CN114933572B - Tubulin histone deacetylase double-target inhibitor and application thereof - Google Patents

Tubulin histone deacetylase double-target inhibitor and application thereof Download PDF

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CN114933572B
CN114933572B CN202210632565.6A CN202210632565A CN114933572B CN 114933572 B CN114933572 B CN 114933572B CN 202210632565 A CN202210632565 A CN 202210632565A CN 114933572 B CN114933572 B CN 114933572B
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保泽庆
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Abstract

The invention provides a double-target inhibitor of tubulin histone deacetylase and application thereof, belonging to the technical field of biological medicine. The double-target inhibitor of the tubulin histone deacetylase has a structure shown as a formula I. The inhibitor has better in-vitro anti-tumor cell proliferation activity and can be used for preparing anti-tumor drugs.

Description

Tubulin histone deacetylase double-target inhibitor and application thereof
Technical Field
The invention relates to the technical field of biological medicine, in particular to a double-target inhibitor of tubulin histone deacetylase and application thereof.
Background
Clinical application shows that when the HDAC (histone deacetylase) inhibitor is singly used for treating tumors, the anti-tumor curative effect is poor, and the toxic and side effects are excessive and the drug resistance development is rapid, so that the side effects are common to the HDAC inhibitor. To solve the above problems, HDAC inhibitors and other antitumor drugs are often used in combination clinically to enhance anticancer effects. However, such "drug cocktail" like multiple pharmacological therapies are often accompanied by poor patient compliance, complex doses, unpredictable pharmacokinetics, pharmacodynamics, and drug-drug interactions. Another strategy is to develop single molecule drugs with multi-targeting capability, which will provide more powerful and durable therapeutic effects, reduced toxic side effects, slowed development of drug resistance, etc. Over the last decade, pharmaceutical chemists have discovered a number of HDAC-based dual-target antitumor drug candidates, some of which have entered the clinical trial stage, such as CUDC-101 (a small molecule EGFR/HDAC dual-target inhibitor), and are currently undergoing phase I clinical trials, the results of which show excellent antitumor effects in a variety of preclinical tumor models.
Studies have reported that the combination of the HDAC inhibitor SAHA and the Tubulin (Tubulin) inhibitor vincristine has a remarkable synergistic effect when used for treating leukemia, which provides a theoretical basis for designing a Tubulin/HDAC dual-target inhibitor. Recently, diana et al rationally designed a Tubulin/HDAC dual-target inhibitor based on the principle of pharmacophore heterozygosity, wherein several compounds showed more potent anticancer activity and slower progression of drug resistance than single drugs. Although there are related reports on dual-target inhibitors of HDAC based on Tubulin, there have been no reports on dual-target inhibitors of HADC which both inhibit Tubulin aggregation and have excellent subtype selectivity, particularly Tubulin/HDAC3 dual-target inhibitors capable of simultaneously inhibiting Tubulin aggregation and selectively inhibiting HDAC 3.
Microtubules composed of α/β -Tubulin play a key role in various cellular processes such as mitotic spindle formation, and are considered as important targets for anticancer therapy. The invention designs a series of microtubulin/histone deacetylase double-target inhibitors, which show good targeting and anti-tumor activity in vivo.
Disclosure of Invention
Based on the above, it is necessary to provide a dual-target inhibitor of tubulin histone deacetylase, which has better in vitro anti-tumor cell proliferation activity.
A dual target inhibitor of tubulin histone deacetylase, the inhibitor having a structure shown in formula i:
wherein R is a fatty ether, an aryl ether, a fatty amine, an aryl amine, or an amide.
The inhibitor provided by the invention has better in-vitro anti-tumor cell proliferation activity.
In one embodiment, the inhibitor is one or more of the following compounds:
the invention also provides an application of the double-target inhibitor of the tubulin histone deacetylase in preparing drugs for inhibiting tumors.
In one embodiment, the tumor is colon cancer, melanoma, acute T-lymphocyte leukemia, or non-small cell lung cancer.
In one embodiment, the tumor is colon cancer and the inhibitor is selected from one or more of the following compounds: compound 3-2, compound 3-5, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound 3-16, compound 3-17, compound 3-21, compound 3-23.
The compound has better activity against colon cancer cells.
In one embodiment, the tumor is colon cancer and the inhibitor is compound 3-12.
In one embodiment, the tumor is melanoma and the inhibitor is one or more of the following compounds: 3-8, 3-9, 3-11, 3-12, 3-15, 3-16, 3-21 and 3-23.
The compound has better anti-melanoma cell activity.
In one embodiment, the inhibitor is one or both of the following compounds: 3-8 of a compound and 3-12 of a compound.
In one embodiment, the tumor is acute T-lymphocyte leukemia and the inhibitor is one or more of the following compounds: 3-6, 3-8, 3-9, 3-10, 3-11, 3-12, 3-16, 3-17, 3-20, and 3-21.
