CN109666006B - 芳基衍生联噻唑类化合物及其制备方法和应用 - Google Patents
芳基衍生联噻唑类化合物及其制备方法和应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明公开了芳基衍生联噻唑类化合物及其制备方法和应用。所述芳基衍生联噻唑类化合物为芳基衍生二噻唑、芳基衍生三噻唑。所述苯基衍生联噻唑类化合物对非小细胞肺癌细胞株A549和结肠癌细胞株HCT116具有显著的抑制作用,用以制备抗肿瘤药物的应用。
Description
技术领域
本发明涉及药物化学技术领域,具体涉及芳基衍生二噻唑类化合物、芳基衍生三噻唑类化合物的制备及其抗肿瘤应用。
背景技术
联噻唑类化合物不仅在自然界中广泛存在,且大都具有优良的生物活性(Synthesis 2005,1907-1922.)。近来,有研究发现丙氨酸衍生的联噻唑类化合物不仅在活性天然产物中存在,而且其自身也可以显著地抑制结肠癌细胞HCT116的增殖(IC50=7.64μM)(ACS Med.Chem.Lett.2017,8,401-406.)。噻唑结构源自于生物体多肽链上半胱氨酸裸露巯基对邻近酰胺键进攻、成环作用,其本身除了具有多种优良的生物活性,还具有低毒,结构刚性、生物兼容性好等优势(Nat.Prod.Rep.2011,28,196-268.)。因此深入挖掘联噻唑类化合物的抗癌潜力,具有重要的意义。芳基单噻唑类化合物在抗癌药物、抗炎症药物、抗菌药物开发中,都取得了优异的结果(Eur.J Med Chem.,2011,46,526-534.;ChemistryCentral Journal.,2017,11,25-34.)。
发明内容
本发明目的在于提供一种芳基联噻唑(芳基衍生二噻唑、芳基衍生三噻唑)类化合物及其制备方法和上述化合物在抑制人结肠癌HCT116细胞和人肺癌A549细胞中的应用,即制备抗肿瘤药物中的应用。
技术方案一:
本发明所述的一种芳基联噻唑(芳基衍生二噻唑、芳基衍生三噻唑)类化合物,其具有如式X所示的结构,
其中,
n选自1或2;
所述R1取代在相应苯环的任意空位上;
R1选自NO2、NHCH3、OH、NHCH2CH3、NH2、OCH3、OCH2CH3、SCH3、OCF3、OCHF2之一;
R2选自COOCH3、COOH、CONH2、CON(OCH3)CH3、CH2OH、CH2NH2之一。
优选方案是,所述R1取代在相应苯环的邻位,即在2’-位;
进一步优选,R1为NH2,n为2,R2为COOCH3。
技术方案二:
上述一种芳基联噻唑类化合物的制备方法,所述方法包括如下步骤:
(1)2-苯基二噻唑目标化合物的制备:步骤1:将如式Ⅰ所示的化合物溶于二氯甲烷中,并依次加入如式Ⅱ所示的芳香族羧酸化合物和三乙胺、三苯基膦、五氟苯基二苯基磷酸酯(FDPP),在20~100℃下反应4~6h,冷却后,向反应混合物中依次加入1,8-二氮杂二环十一碳-7-烯(DBU)、溴代三氯甲烷,继续室温下搅拌反应0.5~4h,加入等体积的饱和氯化铵溶液淬灭反应,用二氯甲烷萃取,无水硫酸钠干燥有机层,旋干,柱层析分离,得到如式Ⅲ所示的化合物;
进一步优选的,所述反应温度为50℃,反应时间为5h或3h;该步骤中各反应物的摩尔比为Ⅰ:Ⅱ:FDPP:三乙胺:三苯基膦:DBU:溴代三氯甲烷=1:4:4:8:12:10;
步骤2:向反应容器中依次加入结构如式Ⅲ所示的化合物、甲醇、四氢呋喃、氢氧化钠水溶液,反应过夜后,向体系中加入加稀盐酸溶液调节pH值=3~4,用乙酸乙酯萃取,无水硫酸钠干燥,旋干,柱层析分离后,制得如式Ⅳ所示的化合物;
进一步优选的,各溶剂的体积比为甲醇:四氢呋喃:氢氧化溶液=1:1:1,氢氧化钠溶液的浓度为2mmol/ml;
步骤3:将如式Ⅳ所示的化合物溶于DCM中,再次加入如式Ⅱ所示的化合物和三乙胺、三苯基膦、五氟苯基二苯基磷酸酯,在20~100℃下反应4~6h,冷却后,向反应混合物中依次加入1,8-二氮杂二环十一碳-7-烯(DBU)、溴代三氯甲烷,继续室温下搅拌反应0.5~4h,加入等体积的饱和氯化铵溶液淬灭反应,用DCM萃取,无水硫酸钠干燥有机层,旋干,柱层析分离后,制得如式Ⅴ所示的化合物;
