CN108148053A - 磺胺三氮唑类Tubulin聚合抑制剂及其合成方法和应用 - Google Patents

磺胺三氮唑类Tubulin聚合抑制剂及其合成方法和应用 Download PDF

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CN108148053A
CN108148053A CN201711406285.9A CN201711406285A CN108148053A CN 108148053 A CN108148053 A CN 108148053A CN 201711406285 A CN201711406285 A CN 201711406285A CN 108148053 A CN108148053 A CN 108148053A
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sulfanilamide
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CN108148053B (zh
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付冬君
李萍
杨佳佳
张赛扬
张雁冰
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Zhengzhou University
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

本发明公开了一类含磺胺‑1,2,3‑三氮唑类化合物、它们的制备方法及其在Tubulin聚合抑制剂的应用，属于抗肿瘤药物化学领域。本发明利用经典的点击化学将磺胺母核与1,2,3‑三氮唑活性单元结合，简单高效，绿色环保地合成了磺胺‑1,2,3‑三氮唑类化合物。其具有如下结构通式：

Description

磺胺三氮唑类Tubulin聚合抑制剂及其合成方法和应用
技术领域
本发明涉及抗肿瘤药物化学领域，具体涉及一类新型磺胺-1,2,3-三氮唑类化合物、它们的制备方法及其作为一类新的抗肿瘤药物先导化合物的应用。
背景技术
微管是大多数真核生物细胞骨架的重要组分，微管不仅在维持细胞形态、保持细胞内部结构的有序性中起重要作用，而且与细胞内的物质运输、细胞运动、细胞的分化发育以及细胞分裂繁殖等生命活动密切相关。微管蛋白(Tubulin)的重要生理作用使其在肿瘤领域中成为重要的靶点。通过拼接原理，合成一系列新型磺胺-1,2,3-三氮唑类化合物，有利于抗肿瘤活性筛选，对开发抗肿瘤药物具有重要意义。目前未见此类化合物的相关报道。
发明内容
本发明目的在于提供一类具有抗肿瘤活性的新型磺胺-1,2,3-三氮唑类化合物。
本发明的另一个目的在于提供一种简单高效，绿色环保的合成新型磺胺-1,2,3-三氮唑类化合物的方法。
本发明的再一个目的在于提供所述化合物在制备抗肿瘤药物及tubulin聚合抑制剂的作用。
本发明所述一类新型磺胺-1,2,3-三氮唑类化合物具有如下通式：
R1为C1-3烷氧基、C1-3烷基、氰基或苯氧基；
Aryl为香豆素环，噻吩或取代噻吩环，苯环或取代的苯环；所述噻吩取代基选卤素，所述苯环取代基选卤素，C1-4烷基。
优选：R1为甲氧基、甲基、氰基或苯氧基；
Aryl为噻吩或卤素单取代的噻吩环，苯环或取代的苯环；所述苯环取代基选溴，氯，甲基，乙基，丙基或丁基。
所述磺胺-1,2,3-三氮唑类化合物选用如下所示化合物：
本发明所述新型磺胺-1,2,3-三氮唑类化合物主要通过下列步骤制得：
(1)化合物(I)的制备方法：
溶剂中，将含芳香环的磺酰氯在碱性条件下和炔丙胺反应得到化合物I，所用的碱是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、十二水磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠中的一种；所用的溶剂为乙醇、甲醇、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、二氯甲烷中之一或其中任意两种的混合物；反应在0-90℃之间进行。
(2)通式(II)的制备方法：
溶剂中，化合物I与取代苄基叠氮化合物在五水硫酸铜及抗坏血酸钠存在下反应，所用的溶剂为丙酮、乙腈、乙醇、甲醇、异丙醇、四氢呋喃、蒸馏水中之一或其中任意两种或三种的混合物；反应在0-90℃之间进行。
本发明优点及创新点：采用拼接原理，将磺胺母核和1,2,3-三氮唑活性单元结合，合成了系列新型磺胺-1,2,3-三氮唑类化合衍生物，并对其进行了抗肿瘤活性筛选及tubulin聚合抑制活性评估。该类化合物体外抗癌活性试验表明对多种肿瘤细胞PC-3、MCF-7、MGC-803均具有一定的抑制作用，同时对Tubulin的聚合有显著的抑制作用，特别是化合物IIf，其微管蛋白聚合抑制活性的IC50值为2.41μM，可作为进一步开发的候选或者先导化合物，应用于制备抗肿瘤药物。合成方法简单高效，绿色环保，收率达80％以上。
