CN103664932A - Indole grafted thiazole hydrazone derivatives, preparation method thereof and inhibiting effect of indole grafted thiazole hydrazone derivatives for polymerization of cancer cell microtubulin - Google Patents

Indole grafted thiazole hydrazone derivatives, preparation method thereof and inhibiting effect of indole grafted thiazole hydrazone derivatives for polymerization of cancer cell microtubulin Download PDF

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CN103664932A
CN103664932A CN201310541158.5A CN201310541158A CN103664932A CN 103664932 A CN103664932 A CN 103664932A CN 201310541158 A CN201310541158 A CN 201310541158A CN 103664932 A CN103664932 A CN 103664932A
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thiazole
indole
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thiazole hydrazone
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CN103664932B (en
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朱海亮
王彦婷
秦亚娟
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Nanjing University
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Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses indole grafted thiazole hydrazone derivatives with the general formula as shown in the specification. Experiments prove that the novel indole grafted thiazole hydrazone derivatives disclosed by the invention have a remarkable inhibiting effect for polymerization of cancer cell microtubulin. Therefore, the indole grafted thiazole hydrazone derivatives can be applied to the preparation of anticancer drugs. The invention discloses a preparation method of the indole grafted thiazole hydrazone derivatives, in the formula, R1 and R2 are selected from hydrogen, C1-10 alkyl groups, naphthenic bases, C1-5 alkoxy groups, halogens, halogen substituted C1-5 alkyl groups, nitryl and amino groups, and R3, R4 and R5 are selected from hydrogen, C1-5 alkyl groups, C1-5 alkoxy groups, halogens, halogen substituted C1-5 alkyl groups, nitryl and amino groups.

Description

One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and the restraining effect to cancer cells tubulin polymerization
Technical field
The present invention relates to the function of class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and inhibition tumor cell tubulin polymerization.
Background technology
Depolymerization and the polymerization of indoles medicine energy inhibition tumor cell tubulin, carry out the activity of anticancer in vivo by destroying microtubule with external morphology and function, thus performance antitumous effect.Some indoles medicine can promote and the polymerized form of stable tubulin (nearest research shows, medicine is due to they interference to microtubule dynamics to the restraining effect of microtubule depolymerization, rather than the change of tubulin polymerization thing amount.); And some indoles medicine is by suppressing the polymerization of microtubule with the strong combination of colchicine binding site.
In recent years, containing thiazole ring compound, at aspects such as drug research and biology, demonstrate more and more important effect, wherein aminothiazole compounds has stronger physiologically active, is especially subject to investigator's attention.Thereby thiazole compound can show multiple biological activity with targeted integration such as plurality of enzymes in organism and acceptors.The inhibition of the generation of tumour and the apoptotic signal of tumour cell own is closely bound up, so apoptosis plays an important role in the chemotherapy of tumour, and a lot of medicines is all by reconstituted cell apoptosis, to reach the object for the treatment of tumour.Excessive ROS (intracellular reactive oxygen species) can induce mitochondrial membrane potential (MMP) collapse, the dead factor in plastosome is discharged, inducing cell death; The accumulation of ROS simultaneously can cause lipid peroxidation, the oxidation inactivation of protein, enzyme and the oxidative damage of DNA.Research shows, tumour cell has the ROS level higher than normal cell, more responsive to the attack of ROS, so the relevant drug development of ROS becomes a focus of antitumor drug research and development.Develop it and there is certain theory significance and actual value, therefore, we design and have synthesized a series of indoles grafting thiazole hydrazone analog derivatives that (E)-4-(4-methoxyl group)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) thiazole is female ring of take.
Summary of the invention
The object of the present invention is to provide class indoles grafting thiazole hydrazone analog derivative and preparation method thereof.
Technical scheme of the present invention is as follows:
1. a class indoles grafting thiazole hydrazone analog derivative, is characterized in that they have following general formula:
Figure BSA0000097143670000021
In formula, R 1, R 2be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-10 alkyl, cycloalkyl, C1-5 alkoxyl group, halogen, halogen replacement;
R 3, R 4, R 5be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-5 alkyl, C1-5 alkoxyl group, halogen, halogen replacement.
