CN108451939B - 2,4-二硝基苯磺酰胺类化合物的用途 - Google Patents

2,4-二硝基苯磺酰胺类化合物的用途 Download PDF

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CN108451939B
CN108451939B CN201810457188.0A CN201810457188A CN108451939B CN 108451939 B CN108451939 B CN 108451939B CN 201810457188 A CN201810457188 A CN 201810457188A CN 108451939 B CN108451939 B CN 108451939B
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张保新
房建国
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Lanzhou University
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Abstract

本发明公开了2,4‑二硝基苯磺酰胺类化合物的新用途，即2,4‑二硝基苯磺酰胺类化合物用于制备硫氧还蛋白还原酶抑制剂的用途，该类化合物为具有如下结构通式的化合物或其药学上可接受的盐：
Figure DDA0001659972080000011
其中，A为3～10元环；R为氢、取代或未取代的脂肪烃基、取代或未取代的脂环烃基、取代或未取代的脂杂环烃基、取代或未取代的芳基、取代或未取代的杂芳基；R1为取代或未取代的脂肪烃基、取代或未取代的脂环烃基、取代或未取代的脂杂环烃基、取代或未取代的芳基、取代或未取代的杂芳基。本发明可为癌症靶向治疗提供一种新的策略。

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2,4-二硝基苯磺酰胺类化合物的用途
技术领域
本发明属于医药领域，具体涉及2,4-二硝基苯磺酰胺类化合物的用途。
背景技术
癌症是严重威胁人类健康的常见疾病，位居人类三大主要致死疾病之首，是目前我国乃至世界范围内仍未解决的首要难题。目前，手术治疗、放射治疗与药物治疗是人类治疗癌症的三条有效途径，其中，化学药物治疗在癌症治疗中起着不可替代的作用。硫氧还蛋白还原酶(TrxR)是一种含硒蛋白，它与NADPH及它的底物硫氧还蛋白(Trx)一起构成了硫氧还蛋白***。该***在细胞增殖、分化和死亡等生理过程中发挥着非常重要的作用。大量研究表明，与正常组织相比，TrxR在多种肿瘤细胞中都处于过表达状态，通过化学药物抑制TrxR的活性已经成为一种有效的癌症靶向治疗策略。
发明内容
本发明的目的在于根据上述背景技术的现状，提供了2,4-二硝基苯磺酰胺类化合物在制备硫氧还蛋白还原酶抑制剂中的新用途。
为了解决上述技术问题，本发明提供了如下的技术方案：
2,4-二硝基苯磺酰胺类化合物的用途，所述2,4-二硝基苯磺酰胺类化合物为具有如下结构通式的化合物或其药学上可接受的盐：
Figure BDA0001659972060000011
Figure BDA0001659972060000021
其中，
A为3～10元环；
R为氢、取代或未取代的脂肪烃基、取代或未取代的脂环烃基、取代或未取代的脂杂环烃基、取代或未取代的芳基、取代或未取代的杂芳基；
R1为取代或未取代的脂肪烃基、取代或未取代的脂环烃基、取代或未取代的脂杂环烃基、取代或未取代的芳基、取代或未取代的杂芳基；
其特征在于，所述2,4-二硝基苯磺酰胺类化合物用于制备硫氧还蛋白还原酶抑制剂的用途。
优选地，所述A为包括0、1、2或3个O、N和/或S杂原子的5～6元环。
优选地，所述2,4-二硝基苯磺酰胺类化合物为具有如下结构式之一的化合物或其药学上可接受的盐：
Figure BDA0001659972060000022
Figure BDA0001659972060000031
Figure BDA0001659972060000041
Figure BDA0001659972060000051
Figure BDA0001659972060000061
Figure BDA0001659972060000071
一种用于抑制硫氧还蛋白还原酶的组合物，包括对硫氧还蛋白还原酶具有抑制活性的如上所述的2,4-二硝基苯磺酰胺类化合物，以及药物上可接受的辅料。
优选地，所述2,4-二硝基苯磺酰胺类化合物为具有如下结构式之一的化合物或其药学上可接受的盐：
Figure BDA0001659972060000072
Figure BDA0001659972060000073
附图说明
