI) calcd for C23H16N3O2, 366.1243 (M+H)+;Found, 366.1239.
1- (5-bromo-1H-3-indole) -3-phenylisoquinoline (4g), yellow solid, mp 232-oC. IR(KBr) cm-13124, 2923, 2854, 1616, 1553, 1433, 1137, 953, 877, 765, 686.1HNMR (DMSO-d 6 , 500 MHz)11.95 (s, 1H), 8.48 (d,J= 8.5 Hz, 1H), 8.34 – 8.32(m, 4H), 8.14-8.12 (m, 1H), 8.10 (d,J= 8.0 Hz, 1H), 7.80 (t,J= 7.5 Hz,1H), 7.67(t,J= 7.5 Hz, 1H), 7.59- 7.55 (m, 3H), 7.47 (t,J= 7.5 Hz, 1H),7.39-7.37 (m, 1H).13C NMR (DMSO-d 6 , 125 MHz)154.3, 148.6, 139.1, 137.7,135.2, 130.2, 129.3, 128.8, 128.7, 128.6, 127.8, 127.5, 126.7, 126.4, 125.2,124.4, 123.1, 113.9, 113.7, 112.7. HRMS (ESI) calcd for C23H16BrN2, 399.0497 (M+H)+; Found, 399.0496.
1- (2-methyl-1H-3-indole) -3-phenylisoquinoline (4H), yellow solid, mp 170-oC. IR(KBr) cm-13174, 3054, 2924, 1617, 1556, 1495, 1462, 1436, 741, 687.1H NMR(DMSO-d 6 , 500 MHz)11.54 (s, 1H), 8.38 (s, 1H), 8.30 (d,J= 8.0 Hz, 2H),8.10 (d,J= 8.0 Hz, 1H), 7.98 (d,J= 8.5 Hz, 1H), 7.51 (t,J= 7.5 Hz, 1H),7.57 - 7.52 (m, 3H), 7.48 (d,J= 8.0 Hz, 1H), 7.45 (t,J= 7.5 Hz, 1H), 7.29(d,J= 8.0 Hz, 1H), 7.13 (t,J= 7.5 Hz, 1H), 7.01 (t,J= 7.5 Hz, 1H), 2.50(s, 3H).13C NMR (DMSO-d 6 , 125 MHz)155.7, 149.0, 139.2, 137.4, 135.9,135.2, 130.2, 128.7, 128.4, 128.1, 127.6, 127.5, 126.9, 126.4, 126.2, 120.7,119.4, 118.7, 114.2, 111.5, 110.9, 12.8. HRMS (ESI) calcd for C24H19N2,335.1548 (M+H)+; Found, 335.1551.
1- (6-cyano-1H-3-indole) -3-phenylisoquinoline (4i), yellow solid, mp 228-oC. IR(KBr) cm-13034, 2923, 2853, 2217, 1619, 1554, 1526, 1495, 1448, 956, 817,693.1H NMR (DMSO-d 6 , 500 MHz)12.27 (s, 1H), 8.41-8.30 (m, 5H), 8.21 (d,J=8.0 Hz, 1H), 8.11-9.09 (m, 2H), 7.81 (t,J= 7.0 Hz, 1H), 7.67 (t,J= 7.5Hz, 1H), 7.57-7.45 (m, 4H).13C NMR (DMSO-d 6 , 125 MHz)154.0, 148.8, 139.0,137.6, 135.3, 131.8, 130.3, 130.0, 128.8, 128.7, 128.6, 127.8, 127.5, 126.7,126.4, 125.4, 122.7, 121.7, 120.4, 116.9, 114.8, 114.1 103.4. HRMS (ESI)calcd for C24H16N3, 346.1344 (M+H)+; Found, 346.1343.