The compound has better activity of resisting acute T lymphocyte leukemia cells.
In one embodiment, the tumor is non-small cell lung cancer and the inhibitor is one or both of the following compounds: 3-8 of a compound and 3-12 of a compound.
The compound has better activity for resisting non-small cell lung cancer cells.
Compared with the prior art, the invention has the following beneficial effects:
the tubulin histone deacetylase double-target inhibitor has good in-vitro anti-tumor cell proliferation activity, has potential anti-colon cancer, melanoma, acute T lymphocyte leukemia and non-small cell lung cancer effects, and can be used for preparing tumor inhibition drugs.
Detailed Description
In order that the invention may be understood more fully, a more particular description of the invention will be rendered by reference to the preferred embodiments that are now set forth. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the following examples and comparative examples, reagents, materials, equipment are commercially available and the experimental procedure is a routine one in the art unless specifically indicated.
Example 1
1. Compound 3-1.
The structural formula of the compound 3-1 is as follows:
2. preparation of Compound 3-1.
(1) The preparation of intermediate 1-2 was carried out as follows.
K is added at 80 DEG C 2 CO 3 (930.28 mg,6.73 mmol) was added to a solution of intermediate 1-1 (1.00 g,2.69 mmol) in 10mL DMF. The mixture was stirred at 80℃for 0.5h, then the halogenated ester (2.96 mmol) was added dropwise to the mixture and stirred at 80℃for 3h. After confirming completion of the reaction by TLC analysis, the solution was cooled to room temperature. By H 2 O dilutes the solvent and adds 1M hydrochloric acid solution to ph=7 until precipitation occurs. Then, the mixture was filtered to obtain a filter residue and further dried to obtain intermediate 1-2 (73% yield).
(2) And (3) preparing an intermediate 1-3.
To 30mL MeOH solution of intermediate 1-2 (1.0 mmol,1.0 eq.) was added LiOH solution (2.5 mmol,2.5 eq., in 10mL H) under ice bath 2 O). The mixture was stirred at room temperature for 2 hours until the reaction was complete. The solvent was removed in vacuo using H 2 O dilutes the residue and adds 4M hydrochloric acid solution to ph=2. The mixture was then filtered to give a filter residue and further dried to give intermediates 1-3 (100% yield), which had the following structural formula.
(3) Preparation of final product 3-1.
To a solution of intermediate 1-3 (1.0 mmol,1.0 eq.) in DMF (15 mL) was added triethylamine (2.5 mmol,2.5 eq.), HOBt (1.2 mmol,1.2 eq.), EDCI (1.2 mmol,1.2 eq.) and stirred for 10min. O-phenylenediamine (1.1 mmol,1.1 eq.) was then added and stirred at room temperature for 4 hours until after the reaction was complete, water was added to the reaction mixture. Then, the mixture was filtered to obtain a filter residue and further dried to obtain compound 3-1 (93% yield) as a yellow solid.
3. And (5) mass spectrometry analysis.
And identifying the obtained compound 3-1 by adopting nuclear magnetic resonance spectrum and high-resolution mass spectrum, wherein the identification result is as follows: 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.57(s,1H),8.00(d,J＝8.5Hz,2H),7.64(s,2H),7.19(d,J＝8.4Hz,2H),7.15(d,J＝7.6Hz,1H),6.94(t,J＝7.3Hz,1H),6.74(d,J＝7.8Hz,1H),6.56(t,J＝7.5Hz,1H),4.90(s,2H),4.82(s,2H),3.87(s,6H),3.80(s,3H). 13 C NMR(101MHz,DMSO-d6)δ184.62,167.15,153.92,152.47,141.90,131.81,129.21,128.08,127.99,127.45,127.30,127.15,126.69,116.10,107.97,68.92,60.21,55.97.m.p.:147.1℃-149.0℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 27 H 26 N 3 O 6 S:520.1464,found:520.1467.HPLC:t R 18.574min,purity97.24％。
example 2
Compound 3-2 having the structural formula:
the preparation method of the compound 3-2 is the same as that of the compound 3-1.
The obtained solid is identified by nuclear magnetic resonance spectrum, and the identification result is as follows: 1 H NMR(400MHz,DMSO)δ9.11(s,1H),8.53(d,J＝4.8Hz,1H),7.95(d,J＝3.6Hz,2H),7.63(s,2H),7.14(d,J＝7.6Hz,1H),7.09(d,J＝8.4Hz,2H),6.88(t,J＝7.2Hz,1H),6.71(d,J＝7.6Hz,1H),6.52(t,J＝7.6Hz,1H),4.80(s,2H),4.05(t,J＝5.6Hz,2H),3.86(s,6H),3.79(s,3H),2.33(t,J＝7.2Hz,2H). 13 C NMR(101MHz,DMSO)δ185.14,173.60,171.63,167.35,154.28,152.88,142.20,132.20,127.49,125.61,119.74,116.27,108.38,60.63,56.38,51.57,33.63.m.p.:125.5℃-127.7℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 28 H 28 N 3 O 6 S:534.1621,found:534.1625.HPLC:t R 17.671min,purity 98.19%. From the above identification results, the obtained product was 3-2.