附图用来提供对本发明的进一步理解，并且构成说明书的一部分，与本发明的实施例一起用于解释本发明，并不构成对本发明的限制。在附图中：
图1是部分2,4-二硝基苯磺酰胺类化合物细胞外抑制硫氧还蛋白还原酶活性；
图2是化合物7细胞外对各种酶的抑制活性。
具体实施方式
以下结合附图对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
本发明的2,4-二硝基苯磺酰胺类化合物具有如下结构通式的化合物或其药学上可接受的盐：
Figure BDA0001659972060000081
其中，
A为3～10元环；
R为氢、取代或未取代的脂肪烃基、取代或未取代的脂环烃基、取代或未取代的脂杂环烃基、取代或未取代的芳基、取代或未取代的杂芳基；
R1为取代或未取代的脂肪烃基、取代或未取代的脂环烃基、取代或未取代的脂杂环烃基、取代或未取代的芳基、取代或未取代的杂芳基。
所述取代或未取代的脂肪烃基的例子如：C1-C20烷基，烯基C1-C20烷基、炔基C1-C20烷基、对乙氧基苯基C1-C20烷基、邻乙氧基苯基C1-C20烷基、间乙氧基苯基C1-C20烷基、对甲氧基苯基C1-C20烷基、邻甲氧基苯基C1-C20烷基、间甲氧基苯基C1-C20烷基、苯基C1-C20烷基、卤代苯基C1-C20烷基、萘基C1-C20烷基、呋喃基C1-C20烷基、四氢化呋喃基C1-C20烷基、哌啶基C1-C20烷基、环烷基C1-C20烷基、噻吩基C1-C20烷基、吡啶基C1-C20烷基、吡咯基C1-C20烷基、吗啉基C1-C20烷基、哌嗪基C1-C20烷基、C1-C20烷基酰基、
Figure BDA0001659972060000082
C1-C20烷氧羰基C1-C20烷基(如
Figure BDA0001659972060000083
Figure BDA0001659972060000084
)等。
所述取代或未取代的脂环烃基的例子如：环戊基、环己基、C1-C20烷基环戊基、C1-C20烷基环己基、卤代环戊基、卤代环己基、C1-C20烷氧基环戊基、C1-C20烷氧基环己基等。
所述取代或未取代的脂杂环烃基的例子如：四氢呋喃基、四氢吡喃基、四氢噻吩基、硫化环戊烷基、哌啶基、吗啉基、哌嗪基，或被一个或多个C1-C20烷基、C1-C20烷氧基、C1-C20烷氧羰基、卤原子取代的四氢呋喃基、四氢吡喃基、四氢噻吩基、硫化环戊烷基、哌啶基、吗啉基、哌嗪基等。
所述取代或未取代的芳基或杂芳基的例子如：苯基、萘基、C1-C20烷基苯基、C1-C20烷氧基苯基、C1-C20烷氧羰基苯基、卤代苯基、呋喃基、C1-C20烷基呋喃基、C1-C20烷氧基呋喃基、C1-C20烷氧羰基呋喃基、卤代呋喃基、噻吩基、C1-C20烷基噻吩基、C1-C20烷氧基噻吩基、C1-C20烷氧羰基噻吩基、卤代噻吩基、吡啶基、C1-C20烷基吡啶基、C1-C20烷氧基吡啶基、C1-C20烷氧羰基吡啶基、卤代吡啶基、吡咯基、C1-C20烷基吡咯基、C1-C20烷氧基吡咯基、C1-C20烷氧羰基吡咯基、卤代吡咯基、茚基、茚满基、胡椒环基等。
所述的卤为F、Cl、Br、I。
所述的
Figure BDA0001659972060000091
优选具有如下结构式之一：
Figure BDA0001659972060000092
Figure BDA0001659972060000101
本发明的2,4-二硝基苯磺酰胺类化合物并不局限于以下所述的具体实例。、
Figure BDA0001659972060000111
Figure BDA0001659972060000121
Figure BDA0001659972060000131
Figure BDA0001659972060000141
2,4-二硝基苯磺酰胺类化合物的制备：在氩气保护下，将1mmol的胺类化合物溶解于二氯甲烷，然后在冰浴中加入2mmol的三乙胺搅拌15min左右，之后逐滴加入2,4-二硝基苯磺酰氯(1.2mmol)二氯甲烷溶液，反应进程用TLC监测，当反应结束后加入20ml的蒸馏水，用二氯甲烷萃取三次，合并有机相，之后用无水硫酸钠干燥，最后用柱层析分离得到目标化合物。
2,4-dinitro-N-butylbenzenesulfonamide(1)1H NMR(400MHz,DMSO-d6)δ:8.88(d,J＝2.0Hz,1H),8.65(dd,J＝8.8,2.4Hz,1H),8.43(s,1H),8.24(d,J＝8.4Hz,1H),2.95(t,2H),1.44(s,2H),1.30(s,2H),0.84(t,3H)；13C NMR(100MHz,DMSO-d6)δ:150.06,148.08,138.31,131.62,127.68,120.47,42.86,31.60,19.53,13.81；mp:58-59℃.