1- (7-methyl-1H-3-indole) -3-phenylisoquinoline (4j), yellow solid, mp 142-oC. IR(KBr) cm-13338, 3044, 2924, 1613, 1549, 1526, 1491, 1426, 1125, 772, 746,690.1H NMR (DMSO-d 6 , 500 MHz)11.68 (s, 1H), 8.45 (d,J= 8.5 Hz, 1H), 8.32-8.30 (m, 3H), 8.07 (d,J= 8.0 Hz, 1H), 7.97-7.96 (m, 1H), 7.88 (d,J= 7.5Hz, 1H), 7.78 (t,J= 7.5 Hz, 1H), 7.64 (t,J= 7.5 Hz, 1H), 7.54 (t,J= 7.5Hz, 2H), 7.43 (t,J= 7.5 Hz, 1H), 7.07-7.02 (m, 2H), 2.59 (s, 3H).13C NMR(DMSO-d 6 , 125 MHz)155.3, 148.7, 139.2, 137.6, 135.9, 130.1, 128.7, 128.5,127.6, 127.4, 127.2, 127.0, 126.6, 126.4, 125.5, 122.3, 121.0, 120.2, 118.2,114.7, 113.5, 16.9. HRMS (ESI) calcd for C24H19N2, 335.1548 (M+H)+; Found,335.1551.
1- (1H-3-indole) -3- (4-methoxyphenyl) isoquinoline (4k), yellow solid, m.p. 256-orange 257oC.IR (KBr) cm-13145, 2924, 2854, 1608, 1551, 1513, 1432, 1244, 1177, 827, 743.1H NMR (DMSO-d 6 , 500 MHz)11.71 (s, 1H), 8.45 (d,J= 8.5 Hz, 1H), 8.30 (d,J= 8.5 Hz, 2H), 8.20 (s, 1H), 8.10 (s,J= 8.0 Hz, 1H), 8.03-8.00 (m, 2H),7.74 (t,J= 7.5 Hz, 1H), 7.61-7.57 (m, 2H), 7.25 (t,J= 7.5 Hz, 1H), 7.17(t,J= 7.5 Hz, 1H), 7.11 (d,J= 8.5 Hz, 2H), 3.84 (s, 3H).13C NMR (DMSO-d 6 ,125 MHz)159.7, 155.0, 148.6, 137.8, 136.5, 131.7, 130.0, 127.7, 127.6,127.5, 127.0, 126.9, 126.8, 125.1, 121.9, 120.6, 120.0, 114.3, 114.1, 112.2,111.8, 55.2. HRMS (ESI) calcd for C24H19N2O, 351.1497 (M+H)+; Found, 351.1497.
1- (1H-3-indole) -3- (4-fluorophenyl) isoquinoline (4l) as a yellow solid, mp 218. sup. 220oC. IR(KBr) cm-13198, 2924, 1617, 1550, 1528, 1508, 1428, 1222, 1132, 949, 829,728.1H NMR (DMSO-d 6 , 500 MHz)11.72 (s, 1H), 8.45 (d,J= 8.5 Hz, 1H), 8.37-8.35 (m, 2H), 8.28 (s, 1H), 8.05 (t,J= 7.5 Hz, 2H), 8.01-8.00 (m, 1H), 7.77(t,J= 7.5 Hz, 1H), 7.63 (t,J= 7.5 Hz, 1H), 7.58 (d,J= 8.0 Hz, 1H),7.37-7.35 (m, 2H), 7.24 (t,J= 7.5 Hz, 1H), 7.16 (t,J= 7.5 Hz, 1H).13C NMR(DMSO-d 6 , 125 MHz)163.5, 161.5, 155.1, 147.7, 137.6, 136.5, 135.7, 128.5,128.4, 127.9, 127.6, 121.9, 120.5, 120.0, 115.6, 115.5, 114.1, 113.3, 111.9.HRMS (ESI) calcd for C23H16FN2, 339.1298 (M+H)+; Found, 339.1305.