Example 3
Compound 3-3 having the structural formula:
the preparation method of the compound 3-3 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.16(s,1H),8.56(s,1H),7.97(d,J＝8.4Hz,2H),7.63(s,2H),7.14(dd,J＝14.8,8.0Hz,3H),6.89(s,1H),6.71(d,J＝7.9Hz,1H),6.54(d,J＝7.2Hz,1H),4.83(s,2H),4.13(s,2H),3.87(s,6H),3.80(s,3H),2.03(d,J＝33.5Hz,4H). 13 C NMR(101MHz,DMSO)δ184.97,173.37,152.84,142.28,132.19,129.46,128.41,125.79,115.61,108.35,99.93,60.59,56.35,51.73,30.25,24.50.m.p.:124.8℃-126.1℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 29 H 30 N 3 O 6 S:548.1771,found:548.1771.HPLC:t R 18.026min,purity 99.07%. From the above identification results, the obtained product was 3-3.
Example 4
Compound 3-4 having the structural formula:
the preparation method of the compound 3-4 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.14(s,1H),8.55(s,1H),7.95(d,J＝8.0Hz,2H),7.64(s,2H),7.13(dd,J＝17.4,8.0Hz,3H),6.89(t,J＝7.3Hz,1H),6.72(d,J＝7.8Hz,1H),6.54(t,J＝7.3Hz,1H),4.82(s,2H),4.10(s,2H),3.87(s,6H),3.80(s,3H),2.40(s,2H),1.79(s,4H). 13 C NMR(101MHz,DMSO)δ184.62,170.96,167.28,160.77,153.90,152.47,141.90,131.82,129.08,128.04,125.74,125.31,123.51,116.18,115.90,115.26,107.97,67.55,60.21,55.97,35.31,28.15,21.88.m.p.:120.1℃-121.2℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 30 H 32 N 3 O 6 S:562.1934,found:562.1935.HPLC:t R 17.362min,purity 96.22%. From the above identification results, the obtained product was 3-4.
Example 5
Compound 3-5, having the structural formula:
the preparation method of the compound 3-5 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.12(s,1H),8.54(s,1H),7.94(d,J＝7.8Hz,2H),7.64(s,2H),7.16(d,J＝7.1Hz,1H),7.08(s,3H),6.88(d,J＝6.8Hz,1H),6.72(d,J＝7.4Hz,1H),6.54(d,J＝6.5Hz,1H),4.82(s,2H),4.05(d,J＝5.1Hz,3H),3.87(s,7H),3.79(s,3H),2.33(d,J＝17.3Hz,3H),1.72(dd,J＝25.7,8.7Hz,5H),1.58(d,J＝8.7Hz,2H),1.45(d,J＝24.3Hz,4H). 13 C NMR(101MHz,DMSO)δ184.67,173.41,171.19,167.38,160.89,154.02,152.57,141.99,131.91,129.64,129.28,129.14,128.12,125.80,125.38,125.20,123.67,116.28,116.00,115.32,114.80,108.09,60.31,56.06,51.28,35.79,33.31,28.48,25.15.m.p.:122.7℃-124.2℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 31 H 34 N 3 O 6 S:576.2090,found:576.2096.HPLC:t R 18.176min,purity 98.77%. From the above identification results, the obtained product was 3 to 5.
Example 6
Compound 3-6 having the structural formula:
the preparation method of the compound 3-6 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.11(s,1H),8.53(d,J＝4.8Hz,1H),7.95(d,J＝3.9Hz,2H),7.63(s,2H),7.14(d,J＝7.5Hz,1H),7.09(d,J＝8.4Hz,2H),6.88(t,J＝7.4Hz,1H),6.71(d,J＝7.7Hz,1H),6.53(t,J＝7.4Hz,1H),4.80(s,2H),4.08-4.01(m,2H),3.86(s,6H),3.79(s,3H),2.33(s,2H),1.74(s,3H),1.67-1.57(m,2H),1.47(s,3H),1.38(d,J＝21.9Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ184.72,171.28,167.37,162.43,160.86,153.94,152.53,141.93,131.88,129.14,128.10,125.78,125.36,125.14,123.62,116.27,115.97,115.31,108.02,67.83,60.28,56.04,35.86,35.74,30.84,28.52,25.29.m.p.:131.3℃-133.0℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 32 H 36 N 3 O 6 S:590.2247,found:590.2243.HPLC:t R 18.432min,purity 99.12%. From the above identification results, the obtained product was 3-6.