2,4-dinitro-N-isobutylbenzenesulfonamide(2)1H NMR(400MHz,DMSO-d6)δ:8.86(d,J＝2.8Hz,1H),8.80(s,1H),8.28(dd,J＝9.6,2.4Hz,1H),7.22(d,J＝9.6Hz,1H),3.52(m,2H),1.73(m,1H),1.56(m,2H),0.95(s,3H),0.93(s,3H)；13C NMR(100MHz,DMSO-d6)δ:148.36,135.98,130.35,124.38,113.84,41.87,37.49,25.96,22.38；mp:79-80℃.
1-((2,4-dinitrophenyl)sulfonyl)piperidine(3)1H NMR(400MHz,DMSO-d6)δ:8.97(d,J＝2.0Hz,1H),8.58(dd,J＝8.8,2.4Hz,1H),8.27(d,J＝8.4Hz,1H),3.23(t,4H),1.58(t,4H),1.50(t,2H)；13C NMR(100MHz,DMSO-d6)δ:149.64,148.30,137.87,132.54,125.87,119.61,47.02,25.50,23.45；mp:138-139℃.
1-((2,4-dinitrophenyl)sulfonyl)-2-methylpiperidine(4)1H NMR(400MHz,DMSO-d6)δ:8.93(d,J＝2.4Hz,1H),8.58(dd,J＝8.8,2.4Hz,1H),8.34(d,J＝8.8Hz,1H),4.17(d,J＝3.2Hz,1H),3.64(dd,J＝13.6,3.2Hz,1H),3.20(m,1H),1.63(m,5H),1.32(m,1H),1.15(d,J＝6.8Hz,3H)；13C NMR(100MHz,DMSO-d6)δ:149.51,139.74,132.42,126.07,119.80,49.83,41.22,30.33,25.51,17.91,16.25；mp:121-122℃.
1-((2,4-dinitrophenyl)sulfonyl)-3-methylpiperidine(5)1H NMR(400MHz,DMSO-d6)δ:8.97(d,J＝2.0Hz,1H),8.58(dd,J＝8.8,2.0Hz,1H),8.28(d,J＝8.4Hz,1H),3.64(m,2H),2.79(m,1H),2.48(t,1H),1.73(m,2H),1.64(m,1H),1.49(m,1H),1.06(m,1H),0.87(d,J＝6.4Hz,3H)；13C NMR(100MHz,DMSO-d6)δ:149.62,137.96,132.52,125.89,119.60,52.99,46.54,31.99,31.02,25.00,18.73；mp:135-136℃.
1-((2,4-dinitrophenyl)sulfonyl)-4-methylpiperidine(6)1H NMR(400MHz,DMSO-d6)δ:8.97(d,J＝2.0Hz,1H),8.58(dd,J＝8.8,2.4Hz,1H),8.27(d,J＝8.8Hz,1H),3.72(d,J＝12.4Hz,2H),2.80(m,2H),1.71(m,2H),1.49(m,1H),1.17(m,2H),0.89(d,J＝6.4Hz,3H)；13C NMR(100MHz,DMSO-d6)δ:149.63,137.94,132.53,125.88,119.62,46.47,33.62,30.15,21.43；mp:134-135℃.