进一步优选的,所述反应温度为50℃,反应时间为5h或3h,该步骤中各反应物的摩尔比为Ⅱ:Ⅳ:FDPP:三乙胺:三苯基膦:DBU:溴代三氯甲烷=1.5:1:2:12:12:15:12;
步骤4:将如式Ⅴ所得化合物酰胺化、还原,可制备得到芳基衍生二噻唑化合物;
进一步优选的,酰胺化试剂选氨水,还原试剂选四氢铝锂;
(2)2-苯基三噻唑目标化合物的制备:
步骤5:将如式Ⅴ依照步骤2相同操作水解后,制备得到如式Ⅵ所示的化合物;
进一步优选的,各溶剂的体积比为甲醇:四氢呋喃:氢氧化溶液=1:1:1,氢氧化钠溶液的浓度为2mmol/ml;
步骤6:按照步骤3相同操作,将如式Ⅵ所示的化合物溶于DCM中,并依次加入如式Ⅱ所示的化合物和三乙胺、三苯基膦、五氟苯基二苯基磷酸酯、1,8-二氮杂二环十一碳-7-烯、溴代三氯甲烷,制得如式Ⅶ所示的化合物;
进一步优选的,所述反应温度为50℃,反应时间为5h或3h,该步骤中各反应物的摩尔比为Ⅱ:Ⅵ:FDPP:三乙胺:三苯基膦:DBU:溴代三氯甲烷=1.5:1:2:12:12:15:12;
步骤7:将如式Ⅶ所得化合物酰胺化、水解、还原,可制备得到目标芳基衍生三噻唑化合物;
进一步优选的,酰胺化试剂选氨水,还原试剂选四氢铝锂;
上述制备方法中所述式Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅵ、Ⅶ的化合物如下所述:
其中,式Ⅰ,Ⅲ~Ⅶ中,R1选自NO2、NHCH3、OH、NHCH2CH3、NH2、OCH3、OCH2CH3、SCH3、OCF3、OCHF2。
本制备方法针对合成苯基衍生联噻唑类化合物具有优势,实验可重复性强,稳定性好,实验反应步骤少,实验环境温和,产率较好,避免使用昂贵金属催化剂,在较小投入条件下,适合大规模制备。
技术方案三:
经实验证实:本发明所述苯基衍生联噻唑类化合物对非小细胞肺癌细胞株A549和结肠癌细胞株HCT116具有显著的抑制作用,因此可以用以制备抗肿瘤药物,具备良好的开发前景。
上述芳基联噻唑类化合物在制备抑制肿瘤(肺癌、结肠癌)细胞增殖药物中的应用。
具体实施方式
下面结合实施例进一步描述本发明,但不以任何方式限制本发明的范围。
实施例1——二噻唑化合物5,6,7的制备:
步骤1.在室温搅拌下,依次向圆底烧瓶中加入FDPP(4mmol)、二氯甲烷、邻硝基苯甲酸(4mmol)、三乙胺(8mmol)、叠氮胱氨酸二甲酯(1mmol)、三苯基膦(8mmol),50℃下搅拌反应5h,反应完毕后,向体系中依次加入DBU(12mmol)、溴代三氯甲烷(10mmol),搅拌反应3h。反应结束后,加入等体积的饱和氯化铵溶液,用二氯甲烷萃取(3×15ml),无水无水硫酸钠干燥有机层,旋干,用V石油醚/V乙酸乙酯=2:1过柱,得到淡黄色固体化合物3,产率66%。1H NMR(400MHz,CDCl3)δ:3.95(s,3H),7.62-7.68(m,1H),7.69-7.72(m,2H),8.00(dd,J=1.2Hz,J=8.4Hz,1H),8.34(s,1H);13C NMR(100MHz,CDCl3)δ:52.7,124.8,127.8,129.5,131.2,132.3,132.9,147.6,148.7,161.7,163.3;ESI-HRMS calcd for C11H8N2NaO4S([M+Na]+)287.0102,found 287.0088.。