Example 7
Compound 3-7 having the structural formula:
the preparation method of the compound 3-7 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.68(s,1H),8.56(s,1H),8.04-7.94(m,4H),7.68-7.56(m,4H),7.48(dd,J＝36.8,6.8Hz,2H),7.20(s,3H),6.97(d,J＝6.5Hz,1H),6.79(d,J＝7.5Hz,1H),6.60(s,1H),5.27(d,J＝25.7Hz,2H),4.91(s,2H),3.87(s,6H),3.80(s,3H). 13 C NMR(101MHz,DMSO-d6)δ184.62,169.87,167.17,165.06,160.33,160.25,153.95,152.49,143.16,141.92,140.05,137.83,136.09,134.20,131.82,129.38,129.21,128.09,128.01,127.56,127.48,127.33,127.17,126.73,126.55,125.60,123.27,116.29,116.15,115.72,115.63,108.00,69.05,60.23,55.98.m.p.:135.2℃-138.9℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 33 H 30 N 3 O 6 S:596.1777,found:596.1779.HPLC:t R 16.183min,purity 96.91%. From the above identification results, the obtained product was 3-7.
Example 8
Compound 3-8, having the structural formula:
the preparation method of the compound 3-8 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.41(s,1H),8.56(s,1H),7.98(dd,J＝8.5,4.4Hz,2H),7.75(t,J＝8.7Hz,1H),7.70-7.64(m,2H),7.63(s,2H),7.57-7.51(m,2H),7.34(d,J＝7.7Hz,1H),7.20(dd,J＝8.3,5.9Hz,2H),6.95-6.88(m,1H),6.75(d,J＝7.9Hz,1H),6.66(d,J＝16.1Hz,1H),6.59(d,J＝7.6Hz,1H),5.24(d,J＝5.6Hz,2H),4.94(s,2H),3.87(s,6H),3.79(s,3H). 13 C NMR(101MHz,DMSO)δ184.64,167.18,163.47,153.93,152.48,141.91,141.60,139.11,138.13,134.58,131.82,129.22,128.25,128.09,127.80,127.55,125.80,124.71,123.49,122.59,117.41,116.27,116.01,115.67,114.68,107.98,60.22,55.98,48.73.m.p.:141.0℃-143.7℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 35 H 32 N 3 O 6 S:622.1934,found:622.1930.HPLC:t R 17.362min,purity 98.57%. From the above identification results, the obtained product was 3 to 8.
Example 9
Compound 3-9 having the structural formula:
the preparation method of the compound 3-9 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.16(s,1H),8.60(s,1H),8.04(s,2H),7.63(s,2H),7.21(d,J＝39.0Hz,3H),6.90(s,3H),6.72(s,2H),6.54(s,2H),5.25(s,1H),4.85(s,2H),3.83(d,J＝28.4Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ185.64,169.16,167.18，152.90,142.42,132.19,128.68,125.84,123.66,117.14,116.52,116.19,108.38,69.61，60.63,56.40.m.p.:130.1℃-131.2℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 29 H 28 N 3 O 6 S:546.1621,found:546.1623.HPLC:t R 17.725min,purity 98.04%. From the above identification results, the obtained product was 3 to 9.
Example 10
Compound 3-10, having the structural formula:
the preparation method of the compound 3-10 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.07(s,1H),8.62(s,1H),8.55(s,1H),8.06(s,5H),7.99(s,2H),7.63(s,3H),7.27(d,J＝7.2Hz,1H),7.00(s,1H),6.79(d,J＝7.6Hz,1H),6.63(d,J＝7.7Hz,1H),5.05(s,2H),3.82(dd,J＝27.1,12.8Hz,11H). 13 C NMR(101MHz,DMSO)δ185.12,167.37,159.43,158.84,154.45,152.91,152.84,143.12,142.35,142.29,140.46,132.20,132.11,130.12,128.92,127.49,127.38,126.11,122.42,121.28,116.79,116.68,108.39,60.63,60.58,56.40,56.30,18.95.m.p.:127.3℃-128.8℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 28 H 27 N 4 O 6 S:547.1573,found:547.1567.HPLC:t R 13.796min,purity 99.37%. From the above identification results, the obtained product was 3 to 10.
Example 11
Compounds 3-11 have the following structural formula:
the preparation method of the compound 3-11 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.30(s,1H),9.20(s,1H),8.67(s,2H),8.56(s,1H),7.97(d,J＝8.3Hz,2H),7.77(d,J＝7.8Hz,2H),7.13(d,J＝7.5Hz,1H),6.89(s,1H),6.70(d,J＝7.7Hz,1H),6.53(d,J＝7.5Hz,1H),4.86(s,2H),3.87(s,6H),3.79(s,3H),2.81(s,4H). 13 C NMR(101MHz,DMSO)δ176.75,166.46,154.17,152.50,141.97,134.74,131.96,131.71,130.42,127.93,126.84,107.98,60.22,56.00,28.55.m.p.:125.3℃-127.0℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 29 H 29 N 4 O 6 S:561.1730,found:561.1736.HPLC:t R 13.541min,purity 98.67%. From the above identification results, the obtained product was 3-11.