4-((2,4-dinitrophenyl)sulfonyl)morpholine(7)1H NMR(400MHz,DMSO-d6)δ:9.00(d,J＝2.4Hz,1H),8.60(dd,J＝8.8,2.4Hz,1H),8.28(d,J＝8.8Hz,1H),3.67(t,4H),3.24(t,4H)；13C NMR(100MHz,DMSO-d6)δ:150.69,148.32,134.25,132.77,127.34,120.47,65.97,46.17；mp:143-144℃.
1-((2,4-dinitrophenyl)sulfonyl)pyrrolidine(8)1H NMR(400MHz,DMSO-d6)δ:8.86(d,J＝2.8Hz,1H),8.48(d,J＝6.8Hz,1H),8.29(dd,J＝9.6,2.4Hz,1H),7.29(d,J＝9.6Hz,1H),4.27(m,1H),2.14(m,2H),1.76(m,2H),1.68(m,4H)；13C NMR(100MHz,DMSO-d6)δ:147.91,135.87,130.34,130.14,124.43,114.61,54.76,33.47,24.00；mp:67-68℃
2,4-dinitro-N-benzylbenzenesulfonamide(9)1H NMR(400MHz,DMSO-d6)δ:9.02(t,1H),8.85(d,J＝2.0Hz,1H),8.52(dd,J＝8.8,2.0Hz,1H),8.13(d,J＝8.8Hz,1H),7.28(m,5H),4.22(d,J＝6.0Hz,2H)；13C NMR(100MHz,DMSO-d6)δ:149.88,147.82,138.51,137.34,131.77,129.09,128.73,128.09,127.80,127.45,127.33,120.37,46.72；mp:136-137℃.
2,4-dinitro-N-(2-methoxybenzyl)benzenesulfonamide(10)1H NMR(400MHz,DMSO-d6)δ:8.83(d,J＝2.0Hz,1H),8.76(s,1H),8.52(dd,J＝8.8,2.0Hz,1H),8.09(d,J＝8.4Hz,1H),7.21(m,2H),6.87(m,2H),4.17(s,3H),3.68(s,3H)；13C NMR(100MHz,DMSO-d6)δ:157.28,149.16,147.36,140.08,132.76,130.42,129.93,126.48,123.35,120.12,120.00,109.86,55.15,45.42；mp:156-157℃.
2,4-dinitro-N-(3-methoxybenzyl)benzenesulfonamide(11)1H NMR(400MHz,DMSO-d6)δ:8.99(s,1H),8.85(d,J＝2.0Hz,1H),8.50(dd,J＝8.8,2.4Hz,1H),8.11(d,J＝8.8Hz,1H),7.17(t,1H),6.81(m,3H),4.18(s,2H),3.67(s,3H)；13C NMR(100MHz,DMSO-d6)δ:159.80,149.49,147.69,139.62,136.68,132.49,129.87,126.66,120.34,120.15,113.85,113.31,55.20,48.01；mp:101-102℃.
2,4-dinitro-N-(4-methoxybenzyl)benzenesulfonamide(12)1H NMR(400MHz,DMSO-d6)δ:8.91(s,1H),8.83(d,J＝2.0Hz,1H),8.50(dd,J＝8.4,2.0Hz,1H),8.07(d,J＝8.8Hz,1H),7.14(d,J＝8.4Hz,2H),6.79(d,J＝8.4Hz,2H),4.14(d,J＝4.4Hz,2H),3.68(s,3H)；13C NMR(100MHz,DMSO-d6)δ:159.07,149.77,147.75,138.65,131.83,129.59,129.17,127.35,120.30,114.10,55.48,46.32；mp:157-158℃.
1-((2,4-dinitrophenyl)sulfonyl)-1H-pyrrole(13)1HN MR(400MHz,DMSO-d6)δ:12.03(s,1H),8.93(dd,J＝8.4,2.0Hz,1H),8.86(d,J＝2.4Hz,1H),8.64(d,J＝8.8Hz,1H),7.03(d,J＝1.2Hz,1H),6.29(m,1H),6.12(m,1H)；13C NMR(100MHz,DMSO-d6)δ:149.38,148.90,144.95,129.97,129.85,128.46,124.25,121.05,113.42,109.59；mp:148-149℃.