2. prepare a class indoles grafting thiazole hydrazone analog derivative method for making claimed in claim 1, they are synthesized by the following step:
Figure BSA0000097143670000022
Step 1., in stink cupboard, under cold condition, adds in flask after organic solvent DMF certain volume, slowly drips the POCl of same volume 3again the compound 1 that is dissolved in same volume organic solvent is added drop-wise in above-mentioned flask, stirring reaction is after for some time, rising temperature, to room temperature, is followed the tracks of reaction through TLC, after question response is complete, reaction solution is poured in the frozen water of certain volume, with alkali, regulate pH value to slight alkalinity, then use organic solvent extraction, be spin-dried for and obtain yellow powder 2.
Step 2. is mixed compound 2 obtained above and thiosemicarbazide, adds a certain amount of organic solvent dissolution, stirring reaction at room temperature, TLC follows the tracks of reaction, after reacting completely, filtration, purified must yellow powder 3.
Step 3. is compound 3 obtained above, containing various substituent alpha-brominated methyl phenyl ketones, is dissolved in appropriate organic solvent, through TLC, follows the tracks of reaction, after reacting completely, filters, and purifiedly obtains target compound indole derivatives of the present invention.
3. experimental result shows, new indole grafting thiazole hydrazone analog derivative of the present invention has obvious restraining effect to the polymerization of cancer cells microtubule.Therefore indoles grafting thiazole hydrazone analog derivative of the present invention can be applied to prepare cancer therapy drug.
Embodiment:
Embodiment mono-: the preparation of (E)-4-(4-p-methoxy-phenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) thiazole
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mL POCl 3slowly drop in flask, then the 1-skatole (1.32g, 10.0mmoL) that is dissolved in 10mL DMF is slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na 2cO 3or K 2cO 3regulate pH value to 9, be extracted with ethyl acetate, be spin-dried for and obtain yellow powder.Get solid obtained above (0.61g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.43mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 77.9mg such as add again, 0.43mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 82.3%.m.p.205～207 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.84 (s, 3H), 3.74 (s, 3H), 6.92～7.07 (m, 2H), 7.16～7.35 (m, 2H), 7.50～7.56 (m, 2H), 7.64～7.76 (m, 2H), 7.92 (s, 1H), 8.21 (d, J=5.76Hz, 1H), 8.55 (s, 1H) .MS (ESI): 363.12 ([M+H] +) .Anal.calc.for C 20h 18n 4oS:C, 66.28; H, 5.01; O, 4.41%; N, 15.46%; Found:C, 66.26; H, 5.02; O, 4.42%; N, 15.46%.
Embodiment bis-: the preparation of (E)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine)-4-phenyl thiazole
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with α bromoacetophenone, obtains yellow powder shape target compound.Productive rate 69.5%.m.p.207～208 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.83 (s, 3H), 7.21～7.33 (m, 4H), 7.42 (t, J=7.58Hz, 2H), 7.52 (d, J=8.08Hz, 1H), 7.77 (s, 1H), 7.87 (d, J=7.28Hz, 2H), 8.23～8.27 (m, 2H), 11.84 (s, 1H) .MS (ESI): 333.11 ([M+H] +) .Anal.calc.for C 19h 16n 4s:C, 68.65; H, 4.85; N, 16.85%; Found:C, 68.63; H, 4.86; N, 16.86%.
Embodiment tri-: the preparation of (E)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine)-4-(4-(trifluoromethyl) phenyl) thiazole
Figure BSA0000097143670000042
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with 4-trifluoromethyl-alpha-bromoacetophenone, obtains yellow powder shape target compound.Productive rate 86.3%.m.p.230～235 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.83 (s, 3H), 7.21～7.29 (m, 2H), 7.36 (s, 1H), 7.52 (d, J=8.08Hz, 1H), 7.61 (d, J=8.56Hz, 2H), 7.80 (t, J=10.26Hz, 3H), 8.18～8.20 (m, 2H), 11.82 (s, 1H) .MS (ESI): 401.1 ([M+H] +) .Anal.calc.for C 20h 15f 3n 4s:C, 59.99; H, 3.78; N, 13.99%; Found:C, 59.98; H, 3.77; N, 13.97%.
Embodiment tetra-: the preparation of (E)-4-(4-bromophenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) thiazole
Figure BSA0000097143670000051
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 87.3%.m.p.237～241 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.83 (s, 3H), 7.21～7.31 (m, 2H), 7.37 (s, 1H), 7.52 (d, J=8.08Hz, 1H), 7.61 (d, J=8.56Hz, 2H), 7.80 (t, J=10.26Hz, 3H), 8.22～8.26 (m, 2H), 11.9 (s, 1H) .MS (ESI): 411.02 ([M+H] +) .Anal.calc.for C 19h 15brN 4s:C, 55.48; H, 3.68; N, 13.62%; Found:C, 55.47; H, 3.66; N, 13.64%.