Example 12
Compound 3-12, having the structural formula:
the preparation method of the compound 3-12 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.23(s,1H),9.11(s,1H),8.57(s,1H),7.97(d,J＝8.4Hz,2H),7.79(d,J＝8.4Hz,2H),7.63(s,2H),7.18(d,J＝7.7Hz,1H),6.89(t,J＝7.4Hz,1H),6.71(d,J＝7.8Hz,1H),6.54(d,J＝7.3Hz,1H),4.83(s,2H),3.87(s,7H),3.80(s,3H),2.42(dt,J＝14.1,7.1Hz,4H),2.00-1.86(m,2H). 13 C NMR(101MHz,DMSO)δ184.67,171.35,167.21,153.96,152.48,141.92,131.80,129.32,127.14,125.73,125.39,123.45,119.37,116.11,115.83,107.97,60.22,55.97,35.74,34.91,21.06.m.p.:125.3℃-127.6℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 30 H 31 N 4 O 6 S:575.1886,found:575.1885.HPLC:t R 14.279min,purity 98.29%. From the above identification results, the obtained product was 3-12.
Example 13
Compound 3-13 having the structural formula:
the preparation method of the compound 3-13 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.20(s,1H),9.10(s,1H),8.57(s,1H),7.97(d,J＝8.3Hz,2H),7.79(d,J＝5.7Hz,2H),7.63(s,2H),7.15(s,1H),6.89(s,1H),6.72(s,1H),6.53(s,1H),4.82(s,2H),3.87(s,7H),3.80(s,3H),2.41-2.26(m,4H),1.66(s,2H),1.60(s,2H). 13 C NMR(101MHz,DMSO)δ184.62,173.21,171.56,170.97,167.18,153.95,152.47,141.90,131.78,129.27,127.12,125.70,125.31,123.50,119.32,116.14,115.86,107.96,60.19,56.01,55.96,51.20,36.35,33.02,25.02,18.53.m.p.:132.7℃-134.3℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 31 H 33 N 4 O 6 S:589.2043,found:589.2047.HPLC:t R 13.124min,purity 96.79%. From the above identification results, the obtained product was 3-13.
Example 14
Compounds 3-14 have the following structural formula:
the preparation method of the compound 3-14 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.18(s,1H),9.08(s,1H),8.57(s,1H),7.97(d,J＝8.5Hz,2H),7.78(d,J＝8.4Hz,2H),7.63(s,2H),7.15(d,J＝7.7Hz,1H),6.88(s,1H),6.71(d,J＝7.8Hz,1H),6.52(s,1H),4.80(s,2H),3.87(s,6H),3.80(s,3H),2.41-2.29(m,4H),1.64(dd,J＝14.5,7.2Hz,4H),1.38(d,J＝7.1Hz,2H). 13 C NMR(101MHz,DMSO)δ184.66,171.65,171.09,167.19,153.94,152.47,141.85,141.68,131.79,129.29,127.13,125.66,125.26,123.54,119.31,116.13,115.85,107.95,60.20,55.96,36.36,35.61,25.07,24.81,18.53.m.p.:125.3℃-127.8℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 32 H 35 N 4 O 6 S:603.2199,found:603.2207.HPLC:t R 15.708min,purity 98.26%. From the above identification results, the obtained product was 3-14.
Example 15
Compound 3-15 having the structural formula:
the preparation method of the compound 3-15 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.41(s,1H),9.28(s,1H),8.60(s,1H),7.99(d,J＝7.1Hz,2H),7.85(d,J＝6.7Hz,2H),7.67(s,2H),7.21(d,J＝6.6Hz,1H),6.91(s,1H),6.74(d,J＝7.3Hz,1H),6.56(s,1H),4.90(s,2H),3.91(s,6H),3.83(s,3H),2.38(d,J＝7.0Hz,4H),2.33(s,2H),1.64(s,3H),1.33(s,3H). 13 C NMR(101MHz,DMSO)δ173.37,171.75,167.25,152.48,141.80,131.80,127.09,125.21,119.34,115.87,107.98,60.23,55.98,51.17,38.87,33.23,28.47,24.86,24.31.m.p.:128.5℃-130.1℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 33 H 37 N 4 O 6 S:617.2356,found:617.2359.HPLC:t R 15.424min, purity98.49%. From the above identification results, the obtained product was 3-15.
Example 16
Compounds 3-16, having the structural formula:
the preparation method of the compound 3-16 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.66(s,1H),9.82(d,J＝9.4Hz,1H),8.61(s,1H),8.11(d,J＝8.6Hz,3H),8.07-7.96(m,2H),7.65(s,1H),7.19(d,J＝7.4Hz,1H),6.99(t,J＝6.9Hz,1H),6.80(d,J＝7.9Hz,1H),6.61(t,J＝7.2Hz,1H),4.94(s,2H),3.89(s,6H),3.81(s,3H). 13 C NMR(101MHz,DMSO)δ186.42,181.51,171.29,165.11,154.42,152.91,143.67,137.41,132.21,128.29,128.12,127.48,127.24,127.08,123.44,121.11,116.63,116.52,108.40,60.64,56.39.m.p.:133.1℃-134.2℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 33 H 29 N 4 O 6 S:609.1730,found:609.1735.HPLC:t R 18.196min,purity 96.76%. From the above identification results, the obtained product was 3-16.