具体实施方式
以下通过实施例对本发明进行更好地说明。
实施例1化合物(I)的制备
将噻吩磺酰氯(0.96g,5mmol)和无水碳酸钾(1.38g,10mmol)混合，加入10mL的二氯乙烷，体系中加入炔丙胺(5mmol)，升温到60℃，继续反应。TLC监测反应进程，待反应结束后，向体系中加入蒸馏水，淬灭反应，然后用二氯乙烷萃取3次，再用饱和食盐水反萃二氯乙烷相3次，每次10mL，最后有机相用无水硫酸镁干燥，滤除硫酸镁，滤液减压蒸馏除去二氯乙烷。所得粗产品用硅胶柱柱层析分离纯化，石油醚/乙酸乙酯＝10:1洗脱，得化合物(I)。
实施例2通式(II)的制备
加入化合物(I)(5mmol)和3-甲氧基苯基苄基叠氮化合物(6mmol)，然后加入20mL THF/H2O(10ml/10ml)溶解，最后加入五水硫酸铜(1mmol)和抗坏血酸钠(0.5mmol)，室温搅拌过夜。TLC监测反应进程，待反应结束后，向体系中加入蒸馏水，然后用二氯乙烷萃取6次，再用饱和食盐水反萃二氯乙烷相3次，每次10mL，最后有机相用无水硫酸镁干燥，滤除硫酸镁，滤液减压蒸馏除去二氯乙烷。所得粗产品用硅胶柱柱层析分离纯化，石油醚/乙酸乙酯＝7:1洗脱，得化合物(IIa)。
采用化合物IIa合成方法制备化合物IIb-IIl。
IIa：白色固体,yield：80.1％,mp:104-106℃.1H NMR(400MHz,DMSO)δ8.34(s,1H,NH),7.95(s,1H,Ar),7.88(dd,J＝5.0,1.3Hz,1H,Ar),7.57(dd,J＝3.7,1.3Hz,1H,Ar),7.40(tt,J＝9.4,5.1Hz,3H,Ar),7.15(ddd,J＝11.0,6.2,2.3Hz,2H,Ar),7.08–6.97(m,4H,Ar),6.94(dd,J＝8.1,1.8Hz,1H,Ar),5.54(s,2H,PhCH2),4.12(s,2H,NHCH2).13C NMR(100MHz,DMSO)δ157.38,156.69,144.03,141.65,138.60,132.96,132.18,130.90,130.61,128.10,124.21,123.98,123.34,119.27,118.53,118.43(Ar),52.77(PhCH2),38.75(NHCH2).HRMS(ESI)calcd for C20H19N4O3S2[M+H]+:427.0898,found:427.0899.IR:3176,3100,1489,1331,1253,1215,1151,750,688,593,529cm-1.
IIb：白色固体,yield：88.3％,mp:110-111℃.1H NMR(400MHz,DMSO)δ8.52(s,1H,NH),8.00(s,1H,Ar),7.55–7.29(m,4H,Ar),7.25–7.10(m,2H,Ar),7.07–6.97(m,4H,Ar),6.98–6.88(m,1H,Ar),5.55(s,2H,PhCH2),4.15(s,2H,NHCH2).13C NMR(100MHz,DMSO)δ157.39,156.68,143.77,140.18,138.60,134.89,132.04,130.91,130.61,128.30,124.21,124.09,123.28,119.27,118.52,118.43(Ar),52.78(PhCH2),38.66(NHCH2).HRMS(ESI)calcd forC20H18ClN4O3S2[M+H]+:461.0512,found:461.0509.IR:3120,1488,1412,1328,1252,1159,786,685,612,523cm-1.
IIc：白色固体,yield：89.1％,mp:111-112℃.1H NMR(400MHz,DMSO)δ8.50(s,1H,NH),8.00(s,1H,Ar),7.48–7.33(m,4H,Ar),7.29(d,J＝4.0Hz,1H,Ar),7.16(t,J＝7.4Hz,1H,Ar),7.08–6.98(m,4H,Ar),6.94(dd,J＝8.1,1.8Hz,1H,Ar),5.55(s,2H,PhCH2),4.14(s,2H,NHCH2).13C NMR(100MHz,DMSO)δ157.39,156.68,143.79,142.76,138.60,132.79,131.69,130.91,130.61,124.21,124.09,123.28,119.28,118.70,118.52,118.43(Ar),52.78(PhCH2),38.67(NHCH2).HRMS(ESI)calcd for C20H18BrN4O3S2[M+H]+:505.0007,found:505.0004.IR:3118,1489,1403,1328,1253,1158,1086,819,786,749,605,522cm-1.