1-((2,4-dinitrophenyl)sulfonyl)-1H-benzo[d]imidazole(14)1H NMR(400MHz,DMSO-d6)δ:9.00(s,1H),8,76(s,1H),8.72(d,J＝8.8Hz,1H),8.65(dd,J＝8.8,2.4Hz,1H),7.86(m,2H),7.52(m,2H)；13C NMR(100MHz,DMSO-d6)δ:152.01,147.94,143.75,142.88,133.58,133.01,130.26,128.44,126.59,126.03,121.79,121.51,112.90；mp:182-184℃.
2,4-dinitro-N-(pyridin-2-yl)benzenesulfonamide(15)1H NMR(400MHz,DMSO-d6)δ:10.33(s,1H),8.81(d,J＝2.4Hz,1H),8.46(m,2H),8.31(dd,J＝4.8,1.2Hz,1H),7.85(m,1H),7.28(d,J＝8.4Hz,1H),7.15(m,1H)；13C NMR(100MHz,DMSO-d6)δ:152.21,148.12,143.37,138.77,138.65,132.67,129.82,123.08,119.79,119.75,115.06；mp:153-154℃.
2,4-dinitro-N-(naphthalen-1-yl)benzenesulfonamide(16)1H NMR(400MHz,DMSO-d6)δ:11.02(s,1H),8.89(d,J＝1.6Hz,1H),8.51(dd,J＝8.8,2.4Hz,1H),8.04(d,J＝8.8Hz,2H),7.95(m,2H),7.52(m,3H),7.30(d,J＝7.2Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:150.35,147.81,137.42,134.36,132.32,131.15,130.39,128.54,128.39,127.46,127.02,126.88,126.06,125.33,120.60；mp:167-168℃.
2,4-dinitro-N-(4-ethoxycarbonylphenyl)benzenesulfonamide(17)1H NMR(400MHz,DMSO-d6)δ:11.56(s,1H),8.90(s,1H),8.60(d,J＝8.8Hz,1H),8.28(dd,J＝8.4,1.6Hz,1H),7.89(t,3H),7.27(t,3H),4.29(m,2H),1.29(t,3H)；13C NMR(100MHz,DMSO-d6)δ:165.43,150.65,148.23,141.07,136.30,132.13,131.43,131.15,127.80,126.33,120.92,119.80,61.07,14.56；mp:183-184℃.
2,4-dinitro-N-phenylbenzenesulfonamide(18)1H NMR(400MHz,DMSO-d6)δ:8.88(d,J＝2.0Hz,1H),8.60(dd,J＝8.8,2.4Hz,1H),8.22(d,J＝8.8Hz,1H),7.32(t,2H),7.15(m,3H)；13C NMR(100MHz,DMSO-d6)δ:150.46,148.28,136.74,136.38,132.00,129.89,127.63,125.74,121.54,120.74；mp:110-111℃.
2,4-dinitro-N-(2-tolyl)benzenesulfonamide(19)1H NMR(400MHz,DMSO-d6)δ:10.35(s,1H),8.91(d,J＝2.0Hz,1H),8.58(dd,J＝8.8,2.4Hz,1H),8.02(d,J＝8.8Hz,1H),7.23(m,3H),7.02(d,J＝7.6Hz,1H),2.10(m,3H)；13C NMR(100MHz,DMSO-d6)δ:149.99,148.24,138.71,133.79,133.11,132.88,131.49,127.93,127.12,126.88,125.64,120.66,17.89；mp:151-152℃.
2,4-dinitro-N-(3-tolyl)benzenesulfonamide(20)1H NMR(400MHz,DMSO-d6)δ:10.96(s,1H),8.88(d,J＝2.4Hz,1H),8.61(dd,J＝8.8,2.4Hz,1H),8.21(d,J＝8.8Hz,1H),7.19(t,1H),6.96(t,3H),2.23(s,3H)；13C NMR(100MHz,DMSO-d6)δ:150.03,148.48,139.98,137.75,134.41,133.51,129.50,128.09,126.73,124.02,120.62,120.22,21.30；mp:140-141℃.