Embodiment five: (E)-4-(3-bromophenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) phenyl) preparation of thiazole
Figure BSA0000097143670000052
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 3-, obtains yellow powder shape target compound.Productive rate 84.5%.m.p.195～198 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.83 (s, 3H), 7.22～7.31 (m, 2H), 7.38 (t, J=7.86Hz, 1H), 7.45 (s, 1H), 7.51 (t, J=7.06Hz, 2H), 7.78 (s, 1H), 7.87 (d, J=7.88Hz, 1H), 8.06 (s, 1H), 8.24 (t, J=8.10Hz, 2H), 11.92 (s, 1H) .MS (ESI): 411.02 ([M+H] +) .Anal.calc.for C 19h 15brN 4s:C, 55.48; H, 3.68; N, 13.62%; Found:C, 55.46; H, 3.69; N, 13.64%.
Embodiment six: (E)-4-(o-methoxyphenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine)-4 phenyl) preparation of thiazole
Figure BSA0000097143670000061
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound with O-methoxy-alpha-brominated methyl phenyl ketone.Productive rate 81.3%.m.p.218～219 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.84 (s, 3H), 3.92 (s, 3H), 7.05 (t, J=5.6Hz, 1H), 7.15 (d, J=8.20Hz, 1H), 7.23～7.38 (m, 4H), 7.53 (d, J=8.08Hz, 1H), 7.83 (s, 1H), 7.92 (s, 1H), 8.22～8.27 (m, 1H), 8.34 (s, 1H), 12.1 (s, 1H) .MS (ESI): 363.12 ([M+H] +) .Anal.calc.for C 20h 18n 4oS:C, 66.28; H, 5.01; O, 4.41; N, 15.46%; Found:C, 66.29; H, 5.03; O, 4.43; N, 15.45%.
Embodiment seven: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-p-methoxy-phenyl) thiazole
Figure BSA0000097143670000062
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mL POCl 3slowly drop in flask, then the 1-H indoles (1.17g, 10.0mmoL) that is dissolved in 10mL DMF is slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na 2cO 3or K 2cO 3regulate pH value to 9, the solid filtering post-drying of separating out, obtains yellow powder.Get solid obtained above (0.55g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.46mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 11mg such as add again, 0.46mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 81%.m.p.205～207 ℃ .1H NMR (DMSO-d6,400MHz) δ: 6.92～7.09 (m, 2H), 7.09～7.29 (m, 3H), 7.44～7.76 (m, 3H), 7.79 (d, J=8.80Hz, 1H), 7.85～7.92 (m, 1H), 8.07～8.24 (m, 1H), 8.37～8.57 (m, 1H), 11.66 (s, 1H) .MS (ESI): 349.10 ([M+H] +) .Anal.calc.for C 19h 16n 4oS:C, 65.50; H, 4.63; O, 4.59; N, 16.08%; Found:C, 65.47; H, 4.64; O, 4.58; N, 16.06%.
Embodiment eight: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-phenyl thiazole
Figure BSA0000097143670000071
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 84.2%.m.p.245～246 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.18～7.25 (m, 2H), 7.32～7.37 (m, 2H), 7.43～7.48 (m, 2H), 7.7～7.86 (m, 3H), 8.23 (d, J=6Hz, 1H), 8.37 (s, 1H), 11.6 (s, 1H) .MS (ESI): 319.09 ([M+H] +) .Anal.calc.for C 18h 14n 4s:C, 67.90; H, 4.43; N, 17.60%; Found:C, 67.89; H, 4.42; N, 17.58%.
Embodiment nine: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(o-methoxyphenyl) thiazole
Figure BSA0000097143670000081
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with O-methoxy-α-methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 85.4%.m.p.245～246 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.92 (s, 3H), 7.07 (t, J=5.6,1H), 7.17～7.29 (m, 3H), 7.34 (s, 1H), 7.40 (t, J=5.31Hz, 1H), 7.49 (d, J=5.40Hz, 1H), 7.84～7.91 (m, 2H), 8.21 (d, J=5.49Hz, 1H), 8.45 (s, 1H), 11.71 (s, 1H) .MS (ESI): 349.10 ([M+H] +) .Anal.calc.for C 19h 16n 4oS:C, 65.50; H, 4.63; O, 4.59; N, 16.08%; Found:C, 65.48; H, 4.64; O, 4.60; N, 16.07%.