IId：白色固体,yield：81.9％,mp:144-146℃.1H NMR(400MHz,DMSO)δ8.28(s,1H,NH),8.19(dd,J＝9.1,5.9Hz,2H,Ar),8.00–7.87(m,2H,Ar),7.53(d,J＝8.7Hz,1H,Ar),7.38(dt,J＝16.3,7.9Hz,3H,Ar),7.16(t,J＝7.4Hz,1H,Ar),7.06–6.96(m,4H,Ar),6.93(d,J＝8.2Hz,1H,Ar),6.63(d,J＝9.6Hz,1H,Ar),5.51(s,2H,PhCH2),4.10(s,2H,NHCH2).13C NMR(100MHz,DMSO)δ159.75,157.37,156.67,156.01,144.08,144.01,138.57,136.90,130.85,130.60,130.12,127.96,124.21,124.00,123.19,119.27,119.25,118.46,118.40,118.07,117.93(Ar),52.72(PhCH2),38.55(NHCH2).HRMS(ESI)calcd for C25H21N4O5S[M+H]+:489.1237,found:489.1233.IR:3256,3137,1744,1488,1321,1252,1157,1107,834,751,601cm-1.
IIe:白色固体,yield：86.8％,mp:127-130℃.1H NMR(400MHz,DMSO)δ8.14(s,1H,NH),7.89(s,1H,Ar),7.77(dd,J＝5.3,3.4Hz,2H,Ar),7.69–7.47(m,3H,Ar),7.47–7.27(m,3H,Ar),7.16(t,J＝7.4Hz,1H,Ar),7.09–6.84(m,5H,Ar),5.51(s,2H,PhCH2),4.05(s,2H,NHCH2).13C NMR(100MHz,DMSO)δ157.37,156.69,144.17,140.82,138.58,132.86,130.89,130.61,129.57,126.97,124.21,123.92,123.32,119.26,118.52,118.42(Ar),52.74(PhCH2),38.55(NHCH2).HRMS(ESI)calcd for C22H21N4O3S[M+H]+:421.1338,found:421.1334.IR:3269,3123,1587,1495,1322,1253,1215,1157,690,587cm-1.
IIf：白色固体,yield：86.5％,mp:118-121℃.1H NMR(400MHz,DMSO)δ8.03(s,1H,NH),7.91(s,1H,Ar),7.66(d,J＝8.2Hz,2H,Ar),7.52–7.27(m,5H,Ar),7.16(t,J＝7.4Hz,1H,Ar),7.08–6.97(m,4H,Ar),6.94(dd,J＝8.0,2.1Hz,1H,Ar),5.52(s,2H,PhCH2),4.01(s,2H,NHCH2),2.37(s,3H,CH3).13C NMR(100MHz,DMSO)δ156.88,156.20,143.76,142.62,138.11,137.45,130.37,130.10,129.51,126.56,123.70,123.42,122.78,118.76,118.01,117.92(Ar),52.25(PhCH2),38.07(NHCH2),20.93(CH3).HRMS(ESI)calcd for C23H23N4O3S[M+H]+:435.1497,found:435.1491.IR:3294,3251,1590,1491,1328,1265,1160,819,755,687,557cm-1.
IIg:白色固体,yield：89.3％,mp:137-139℃.1H NMR(400MHz,DMSO)δ8.05(s,1H,NH),7.95(s,1H,Ar),7.72(d,J＝8.5Hz,2H,Ar),7.59(d,J＝8.6Hz,2H,Ar),7.39(dt,J＝11.7,8.1Hz,3H,Ar),7.16(t,J＝7.4Hz,1H,Ar),7.10–6.84(m,5H,Ar),5.53(s,2H,PhCH2),4.02(s,2H,NHCH2),1.30(s,9H,CH3).13C NMR(100MHz,DMSO)δ157.39,156.68,155.88,144.32,138.64,137.88,130.89,130.60,126.94,126.46,124.21,123.98,123.26,119.27,118.46,118.41(Ar),52.76(PhCH2),38.61(NHCH2),35.30(C(CH3)3),31.28(C(CH3)3).HRMS(ESI)calcd for C26H29N4O3S[M+H]+:477.1967,found:477.1960.IR:3268,1593,1488,1322,1242,1163,1047,754,570cm-1.