1- (1H-3-indole) -7-methyl-3-phenylisoquinoline (4m), yellow solid, m.p. 226-oC. IR(KBr) cm-13205, 3051, 2920, 1615, 1552, 1530, 1495, 1433, 1321, 1103, 871,743, 690.1H NMR (DMSO-d 6 , 500 MHz)11.67 (s, 1H), 8.31 (d,J= 7.5 Hz, 1H),8.24-8.23 (m, 2H), 8.08 (d,J= 8.0 Hz, 2H), 8.01-8.00 (m, 1H), 7.97 (d,J=8.0 Hz, 1H), 7.61-7.57 (m, 2H), 7.53 (t,J= 7.5 Hz, 2H), 7.42 (t,J= 7.5Hz, 1H), 7.24 (t,J= 7.5 Hz, 1H), 7.16 (t,J= 7.5 Hz, 1H), 3.40 (s, 3H).13CNMR (DMSO-d 6 , 125 MHz)154.5, 148.0, 139.3, 136.7, 136.4, 135.8, 132.2,128.7, 128.3, 127.6, 127.5, 127.0, 126.3, 125.8, 125.7, 121.8, 120.6, 119.9,114.3, 113.3, 111.8, 21.6. HRMS (ESI) calcd for C24H19N2, 335.1548 (M+H)+;Found, 335.1551.
1- (4-chloro-1H-3-indole) -3-phenylisoquinoline (4n), yellow solid, mp 189-oC. IR(KBr) cm-13158, 2923, 2855, 1619, 1563, 1488, 1441, 1341, 1189, 771, 743,699.1H NMR (DMSO-d 6 , 500 MHz)11.91 (s, 1H), 8.40 (s, 1H), 8.27 (d,J= 7.5Hz, 2H), 8.07 (d,J= 8.0 Hz, 1H), 7.86 (d,J= 8.0 Hz, 1H), 7.78-7.72 (m,2H), 7.58 (d,J= 7.5 Hz, 1H), 7.54-7.49 (m, 3H), 7.42 (t,J= 7.5 Hz, 1H),7.20 (t,J= 7.5 Hz, 1H), 7.08 (t,J= 7.5 Hz, 1H).13C NMR (DMSO-d 6 , 125 MHz)155.7, 148.5, 139.1, 137.4, 136.5, 130.1, 128.7, 128.6, 128.4, 128.1,127.7, 127.6, 127.2, 126.9, 126.6, 124.7, 122.3, 120.2, 115.0, 113.9,111.1.HRMS (ESI) calcd for C23H16ClN2, 355.1002 (M+H)+; Found, 355.1008.
1-（1H-3-indole) -3- (4-chlorophenyl) isoquinoline (4o), yellow solid, m.p. 225-oC. IR(KBr) cm-13210, 2958, 2925, 2856, 1729, 1615, 1550, 1529, 1459, 1275, 1128,957, 824, 744.1H NMR (DMSO-d 6 , 500 MHz)11.91 (s, 1H), 8.45 (s, 1H), 8.34-8.32 (m, 3H), 8.07-7.99 (m, 3H), 7.78 (d,J= 7.5 Hz, 1H), 7.64 (t,J= 7.5Hz, 1H), 7.60-7.56 (m, 3H), 7.23 (t,J= 7.5 Hz, 1H), 7.15 (t,J= 7.5 Hz,1H).13C NMR (DMSO-d 6 , 125 MHz)155.3, 147.5, 138.1, 137.6, 136.4, 133.2,130.2, 128.7, 128.1, 127.9, 127.7, 127.4, 127.0, 126.8, 125.5, 121.9, 120.5,120.1, 114.1, 113.7, 111.8. HRMS (ESI) calcd for C23H16ClN2, 355.1002 (M+H)+;Found, 355.1008.