Example 17
Compound 3-17, having the structural formula:
the preparation method of the compound 3-17 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.79(s,1H),9.70(s,1H),8.59(s,1H),8.03(d,J＝7.6Hz,2H),7.88(d,J＝7.8Hz,2H),7.63(s,2H),7.36-7.24(m,1H),7.19(d,J＝14.8Hz,1H),6.94(s,1H),6.76(s,1H),6.59(d,J＝6.7Hz,1H),5.00(s,2H),3.88(s,6H),3.80(s,3H). 13 C NMR(101MHz,DMSO)δ184.67,167.04,162.57,162.00,154.03,152.50,141.93,141.66,141.10,134.68,133.18,131.79,129.53,127.93,127.30,126.24,124.83,122.74,119.81,116.13,115.91,107.98,60.22,55.99,54.89.m.p.:137.1℃-138.2℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 29 H 27 N 4 O 6 S:559.1573,found:559.1570.HPLC:t R 17.324min,purity 97.67%. From the above identification results, the obtained product was 3-17.
Example 18
Compounds 3-18 having the structural formula:
the preparation method of the compound 3-18 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.17(s,1H),9.08(s,1H),8.57(s,2H),8.31(s,1H),7.96(d,J＝8.8Hz,2H),7.77(d,J＝8.4Hz,2H),7.63(s,2H),7.14(d,J＝7.6Hz,1H),6.89(d,J＝6.8Hz,1H),6.70(d,J＝7.6Hz,1H),6.54(t,J＝13.2Hz,1H),4.80(s,2H),3.87(s,6H),3.80(s,3H). 13 C NMR(101MHz,DMSO)δ169.16,167.37,154.02,152.90,142.42,141.98,138.55,132.19,128.68,125.84,123.66,117.14,116.52,108.38,60.63,55.96.m.p.:135.3℃-136.8℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 31 H 27 N 4 O 6 S 2 :615.1294,found:615.1299.HPLC:t R 17.271min,purity 98.11%. From the above identification results, the obtained product was 3-18.
Example 19
Compounds 3-19 have the following structural formula:
the preparation method of the compound 3-19 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.23(s,1H),7.79(d,J＝8.5Hz,2H),7.65(s,2H),7.15(d,J＝7.6Hz,1H),6.91(t,J＝7.0Hz,1H),6.75(d,J＝8.6Hz,2H),6.72(s,1H),6.71-6.66(m,1H),6.54(t,J＝7.2Hz,1H),5.82(s,1H),4.84(s,2H),3.99(d,J＝5.8Hz,2H),3.87(s,6H),3.80(d,J＝5.0Hz,3H). 13 C NMR(101MHz,DMSO)δ183.32,168.33,158.38,158.88,154.45,152.91,152.84,143.82,142.35,140.46,132.20,127.49,127.38,126.11,122.42,121.28,116.79,116.68,108.39,60.69,56.39,18.30.m.p.:141.8℃-143.1℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 27 H 27 N 4 O 5 S:519.1624,found:519.1633.HPLC:t R 16.361min,purity 98.40%. From the above identification results, the obtained product was 3-19.
Example 20
Compound 3-20, having the structural formula:
the preparation method of the compound 3-20 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.15(s,1H),8.41(s,1H),7.76(d,J＝8.6Hz,2H),7.65(s,2H),7.20-7.13(m,1H),6.96-6.84(m,1H),6.72(t,J＝8.0Hz,3H),6.57-6.49(m,1H),6.44(s,1H),5.75(s,1H),4.85(s,2H),3.87(s,6H),3.79(s,3H),3.43(dd,J＝12.5,6.5Hz,2H),2.64(t,J＝6.8Hz,2H). 13 C NMR(101MHz,DMSO)δ177.89,167.22,153.12,152.53,143.97,134.78,132.08,131.82,130.42,127.93,126.84,108.28,60.22,56.00.m.p.:134.6℃-136.2℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 28 H 29 N 4 O 5 S:533.1780,found:533.1789.HPLC:t R 17.332min,purity 97.83%. From the above identification results, the obtained product was 3-20.