Embodiment ten: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(3-bromophenyl) thiazole
Figure BSA0000097143670000082
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-α of 3--methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 88.4%.m.p.237～238 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.18～7.23 (m, 2H), 7.38 (s, 1H), 7.45 (d, J=7.40Hz, 2H), 7.61 (d, J=8.52Hz, 2H), 7.76～7.82 (m, 3H), 8.27 (d, J=7.68Hz, 1H), 8.30 (s, 1H), 11.56 (s, 1H) .MS (ESI): 397.00 ([M+H] +) .Anal.calc.for C 18h 13brN 4s:C, 54.42; H, 3.30; N, 14.10%; Found:C, 54.43; H, 3.33; N, 14.12%.
Embodiment 11: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-trifluoromethyl) thiazole
Figure BSA0000097143670000091
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with 4-trifluoromethyl-alpha-methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 90.4%.m.p.201～202 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.11～7.37 (m, 3H), 7.44～7.62 (m, 2H), 7.62～7.81 (m, 3H), 7.85 (s, 1H), 7.94～8.02 (m, 1H), 8.01～8.25 (m, 1H), 8.34～8.47 (m, 1H), 11.6 (s, 1H) .MS (ESI): 387.08 ([M+H] +) .Anal.calc.for C 19h 13f 3n 4s:C, 59.06; H, 3.39; N, 14.50%; Found:C, 59.04; H, 3.38; N, 14.52%.
Embodiment 12: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-bromophenyl) thiazole
Figure BSA0000097143670000092
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-α of 4--methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 87.2%.m.p.209～210 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.17～7.24 (m, 2H), 7.37 (s, 1H), 7.45 (d, J=7.40Hz, 2H), 7.61 (d, J=8.52Hz, 2H), 7.79～7.83 (m, 3H), 8.22 (d, J=7.68Hz, 1H), 8.30 (s, 1H), 11.60 (s, 1H) .MS (ESI): 397.00 ([M+H] +) .Anal.calc.for C 18h 13brN 4s:C, 54.42; H, 3.30; N, 14.10%; Found:C, 54.44; H, 3.29; N, 14.11%.
Embodiment 13: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-((1,1 '-biphenyl)-4-yl) thiazole
Figure BSA0000097143670000101
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with O-methoxy-α-methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 85.4%.m.p.245～246 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.15～7.23 (m, 2H), 7.38 (s, 1H), 7.42 (d, J=7.40Hz, 2H), 7.59 (d, J=8.50Hz, 2H), 7.79～7.83 (m, 3H), 7.80～7.92 (m, 4H), 7.93～7.95 (m, 1H), 8.35 (d, J=7.68Hz, 1H), 8.38 (s, 1H), 11.68 (s, 1H) .MS (ESI): 395.13 ([M+H] +) .Anal.calc.for C 24h 18n 48:C, 73.07; H, 4.60; N, 14.20%; Found:C, 73.06; H, 4.61; N, 14.22%.
Embodiment 14: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-p-methoxy-phenyl) thiazole
Figure BSA0000097143670000102
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mL POCl 3slowly drop in flask, 5-methoxy-Indole (the 1.47g of 10mL DMF will be dissolved in again, 10.0mmoL) be slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na 2cO 3or K 2cO 3regulate pH value to 9, the solid filtering post-drying of separating out, obtains yellow powder.Get solid obtained above (0.67g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.41mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 9.39mg such as add again, 0.41mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 81%.m.p.205～207 ℃. 1h NMR (DMSO-d6,400MHz) δ: 3.80 (s, 3H), 3.87 (s, 3H), 6.88～6.85 (m, 1H), 7.02～6.96 (m, 2H), 7.15 (s, 1H), 7.36 (d, J=6.57Hz, 1H), 7.90～7.66 (m, 4H), 8.34 (s, 1H), 11.47 (s, 1H) .MS (ESI): 379.12 ([M+H] +) .Anal.calc.for C 20h 18n 4o 2s:C, 63.47; H, 4.79; O, 8.46; N, 14.80%; Found:C, 63.48; H, 4.78; O, 8.45; N, 14.79%.