7-chloro-1- (1H-3-indole) -3-phenylisoquinoline (4p), yellow solid, m.p. 215-oC. IR(KBr) cm-13283, 2954, 1588, 1556, 1544, 1534, 1480, 1424, 1242, 1088, 874,743, 689.1H NMR (DMSO-d 6 , 500 MHz)11.75 (s, 1H), 8.39-8.36 (m, 2H), 8.32(d,J= 7.5 Hz, 2H), 8.13 (d,J= 8.5 Hz, 2H), 8.07-8.03 (m, 2H), 7.82 (d,J= 7.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.46 (t,J= 7.5 Hz, 1H), 7.25 (t,J= 7.5Hz, 1H), 7.18 (t,J= 7.5 Hz, 1H).13C NMR (DMSO-d 6 , 125 MHz)154.4, 149.3,138.8, 136.5, 136.2, 131.5, 130.7, 130.0, 128.8, 128.7, 128.0, 126.7, 126.5,125.9, 125.8, 122.0, 120.4, 120.2, 113.7, 113.2, 111.9. HRMS (ESI) calcd forC23H16ClN2, 355.1002 (M+H)+; Found, 355.1007.
7-chloro-3- (1H)-3-indole) -3- (4-chlorophenyl) isoquinoline (4q) as a yellow solid, m.p. 217-218oC.IR (KBr) cm-13243, 2923, 1595, 1541, 1455, 1425, 1241, 1088, 876, 829, 742.1H NMR (DMSO-d 6 , 500 MHz)11.76 (s, 1H), 8.38 (s, 2H), 8.33 (s,J= 8.0 Hz,2H), 8.11 (d,J= 8.5 Hz, 2H), 8.07-8.06 (m, 1H), 8.01 (d,J= 8.0 Hz, 1H),7.82 (d,J= 7.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.25 (t,J= 7.5 Hz, 1H), 7.17(t,J= 7.5 Hz, 1H).13C NMR (DMSO-d 6 , 125 MHz)154.5, 148.0, 137.7, 136.5,136.0, 133.5, 131.7, 130.8, 130.0, 128.8, 128.1, 126.6, 126.0, 125.8, 122.0,120.3, 120.2, 113.6, 113.4, 112.0. HRMS (ESI) calcd for C23H15Cl2N2, 389.0612(M+H)+; Found, 389.0615.
Test example
The compounds 3c, 3d, 3g, 3h, 3i, 3j, 3l, 3m, 3n and 3o obtained above were selected and subjected to the following activity measurement
Experimental materials:
1 human cancer cell line: all purchased from Shanghai cell bank of Chinese academy of sciences;
2, tested drugs: after being dissolved by DMSO, the mixture is prepared into 10000 micrograms per milliliter of initial concentration for standby;
30.9% physiological saline: lot number 201721112, specification 250 mL: 2.25 g, zheng zhou yong and pharmaceutical limited;
45-fluorouracil injection (5-Fu), lot 140107, size 10 mL: 0.25 g/count, a product of Shanghai Xue Donghai general pharmaceutical Co., Ltd.
Experimental methods
Cells were routinely seeded in complete medium at 37 ℃ with 5% CO2Saturated humidity culture, amplification, digestion of cells with 0.25% trypsin, addition of culture medium and dilution to 1 × 105one/mL tumor cell suspension (trypan blue staining, number of live cells > 95%) was used for the experiment. A96-well sterile culture plate is provided with negative control wells, positive control wells and different concentration wells of the test sample, wherein the concentration is set to 64, 32, 16, 8, 4, 2, 1, 05 micrograms per milliliter with 3 duplicate wells per concentration. Inoculating the prepared cell suspension to a 96-hole sterile culture plate, and adding compounds with different concentrations after culturing for 24 h. And adding an equal amount of culture solution into the negative control holes, and placing the negative control holes into an incubator for culture. After 72 hours, the cells were removed, 20. mu.L of MTT was added to each well, and the cells were cultured for 4 hours, centrifuged after removal, and the supernatant was aspirated. To each well, 150. mu.L of DMSO was added, and the violet formazan crystals were dissolved completely by shaking. OD value of each well was measured by a microplate reader, and IC thereof was calculated from SPSS50。
Results of the experiment
Evaluation data of antitumor activity of the compound on five human tumor cells
The experimental results show that: the compounds show excellent antitumor activity, especially show excellent activity on SW620 colon cancer cells, compounds 3c, 3d and 3n, show broad-spectrum antitumor activity at the same time, and the activity of the compound 3n on MCF-7 breast cancer, SW620 colon cancer, PC-9 lung adenocarcinoma and other three tumor cells is superior to that of 5-fluorouracil, so that the compound can be used as a candidate or lead compound for further development and applied to the preparation of anticancer drugs.