IIh:白色固体,yield：88.7％,mp:111-113℃.1H NMR(400MHz,DMSO)δ7.95(s,1H,NH),7.70(s,1H,Ar),7.48–7.28(m,3H,Ar),7.17(dd,J＝10.6,4.2Hz,1H,Ar),7.06–6.89(m,7H,Ar),5.48(s,2H,PhCH2),4.04(s,2H,NHCH2),2.50(s,6H,CH3),2.22(s,3H,CH3).13C NMR(100MHz,DMSO)δ157.34,156.71,144.46,141.83,138.74,138.60,134.94,132.01,130.87,130.61,124.20,123.61,123.26,119.22,118.47,118.43(Ar),52.65(PhCH2),37.67(NHCH2),22.98(CH3),20.84(CH3).HRMS(ESI)calcd for C25H27N4O3S[M+H]+:463.1807,found:463.1804.IR:3307,3269,1587,1488,1326,1257,1243,1154,736,657cm-1.
IIi:白色固体,yield：80.8％,mp:97-99℃.1H NMR(400MHz,DMSO)δ8.41(s,1H,NH),7.91(dd,J＝7.8,1.5Hz,1H,Ar),7.83(s,1H,Ar),7.61–7.48(m,2H,Ar),7.48–7.32(m,4H,Ar),7.17(t,J＝7.4Hz,1H,Ar),7.10–6.89(m,5H,Ar),5.50(s,2H,PhCH2),4.17(s,2H,NHCH2).13C NMR(100MHz,DMSO)δ157.36,156.70,144.14,138.53,138.49,134.27,131.99,131.05,130.89,130.79,130.62,127.91,124.21,123.83,123.34,119.26,118.54,118.44(Ar),52.67(PhCH2),38.31(NHCH2).HRMS(ESI)calcd for C22H20ClN4O3S[M+H]+:455.0948,found:455.0945.IR:3137,1593,1489,1451,1332,1253,1212,1157,758,688,585cm-1.
IIj:白色固体,yield：88.1％,mp:145-147℃.1H NMR(400MHz,DMSO)δ8.03(s,1H,NH),7.98(s,1H,Ar),7.83(td,J＝4.6,1.4Hz,1H,Ar),7.77(s,1H,Ar),7.66(d,J＝8.2Hz,2H,Ar),7.60(d,J＝5.0Hz,2H,Ar),7.34(d,J＝8.0Hz,2H,Ar),5.61(s,2H,PhCH2),4.02(s,2H,NHCH2),2.37(s,3H,CH3).13C NMR(100MHz,DMSO)δ143.89,142.62,137.55,137.44,132.88,131.95,131.56,130.03,129.50,126.56,123.62,118.40,111.64(Ar),51.70(PhCH2),38.05(NHCH2),20.93(CH3).HRMS(ESI)calcd for C18H18N5O2S[M+H]+:368.1181,found:368.1181.IR:3265,2217,1430,1323,1160,1049,889,709,546cm-1.
IIk:白色固体,yield：87.7％,mp:145-148℃.1H NMR(400MHz,DMSO)δ8.01(t,J＝6.0Hz,1H,NH),7.87(s,1H,Ar),7.66(d,J＝8.1Hz,2H,Ar),7.34(d,J＝8.0Hz,2H,Ar),7.25(t,J＝7.5Hz,1H,Ar),7.14(dd,J＝15.2,7.5Hz,2H,Ar),7.06(d,J＝7.6Hz,1H,Ar),5.47(s,2H,PhCH2),4.00(d,J＝6.0Hz,2H,NHCH2),2.37(s,3H,CH3),2.29(s,3H,CH3).13C NMR(100MHz,DMSO)δ143.70,142.61,137.92,137.44,135.83,129.51,128.73,128.61,128.55,126.57,125.06,123.27(Ar),52.69(PhCH2),38.09(NHCH2),20.94(CH3),20.89(CH3).HRMS(ESI)calcd for C18H21N4O2S[M+H]+:357.1388,found:357.1385.IR:3258,3121,1452,1325,1160,1098,772,669,558cm-1.