Embodiment 15: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-phenyl thiazole
Figure BSA0000097143670000111
Preparation method, with embodiment seven, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 85.5%.m.p.209～210 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.88 (s, 3H), 6.87 (dd, J 1=9Hz, J 2=9Hz, 1H), 7.33～7.38 (m, 4H), 7.44～7.48 (m, 2H), 7.77 (s, 1H), 7.81～7.84 (m, 3H), 8.40 (s, 1H), 11.50 (s, 1H) .MS (ESI): 349.10 ([M+H] +) .Anal.calc.for C 19h 10n 4oS:C, 65.50; H, 4.63; O, 4.59; N, 16.08%; Found:C, 65.48; H, 4.63; O, 4.58; N, 16.09%.
Embodiment 16: the preparation of (E)-4-(4-bromophenyl)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine) thiazole
Figure BSA0000097143670000112
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 79.8%.m.p.175～176 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.87 (s, 3H), 6.87 (dd, J 1=9Hz, J 2=9Hz, 1H), 7.34～7.37 (m, 2H), 7.61 (d, J=6,3H), 7.73 (s, 1H), 7.78～7.82 (m, 3H), 8.27 (s, 1H), 11.40 (s, 1H) .MS (ESI): 427.01 ([M+H] +) .Anal.calc.for C 19h 15brN 4oS:C, 53.40; H, 3.54; O, 3.74; N, 13.11%; Found:C, 53.41; H, 3.53; O, 3.74; N, 13.12%.
Embodiment 17: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-trifluoromethyl) thiazole
Figure BSA0000097143670000121
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with 4-trifluoromethyl-alpha-bromoacetophenone, obtains yellow powder shape target compound.Productive rate 88.8%.m.p.165～166 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.87 (s, 3H), 6.86 (dd, J 1=8.72Hz, J 2=8.76Hz, 1H), 7.35 (d, J=8.76Hz, 1H), 7.53 (s, 1H), 7.74～7.79 (m, 5H), 8.07 (d, J=8.12Hz, 2H), 8.29 (s, 1H), 11.43 (s, 1H) .MS (ESI): 417.09 ([M+H] +) .Anal.calc.for C 20h 15f 3n 4oS:C, 57.69; H, 3.63; O, 3.84; N, 13.45%; Found:C, 57.68; H, 3.64; O, 3.84; N, 13.43%.
Embodiment 18: the preparation of (E)-4-(3-bromophenyl)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine) thiazole
Figure BSA0000097143670000122
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 3-, obtains yellow powder shape target compound.Productive rate 86.2%.m.p.229～230 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.88 (s, 3H), 6.86 (dd, J 1=6.57Hz, J 2=6.60Hz, 1H), 7.35～7.41 (m, 3H), 7.45 (s, 1H), 7.51 (d, J=7.88Hz, 1H), 7.76 (s, 1H), 7.79 (s, 1H), 7.87 (d, J=7.84Hz, 1H), 8.06 (s, 1H), 8.29 (s, 1H), 11.4 (s, 1H) .MS (ESI): 427.01 ([M+H] +) .Anal.calc.for C 19h 15brN 4oS:C, 53.40; H, 3.54; O, 3.74; N, 13.11%; Found:C, 53.41; H, 3.53; O, 3.74; N, 13.12%.
Embodiment 19: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-(o-methoxyphenyl) thiazole
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with O-methoxy-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 89.8%.m.p.175～176 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.77 (s, 3H), 3.91 (s, 3H), 6.86～6.94 (m, 2H), 7.02～7.22 (m, 2H), 7.33～7.56 (m, 4H), 7.75 (s, 1H), 7.93 (s, 1H), 8.47～8.61 (s, 1H), 11.70 (s, 1H) .MS (ESI): 479.12 ([M+H] +) .Anal.calc.for C 20h 18n 4o 2s:C, 63.47; H, 4.79; O, 8.46; N, 14.80%; Found:C, 63.46; H, 4.78; O, 8.47; N, 14.80%.