Claims (6)
1. An indole-substituted isoquinoline compound is shown in a formula I,
I
wherein R is1Is hydrogen, a halogen atom or a methyl group, R2And R3Hydrogen, halogen atom, methyl, cyano, nitro or methoxy.
2. The method of synthesizing an indole-substituted isoquinoline compound of claim 1 comprising the steps of:
(1) preparation of intermediate Compound 2
Dissolving a compound 1 and 80% hydrazine hydrate in absolute ethyl alcohol, wherein the mass ratio of the compound 2 to the hydrazine hydrate is 5:1-1:1, stirring for 1-2 hours at a certain temperature, completely separating out a solid, filtering, and recrystallizing a crude product with absolute ethyl alcohol to obtain a white solid compound 2.
(2) Preparation of the target Compound
Dissolving an intermediate 2 and an indole compound 3 in a polar organic solvent dimethyl sulfoxide, wherein the mass ratio of the intermediate 2 to the indole compound to the transition metal catalyst silver nitrate is 1: 0.3-2: reacting at 0.1-2 ℃ at 20-100 ℃, detecting the reaction process by TLC, stopping the reaction when the reaction is complete, cooling the reactant to room temperature, filtering to obtain filtrate, removing the solvent by rotary evaporation under reduced pressure, and carrying out column chromatography on the residue to obtain a target product shown in formula I;
the above compounds are distinguished by the following numbers of the compounds in the reaction scheme, wherein R1Is hydrogen, a halogen atom or a methyl group, R2And R3Hydrogen, halogen atom, methyl, cyano, nitro or methoxy.
3. The method of synthesizing an indole-substituted isoquinoline compound according to claim 2, characterized in that: r1H, Cl or Me; r2Is H, F, Cl, Br, CN, NO2Or Me; r3H, Cl, F, Me or methoxy.
4. The method of synthesizing an indole-substituted isoquinoline compound according to claim 2, characterized in that: in the step (1), the mass ratio of the compound 1 to the hydrazine hydrate is 2: 1.
5. The method of synthesizing an indole-substituted isoquinoline compound according to claim 2, characterized in that: the compound 2, the compound 3, and AgNO3The ratio of the amounts of substances of (a) is 0.75: 1: 1.
6. the method of synthesizing an indole-substituted isoquinoline compound according to claim 2, characterized in that: in the step (2), the reaction temperature is 80 ℃.
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| WO2005123672A2 (en) * | 2004-06-14 | 2005-12-29 | Takeda San Diego, Inc. | Kinase inhibitors |
| CN105218426A (en) * | 2014-06-17 | 2016-01-06 | 中国科学院兰州化学物理研究所 | A kind of method of Synthesis of Indole and isoquinilone derivatives |
| CN105503722A (en) * | 2016-01-26 | 2016-04-20 | 湖南科技大学 | Method for synthesizing isoquinoline compound |
| CN105541713A (en) * | 2016-01-26 | 2016-05-04 | 湖南科技大学 | Isoquinoline compound and synthetic method thereof |
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| WO2005123672A2 (en) * | 2004-06-14 | 2005-12-29 | Takeda San Diego, Inc. | Kinase inhibitors |
| CN105218426A (en) * | 2014-06-17 | 2016-01-06 | 中国科学院兰州化学物理研究所 | A kind of method of Synthesis of Indole and isoquinilone derivatives |
| CN105503722A (en) * | 2016-01-26 | 2016-04-20 | 湖南科技大学 | Method for synthesizing isoquinoline compound |
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