IIl:白色固体,yield：82.8％,mp:112-114℃.1H NMR(400MHz,DMSO)δ8.02(s,1H,NH),7.89(s,1H,Ar),7.66(d,J＝8.2Hz,2H,Ar),7.34(d,J＝8.1Hz,2H,Ar),7.28(t,J＝7.9Hz,1H,Ar),6.99–6.85(m,2H,Ar),6.82(d,J＝7.6Hz,1H,Ar),5.49(s,2H,PhCH2),4.01(s,2H,NHCH2),3.74(s,3H,OCH3),2.37(s,3H,CH3).13C NMR(100MHz,DMSO)δ159.40,143.72,142.62,137.45,137.38,129.84,129.51,126.56,123.34,120.00,113.79,113.37(Ar),55.08(OCH3),52.60(PhCH2),38.08(NHCH2),20.92(CH3).HRMS(ESI)calcd for C18H21N4O3S[M+H]+:373.1339,found:373.1334.IR:3294,3247,1600,1322,1286,1265,1091,1040,775,668,557cm-1.。
实施例3上述化合物的抗肿瘤活性测定：
筛选所用化合物均是由本发明合成、纯化而得；样品储备液：称取3-5mg样品置于1.5mLEP管中，然后用DMSO配制成浓度是128×103μg/mL的溶液，4℃保存放置，实验时根据所需浓度利用培养基稀释。取对数生长期的细胞，消化计数后，用培养基调整细胞密度，以4000-5000个cell/孔接种至96孔板中，每孔150μL，培养24h后，弃去培养基，加入用培养基稀释好的药物(50μg/mL、100μg/mL)，每个浓度设6个复孔，另设空白对照组及阴性对照组。药物作用72h后，每孔加入20μLMTT，继续培养4h后，吸去液体，加入150mL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率，计算公式如下：抑制率(％)＝(1-给药组吸光度值/空白组吸光度值)×100％。50μg/mL时抑制率大于50％的样品，重新设置浓度进行细筛。即将待测样品以0.25μg/mL、0.5μg/mL、1μg/mL、2μg/mL、4μg/mL、8μg/mL、16μg/mL、32μg/mL浓度加入96孔板中，培养72h后，检测。试验结果采用SPSS软件计算IC50值和相关系数。实验结果见表1。
表1化合物抑制瘤细胞株的IC50值(单位μM)
a每个数值用平均值±标准偏差(mean±SD)表示，方差分析：p<0.05，5-Fu：5-氟尿嘧啶。CA-4P：康普立停-4P.
实施例4化合物IIf的Tubulin聚合抑制活性的测定：
提取的微管蛋白重悬于冰冷的G-PEM缓冲液(80mM PIPES pH 5.9,5mM MgCl2,1mMEGTA,1mM ATP,5％(v/v)glycerol)，取100ul加至包含100ul化合物IIf的96孔板内，微管蛋白终浓度为5.6g/L，药物浓度设置0uM，1uM，2uM，4uM四个梯度，样品充分混匀，分光光度计检测微管蛋白的聚合，间隔5min，总计60min，IC50值在30分钟使用GraphPad软件计算得到。IIf的微管蛋白聚合抑制活性的IC50值为2.41μM,说明化合物IIf确实能够结合微管蛋白，抑制其聚合。

Claims (6)

1.含磺胺-1,2,3-三氮唑类化合物，其特征在于，具有通式II所示结构：
R1为C1-3烷氧基、C1-3烷基、氰基或苯氧基；
Aryl为香豆素环，噻吩或取代噻吩环，苯环或取代的苯环；所述噻吩取代基选卤素，所述苯环取代基选卤素，C1-4烷基。
2.如权利要求1所述的含磺胺-1,2,3-三氮唑类化合物，其特征在于，R1为甲氧基、甲基、氰基或苯氧基；
Aryl为噻吩或卤素单取代的噻吩环，苯环或取代的苯环；所述苯环取代基选溴，氯，甲基，乙基，丙基或丁基。
3.如权利要求1所述的含磺胺-1,2,3-三氮唑类化合物，其特征在于，选如下化合物之一：
4.如权利要求1-3其中之一所述的含磺胺-1,2,3-三氮唑类化合物在制备药物中的应用，其特征在于，将其做为活性成分用于制备抗肿瘤药物或Tubulin聚合抑制剂。
5.如权利要求4所述的含磺胺-1,2,3-三氮唑类化合物在制备药物中的应用，其特征在于，用于制备乳腺癌、食管癌、胃癌、前列腺癌、子宫癌、卵巢癌、子宫颈癌、结肠癌、直肠癌、甲状腺癌、肺癌、肝癌、甲状腺癌、睾丸癌、肾癌、膀胱癌、小肠癌、胰腺癌或白血病药物中。
6.如权利要求1所述的含磺胺-1,2,3-三氮唑类化合物的制备方法，其特征在于，通过以下步骤实现：
R1，Aryl同权利要求1所述；
(1)化合物(I)的制备方法：
溶剂中，将含芳香环的磺酰氯在碱性条件下和炔丙胺反应得到化合物I，所用的碱是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、十二水磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠中的一种；所用的溶剂为乙醇、甲醇、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、二氯甲烷中之一或其中任意两种的混合物；反应在0-90℃之间进行；
(2)通式(II)的制备方法：
溶剂中，化合物I与取代苄基叠氮化合物在五水硫酸铜及抗坏血酸钠存在下反应，所用的溶剂为丙酮、乙腈、乙醇、甲醇、异丙醇、四氢呋喃、蒸馏水中之一或其中任意两种或三种的混合物；反应在0-90℃之间进行。
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