Embodiment 20: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(4-p-methoxy-phenyl) thiazole
Figure BSA0000097143670000132
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mLPOCl 3slowly drop in flask, then the 5-bromo indole (1.96g, 10.0mmoL) that is dissolved in 10mLDMF is slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na 2cO 3or K 2cO 3regulate pH value to 9, the solid filtering post-drying of separating out, obtains yellow powder.Get solid obtained above (0.85g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.34mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 7.79mg such as add again, 0.34mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 81%.m.p.205～207 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.80 (s, 3H), 7.00 (d, J=8.76Hz, 2H), 7.19 (s, 1H), 7.34～7.37 (m, 1H), 7.44～7.46 (m, 2H), 7.79 (d, J=8.84Hz, 2H), 7.88 (s, 1H), 8.30 (s, 1H), 8.40 (s, 1H), 11.77 (s, 1H) .MS (ESI): 427.01 ([M+H] +) .Anal.calc.for C 19h 15brN 4oS:C, 53.40; H, 3.54; O, 3.74; N, 13.11%; Found:C, 53.42; H, 3.54; O, 3.74; N, 13.12%.
Embodiment 21: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4 phenyl thiazoles
Figure BSA0000097143670000141
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 82.9%.m.p.92～93 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.33～7.36 (m, 3H), 7.41～7.47 (m, 4H), 7.78～7.90 (m, 3H), 8.30～8.41 (m, 2H), 11.80 (s, 1H) .MS (ESI): 397.00 ([M+H] +) .Anal.calc.for C 18h 13brN 4s:C, 53.42; H, 3.30; N, 14.10%; Found:C, 53.41; H, 3.33; N, 14.11%.
Embodiment 22: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(3-bromophenyl) thiazole
Figure BSA0000097143670000151
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 3-, obtains yellow powder shape target compound.Productive rate 86.1%.m.p.94～95 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.33～7.45 (m, 4H), 7.49 (s, 2H), 7.86 (s, 2H), 8.06 (s, 1H), 8.25 (s, 1H), 8.40 (s, 1H), 11.73 (s, 1H) .MS (ESI): 474.91 ([M+H] +) .Anal.calc.for C 18h 12br 2n 4s:C, 45.40; H, 2.54; N, 11.77%; Found:C, 45.41; H, 2.53; N, 11.76%.
Embodiment 23: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(o-methoxyphenyl) thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound with O-methoxy-alpha-brominated methyl phenyl ketone.Productive rate 82.9%.m.p.92～93 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 3.91 (s, 3H), 7.06～7.19 (m, 1H), 7.35～7.52 (m, 5H), 7.74～7.87 (m, 2H), 7.96～8.10 (m, 1H), 8.30～8.50 (m, 2H), 11.6 (s, 1H) .MS (ESI): 427.01 ([M+H] +) .Anal.calc.for C 19h 15brN 4oS:C, 53.40; H, 3.54; O, 3.74; N, 13.11%; Found:C, 53.41; H, 3.53; O, 3.74; N, 13.12%.
Embodiment 24: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(4-trifluoromethyl) thiazole
Figure BSA0000097143670000161
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 79.4%.m.p.175～176 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.17～7.32 (m, 1H), 7.32～7.60 (m, 3H), 7.70～7.80 (m, 2H), 7.85～8.18 (m, 3H), 8.21～8.38 (m, 1H), 8.46～8.67 (m, 1H), 11.83 (s, 1H) .MS (ESI): 464.99 ([M+H] +) .Anal.calc.for C 19h 12brF 3n 4oS:C, 49.05; H, 2.60; N, 12.04%; Found:C, 49.04; H, 2.62; N, 12.03%.
Embodiment 25: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(4-bromophenyl) thiazole
Figure BSA0000097143670000162
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 83.4%.m.p.186～187 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.33～7.45 (m, 3H), 7.54～7.73 (m, 3H), 7.75～7.86 (m, 3H), 8.25 (s, 1H), 8.41 (s, 1H), 11.7 (s, 1H) .MS (ESI): 474.91 ([M+H] +) .Anal.calc.for C 18h 12br 2n 4s:C, 45.40; H, 2.54; N, 11.77%; Found:C, 45.42; H, 2.53; N, 11.76%.
Embodiment 26: the preparation of (E)-4 ((1,1 '-biphenyl)-4-yl)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine) thiazole
Figure BSA0000097143670000171
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound with 4-phenyl-alpha-brominated methyl phenyl ketone.Productive rate 85.5%.m.p.228～229 ℃. 1h NMR (DMSO-d 6, 400MHz) δ: 7.43～7.36 (m, 3H), 7.73～7.57 (m, 3H), 7.86～7.75 (m, 3H), 8.17 (s, 1H), 8.25 (s, 1H), 8.28～8.38 (m, 4H), 8.41 (s, 1H), 11.70 (s, 1H) .MS (ESI): 473.04 ([M+H] +) .Anal.calc.for C 24h 17brN 4s:C, 60.89; H, 3.62; N, 11.84%; Found:C, 60.88; H, 3.64; N, 11.84%.