2,4-dinitro-N-(4-tolyl)benzenesulfonamide(21)1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),8.87(d,J＝2.4Hz,1H),8.60(dd,J＝8.8,2.4Hz,1H),8.18(d,J＝8.8Hz,1H),7.11(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,2H),2.21(s,3H)；13C NMR(100MHz,DMSO-d6)δ:150.40,148.30,136.80,135.28,133.62,132.01,130.30,127.56,122.16,120.69,20.76；mp:120-121℃.
2,4-dinitro-N-(2-methoxyphenyl)benzenesulfonamide(22)1H NMR(400MHz,DMSO-d6)δ:10.25(s,1H),8.86(d,J＝2.4Hz,1H),8.62(dd,J＝8.8,2.0Hz,1H),8.15(d,J＝8.8Hz,1H),7.26(m,1H),7.19(m,1H),6.97(m,2H),3.44(s,3H)；13C NMR(100MHz,DMSO-d6)δ:150.76,138.68,132.99,127.31,126.65,123.99,123.67,121.35,120.68,110.93,55.71；mp:172-173℃.
2,4-dinitro-N-(3-methoxyphenyl)benzenesulfonamide(23)1H NMR(400MHz,DMSO-d6)δ:11.06(s,1H),8.89(d,J＝2.4Hz,1H),8.62(dd,J＝8.8,2.4Hz,1H),8.23(d,J＝8.8Hz,1H),7.22(t,1H),6.72(m,3H),3.69(s,3H)；13C NMR(100MHz,DMSO-d6)δ:160.56,133.55,130.47,130.10,126.73,120.61,115.02,112.50,109.28,107.96,104.04,101.14,55.09；mp:156-157℃.
2,4-dinitro-N-(4-methoxyphenyl)benzenesulfonamide(24)1H NMR(400MHz,DMSO-d6)δ:11.64(s,1H),8.86(s,1H),8.59(d,J＝7.2Hz,1H),8.14(d,J＝7.6Hz,1H),7.06(d,J＝6.8Hz,2H),6.87(d,J＝6.8Hz,2H),3.69(s,3H)；13C NMR(100MHz,DMSO-d6)δ:157.85,150.35,148.26,136.85,132.10,128.51,127.48,125.12,120.59,115.02,55.68；mp:136-137℃.
2,4-dinitro-N-(2,5-dimethoxyphenyl)benzenesulfonamide(25)1H NMR(400MHz,DMSO-d6)δ:10.30(s,1H),8.87(d,J＝2.4Hz,1H),8.62(dd,J＝8.4,2.0Hz,1H),8.17(d,J＝8.8Hz,1H),6.91(d,J＝8.8Hz,1H),6.82(m,2H),3.68(s,3H),3.40(s,3H)；13CNMR(100MHz,DMSO-d6)δ:153.97,144.70,138.55,133.05,126.70,124.67,120.72,111.70,111.49,109.53,56.22,55.84；mp:140-141℃.
2,4-dinitro-N-(2-chlorophenyl)benzenesulfonamide(26)1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),8.90(d,J＝2.4Hz,1H),8.61(dd,J＝8.4,2.0Hz,1H),8.12(d,J＝8.8Hz,1H),7.49(m,1H),7.35(m,2H),7.28(m,1H)；13C NMR(100MHz,DMSO-d6)δ:150.18,148.21,138.38,132.56,131.93,129.85,128.19,128.04,127.33,127.02,126.07,121.01；mp:134-135℃.
2,4-dinitro-N-(3-chlorophenyl)benzenesulfonamide(27)1H NMR(400MHz,DMSO-d6)δ:11.16(s,1H),8.90(d,J＝2.4Hz,1H),8.63(dd,J＝8.8,2.4Hz,1H),8.26(d,J＝8.8Hz,1H),7.36(m,1H),7.21(m,2H),7.12(m,1H)；13C NMR(100MHz,DMSO-d6)δ:150.64,148.26,138.01,136.34,134.08,132.01,131.63,127.83,125.46,120.87,120.63,119.45；mp:153-154℃.
2,4-dinitro-N-(2-fluorophenyl)benzenesulfonamide(28)1H NMR(400MHz,DMSO-d6)δ:10.91(s,1H),8.90(d,J＝2.0Hz,1H),8.64(dd,J＝8.8,2.4Hz,1H),8.19(d,J＝8.8Hz,1H),7.35(m,1H),7.27(m,2H),7.21(m,1H)；13C NMR(100MHz,DMSO-d6)δ:158.47,155.99,150.65,148.08,137.73,132.25,129.67,129.60,129.03,127.83,125.62,123.23,120.80,117.05,116.86；mp:160-162℃.