Example 21
Compound 3-21 having the structural formula:
the preparation method of the compound 3-21 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ10.17(s,1H),8.57(s,1H),7.97(d,J＝8.5Hz,2H),7.78(d,J＝8.4Hz,2H),7.63(s,2H),7.14(d,J＝7.2Hz,1H),6.93-6.85(m,1H),6.71(d,J＝7.8Hz,1H),6.54(d,J＝7.2Hz,1H),5.82(s,1H),4.80(s,2H),3.87(s,6H),3.80(s,3H),3.62(s,2H),2.39-2.23(m,4H),1.61(s,3H),1.10-0.96(m,3H). 13 C NMR(101MHz,DMSO)δ184.97,173.37,167.25,152.48,141.80,131.80,127.09,125.21,119.34,115.87,107.98,60.23,55.98,51.17,33.23,28.47,24.86,24.31.m.p.:146.4℃-148.1℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 32 H 37 N 4 O 5 S:589.2406,found:589.2409.HPLC:t R 17.441min,purity 96.82%. From the above identification results, the obtained product was 3-21.
Example 22
Compound 3-22, having the structural formula:
the preparation method of the compound 3-22 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.28(s,1H),8.65(s,1H),8.00(d,J＝7.3Hz,2H),7.60(s,2H),7.55(d,J＝7.7Hz,2H),7.14(d,J＝7.3Hz,1H),6.90(d,J＝6.8Hz,1H),6.72(d,J＝7.5Hz,1H),6.55(d,J＝6.8Hz,1H),4.84(s,2H),3.86(s,6H),3.79(s,3H),2.77(s,2H),2.64(s,2H). 13 C NMR(101MHz,DMSO)δ184.76,169.53,166.61,154.20,152.57,142.27,142.06,132.36,131.78,130.38,126.61,126.16,125.69,123.18,116.25,115.87,108.05,60.32,56.07,34.71,15.55.m.p.:140.2℃-141.9℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 30 H 28 N 3 O 5 S:542.1671,found:542.1674.HPLC:t R 18.152min,purity 97.85%. From the above identification results, the obtained product was 3-22.
Example 23
Compound 3-23 having the structural formula:
the preparation method of the compound 3-23 is the same as that of the compound 3-1.
Identifying the obtained product by nuclear magnetic resonance, wherein the identification result is that 1 H NMR(400MHz,DMSO)δ9.44(s,1H),8.68(s,1H),8.11(d,J＝7.9Hz,2H),7.80(d,J＝7.9Hz,2H),7.64(s,2H),7.59(s,1H),7.37(d,J＝7.6Hz,1H),7.02(d,J＝15.9Hz,1H),6.93(t,J＝7.2Hz,1H),6.76(d,J＝7.9Hz,1H),6.59(t,J＝7.4Hz,1H),4.96(s,2H),3.88(s,6H),3.81(s,3H). 13 C NMR(101MHz,DMSO)δ184.65,166.65,163.24,154.21,152.52,142.00,141.59,138.40,137.22,133.15,131.72,130.35,128.63,127.00,125.88,124.70,123.75,116.16,108.01,60.24,56.02.m.p.:137.3℃-138.5℃.HRMS(ESI-Q-TOF)m/z:[M+H] + calculated for C 28 H 26 N 3 O 5 S:516.1515,found:516.1518.HPLC:t R 16.842min,purity 96.02%. From the above identification results, the obtained product was 3-23.
Experimental example 1
In vitro antiproliferative activity assay of the above compounds 3-1 to 3-23 on 4 cancer cells.
The tumor inhibition effect of the compounds is proved by the following test method. Experimental results show that the compound has obvious tumor cell inhibition effect, and can be used for treating cancers.
1. Experimental purposes and principles.
The purpose of the experiment is as follows: the MTT method is adopted to detect the inhibition effect of the compound on proliferation of different types of tumor cells.
Experimental principle: MTT colorimetric method is a method for detecting cell survival and growth, and the principle is that succinic dehydrogenase in mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystalline formazan and deposit in cells, while dead cells lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, an enzyme-linked immunosorbent assay (ELISA) is used for detecting an absorbance value (OD value) at 570nM, the number of living cells can be reacted according to the absorbance value, and the smaller the OD value is, the weaker the cell activity is, and the better the proliferation inhibition effect of the drug is.
2. Reagent basic information.
The information on the reagents used in the experiments are shown in the following table:
TABLE 1 basic information on reagents
Reagent name Branding
RPMI-1640 medium powder Gibco
Fetal bovine serum Capricorn Scientific
Dimethyl sulfoxide (DMSO) Sigma
Tetramethyl azoazole blue (MTT) Sigma
3. And (5) preparing a reagent.
1. RPMI-1640 complete medium
1L of RPMI-1640 medium was prepared, and a corresponding amount of RPMI-1640 powder was dissolved in a beaker containing 800ml of triple distilled water and stirred for 4 hours until the powder was completely dissolved. 2g NaHCO is added 3 Stirring until completely dissolved. The pH is regulated by hydrochloric acid with the concentration of 1mol/L to be in the range of 7.2-7.4, and the volume is fixed to 1L. Filtering with a filter membrane with a pore size of 0.22 μm, packaging, and storing at 4deg.C. When in use, 5% of serum is added to form a complete culture medium, thus being applicable to cell culture.