Embodiment 27: the research of indoles grafting thiazole hydrazone analog derivative anti tumor activity in vitro
Adopt MTT[3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazoles are blue] method measures the half-inhibition concentration (IC of indoles grafting thiazole hydrazone analog derivative to human breast cancer cell strain (MCF-7) and Human Lung Cancer cell strain (A549) so).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, add after tri-distilled water dissolving the NaHCO with 5.6% 3solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO 32.00g, HEPES2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl8.00g, KCl0.40g, Na 2hPO 412H 2o0.06g, KH 2pO 40.06g, NaHCO 30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: test sample is dissolved and is made into storing solution with a small amount of tri-distilled water, general by 10 times of preparation storing solutions of experiment maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then add tri-distilled water dissolving.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) cultivation of human breast cancer cell MCF-7: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 ℃, 5%CO 2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, first discard original fluid, then wash with D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) human lung cancer cell A549's cultivation: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 ℃, 5%CO 2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, first discard original fluid, then wash with D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cell is hatched: the tumour cell in the vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 * 10 5individual ml -1.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 ℃, 5%CO 2in incubator, cultivate 24h.Cultivate after 24h, by design, add liquid respectively.
(8) dosing: test liquid is joined respectively in each hole according to the concentration gradient of ultimate density, and each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in to 37 ℃, 5%CO 2in incubator, cultivate 48h.The activity of positive control medicine is measured according to the method for test sample.
(9) mensuration of survivaling cell: in having cultivated 96 orifice plates after 48h, every hole adds MTT40 μ l (being made into 4mg/ml with D-Hanks damping fluid).At 37 ℃, place after 4h, remove supernatant liquor.Every hole adds 150 μ l DMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, utilize automatic microplate reader at 570nm wavelength place, to detect the optical density(OD) (OD value) in each hole.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD experiment-OD blank)/(OD contrast-OD blank)] * 100% (OD experimentthe average optical that represents testing drug group, OD contrastthe average optical that represents control group, OD blankthe average optical that represents control group).
Half-inhibition concentration (IC 50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, on typical curve, try to achieve its corresponding drug level.
The IC recording 50be shown in Table 1.
The inhibition IC of the listed indoles grafting of form 1 the present invention thiazole hydrazone analog derivative to tumour cell 50value
Figure BSA0000097143670000191

Claims (3)

1. a class indoles grafting thiazole hydrazone analog derivative, is characterized in that they have following general formula:
Figure FSA0000097143660000011
In formula, R 1, R 2be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-10 alkyl, cycloalkyl, C1-5 alkoxyl group, halogen, halogen replacement;
R 3, R 4, R 5be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-5 alkyl, C1-5 alkoxyl group, halogen, halogen replacement.
2. prepare a class indoles grafting thiazole hydrazone analog derivative method for making claimed in claim 1, they are become by the following step:
Figure FSA0000097143660000012
Step 1., in stink cupboard, under cold condition, adds in flask after organic solvent DMF certain volume, slowly drips the POCl of same volume 3again the compound 1 that is dissolved in same volume organic solvent is added drop-wise in above-mentioned flask, stirring reaction is after for some time, rising temperature, to room temperature, is followed the tracks of reaction through TLC, after question response is complete, reaction solution is poured in the frozen water of certain volume, with alkali, regulate pH value to slight alkalinity, then use organic solvent extraction, be spin-dried for and obtain yellow powder 2.
Step 2. is mixed compound 2 obtained above and thiosemicarbazide, adds a certain amount of organic solvent dissolution, stirring reaction at room temperature, TLC follows the tracks of reaction, after reacting completely, filtration, purified must yellow powder 3.
Step 3. is compound 3 obtained above, containing various substituent alpha-brominated methyl phenyl ketones, is dissolved in appropriate organic solvent, through TLC, follows the tracks of reaction, after reacting completely, filters, and purifiedly obtains target compound indole derivatives of the present invention.
3. experimental result shows, new indole grafting thiazole hydrazone analog derivative of the present invention has obvious restraining effect to the polymerization of cancer cells microtubule.Therefore indoles grafting thiazole hydrazone analog derivative of the present invention can be applied to prepare cancer therapy drug.
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