2,4-dinitro-N-(3-fluorophenyl)benzenesulfonamide(29)1H NMR(400MHz,DMSO-d6)δ:11.34(s,1H),8.90(d,J＝2.0Hz,1H),8.62(dd,J＝8.8,2.4Hz,1H),8.27(d,J＝8.8Hz,1H),7.38(m,1H),6.98(m,3H)；13C NMR(100MHz,DMSO-d6)δ:163.88,161.45,150.62,148.26,136.35,132.02,131.77,131.67,127.80,120.85,116.80,112.33,112.13,108.03,107.78；mp:160-162℃.
2,4-dinitro-N-(4-fluorophenyl)benzenesulfonamide(30)1H NMR(400MHz,DMSO-d6)δ:10.99(s,1H),8.88(d,J＝2.0Hz,1H),8.61(dd,J＝8.4,2.0Hz,1H),8.19(d,J＝8.8Hz,1H),7.16(s,2H),7.15(s,2H)；13C NMR(100MHz,DMSO-d6)δ:161.48,159.06,150.49,148.23,136.53,132.46,132.08,127.63,124.73,124.64,120.69,116.78,116.56；mp:127-128℃.
实施例1 2,4-二硝基苯磺酰胺类化合物对HeLa细胞的细胞毒活性
药物：上述所制备的目标化合物1～30。
实验方法：于96孔板中，每孔加入5000个细胞，之后用不同浓度的不同的药物作用细胞72h，最后用MTT法测定细胞毒活性，计算化合物的IC50值。
表1.所有化合物在HeLa细胞中的细胞毒活性
Figure BDA0001659972060000201
实施例2 2,4-二硝基苯磺酰胺类化合物体外抑制硫氧还蛋白还原酶活性
药物：选取上述对HeLa细胞具有较高细胞毒性的目标化合物2,3,4,7,8,10,11,12。
实验方法：将还原型烟酰胺腺嘌呤二核苷磷酸(NADPH)、缓冲溶液(TE)和硫氧还蛋白还原酶(TrxR)在室温作用5min后，接着将药物(所有药物的浓度固定为50nM)加入到96孔板中，总体积为50μL，重复两个，在室温下孵育一定的时间后加入50μL含有DTNB和NADPH的混合液于每孔中，然后立即测定前4min内412nm吸光度值的增加，10s读一次数，共25次。以最大浓度的DMSO作为对照，活性用相比对照的百分比来表示，结果如图1所示。
实验结果表明目标化合物2,3,4,7,8,10,11,12在体外均能够很好的抑制硫氧还蛋白还原酶的活性。
目标化合物2,3,4,7,8,10,11,12的结构式分别如下：
Figure BDA0001659972060000202
Figure BDA0001659972060000211
实施例3 2,4-二硝基苯磺酰胺类化合物体外对各种酶的抑制活性
药物：以上述目标化合物7
Figure BDA0001659972060000212
为例。
实验方法：按照文献“Dongzhu Duan,Baoxin Zhang,Juan Yao,Yaping Liu,JinyuSun,Chunpo Ge,Shoujiao Peng,Jianguo Fang；Free Radical Biol.Med.2014,69,15-25”的方法测定化合物7在体外对各种酶活性的抑制情况(U498C TrxR：该酶是将TrxR的498位的Sec突变为Cys。GR:谷胱甘肽还原酶，该酶是一种与TrxR拥有相似结构的酶，同时也是谷胱甘肽***的重要组成部分。GPx：谷胱甘肽过氧化物酶，是一种含硒半胱氨酸的酶)。结果如图2所示。
实验结果说明化合物7是通过选择性作用硒半胱氨酸来抑制硫氧还蛋白还原酶的活性。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (1)

1.2,4-二硝基苯磺酰胺类化合物用于制备治疗子***药物的用途，所述2,4-二硝基苯磺酰胺类化合物结构式如下：
Figure FDF0000012958590000011
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