2、MTT
50ml of centrifugal tube is wrapped with tinfoil paper to avoid light, 250mg of MTT powder is precisely weighed, added into a centrifugal tube, 50ml of PBS is added to completely dissolve the MTT powder, and the MTT powder is filtered and sterilized by a filter membrane with the aperture of 0.22 mu m and split charging and stored in a dark place at the temperature of minus 20 ℃.
3. Compound formulation
The autoclaved EP tube was used to weigh the compounds, and the corresponding amount of DMSO was added to the EP tube to make the liquid 100mM stock solution and diluted to 30mM,10mM,3mM,1mM, respectively. When in use, the working solution with the concentration of 0.1 mu M,0.3 mu M,1 mu M,10 mu M,30 mu M and 100 mu M can be prepared by diluting the culture medium with the corresponding amount by 1000 times.
4. Experimental procedure
(1) Taking logarithmic phase human colon cancer (HCT-116) cells, mouse melanoma (B16-F10) cells, human acute T lymphoblastic leukemia (Jurkat) cells and human non-small cell lung cancer (A549) cells, digesting, and adjusting cell number concentration to 2.5X10 4 Per mL, 100 μl/well was seeded into 96-well plates. At 37 ℃,5% CO 2 The cells were cultured overnight in a cell incubator until the cells adhered to the wall.
(2) The original medium was aspirated and each group was added with different concentrations of compound, 0.1. Mu.M, 0.3. Mu.M, 1. Mu.M, 10. Mu.M, 30. Mu.M, 100. Mu.M, respectively. The culture was continued in a cell incubator for 72 hours with 0.1% DMSO as a control group.
(3) Mu.l MTT solution was added to each well and incubated in an incubator for 4h.
(4) The medium was discarded, 100 μl DMSO was added per well and the formazan crystals were fully dissolved by shaking for 15 min.
(5) Absorbance at 570nm was measured with an enzyme-linked immunosorbent assay.
(6) The cell growth inhibition was calculated according to the following formula:
inhibition ratio = [ (As-Ab)/(Ac-Ab) ] ×100%
As: absorbance (containing cells, MTT, compounds) of experimental wells
Ac: absorbance (cell-containing, MTT, no compound) of control wells
Ab: absorbance of blank wells (without cell and compound, MTT-containing)
Compound IC was calculated by GraphPad Prism 5 software according to the inhibition of cell proliferation by drug at different doses 50 Values.
The activity measurement results are shown in the following table:
TABLE 2 experimental results of in vitro anticancer cell proliferation Activity
According to the above in vitro experimental results, we can obtain that 23 compounds of the invention can inhibit tumor cell proliferation, and the antiproliferative activity of most compounds is equivalent to that of tubulin inhibitor Colchicine, and is more remarkable than that of histone deacetylase inhibitor SAHA.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (9)

1. A dual target inhibitor of tubulin histone deacetylase, wherein the inhibitor is one or more of the following compounds:
2. use of a tubulin/histone deacetylase dual-target inhibitor according to claim 1 for the manufacture of a medicament for inhibiting tumors.
3. The use according to claim 2, wherein the tumor is colon cancer, melanoma, acute T-lymphoblastic leukemia or non-small cell lung cancer.
4. The use according to claim 3, wherein the tumour is colon cancer and the inhibitor is selected from one or more of the following compounds: compound 3-2, compound 3-5, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound 3-16, compound 3-17, compound 3-21, compound 3-23.
5. The use according to claim 4, wherein the tumour is colon cancer and the inhibitor is compound 3-12.
6. The use according to claim 3, wherein the tumour is melanoma and the inhibitor is one or more of the following compounds: 3-8, 3-9, 3-11, 3-12, 3-15, 3-16, 3-21 and 3-23.
7. The use according to claim 6, wherein the inhibitor is one or both of the following compounds: 3-8 of a compound and 3-12 of a compound.
8. The use according to claim 3, wherein the tumour is acute T-lymphoblastic leukaemia and the inhibitor is one or more of the following compounds: 3-6, 3-8, 3-9, 3-10, 3-11, 3-12, 3-16, 3-17, 3-20, and 3-21.
9. The use according to claim 3, wherein the tumour is non-small cell lung cancer and the inhibitor is one or both of the following compounds: 3-8 of a compound and 3-12 of a compound.
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CN108218855A (en) * 2018-03-12 2018-06-29 桑文军 A kind of novel tubulin inhibitor and its application in antitumor drug
CN111943892A (en) * 2019-05-17 2020-11-17 上海中泽医药科技有限公司 Histone deacetylase subtype inhibitor thioacetylarylamine compound and application thereof

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CN108218855A (en) * 2018-03-12 2018-06-29 桑文军 A kind of novel tubulin inhibitor and its application in antitumor drug
CN111943892A (en) * 2019-05-17 2020-11-17 上海中泽医药科技有限公司 Histone deacetylase subtype inhibitor thioacetylarylamine compound and application thereof

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