步骤2.室温下,向圆底烧瓶中加入化合物3(1mmol),加入12ml MeOH/THF/2.0NNaOH(2:2:2)使之溶解,点板检测反应(展开剂V石油醚/V乙酸乙酯=2:1),反应结束后,向反应体系中加入10ml的水,用2N的HCl调节pH=2,EA萃取(3×20ml),无水硫酸钠干燥,旋干,得化合物4。化合物4无需进一步纯化,溶解于10ml二氯甲烷中后,依次向圆底烧瓶中加入FDPP(2mmol)、三乙胺(12mmol)、叠氮胱氨酸二甲酯(1.5mmol)、三苯基膦(12mmol),50℃下搅拌反应5h,反应完毕后,向体系中依次加入DBU(15mmol)、溴代三氯甲烷(12mmol),搅拌反应3h。反应结束后,加入等体积的饱和氯化铵溶液,用二氯甲烷萃取(3×15ml),无水无水硫酸钠干燥有机层,旋干,用V石油醚/V乙酸乙酯=1:1过柱,得到黄色固体化合物5,产率61%。1H NMR(400MHz,CDCl3)δ:3.98(s,3H),7.63(dt,J=1.6Hz,J=8.0Hz,1H),7.69(dt,J=1.6Hz,J=8.0Hz,1H),7.79(dd,J=1.6Hz,J=8.0Hz,1H),7.87(dt,J=1.6Hz,J=8.0Hz,1H),8.20(s,1H),8.28(s,1H);13C NMR(100MHz,CDCl3)δ:52.5,118.8,124.4,126.4,128.5,130.9,131.2,132.3,147.6,149.3,161.8,162.9;ESI-HRMS calcd for C14H9N3NaO4S2([M+Na]+)369.9932,found 369.9920.。
步骤3.室温下,化合物5(0.4mmol)溶解于6ml THF中,加入2.0mmol二氯化锡,回流直至反应结束,,体系中加入1N NaHCO3溶液,然后用乙酸乙酯萃取三次,合并有机相,加入无水硫酸钠干燥,柱色谱分离得化合物6,产率80%。1H NMR(400MHz,DMSO-d6)δ:3.89(s,3H),6.65(t,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),7.02(s,br,2H),7.21(t,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),8.35(s,1H),8.61(s,1H);13C NMR(100MHz,DMSO-d6)δ:52.2,113.0,115.9,116.1,116.7,129.0,129.6,131.5,146.5,146.8,146.9,161.2,162.2,169.9;ESI-HRMS calcd for C14H11N3NaO2S2([M+Na]+)340.0190,found 340.0158.。
步骤4.将0.5mmol化合物6用6ml的甲醇溶解后,再向体系中加入3ml的氨水,加入磁子搅拌两个小时,TLC检测,直至原料点消失。向体系中加入饱和氯化铵溶液淬灭反应,用DCM(3x20ml)萃取,合并有机相,柱色谱分离得到黄褐色固体7,产率88%。1H NMR(400MHz,DMSO-d6)δ:8.31(s,1H),8.24(s,1H),7.86(s,1H),7.72(s,1H),7.62(d,J=7.8Hz,1H),7.21(t,J=7.5Hz,1H),7.03(s,br,2H),6.89(d,J=8.2Hz,1H),6.65(t,J=7.4Hz,1H);13CNMR(100MHz,DMSO-d6)δ:169.9,162.2,161.4,151.3,147.3,146.6,131.5,129.0,124.5,116.7,115.9,115.6,113.1;ESI-HRMS calcd for C13H10N4NaOS2([M+Na]+)325.0194,found325.0194.。
实施例2——三噻唑化合物9,10的制备:
以二噻唑化合物5为起始原料,制备方法类同实施例1中化合物5和6的合成,制备得到目标三噻唑化合物9,10。
步骤5.室温下,向圆底烧瓶中加入化合物5(1mmol),加入12ml MeOH/THF/2.0NNaOH(2:2:2)使之溶解,点板检测反应(展开剂V石油醚/V乙酸乙酯=2:1),反应结束后,向反应体系中加入10ml的水,用2N的HCl调节pH=2,EA萃取(3×20ml),无水硫酸钠干燥,旋干,得化合物8。化合物8无需进一步纯化,溶解于10ml二氯甲烷中后,依次向圆底烧瓶中加入FDPP(2mmol)、三乙胺(12mmol)、叠氮胱氨酸二甲酯(1.5mmol)、三苯基膦(12mmol),50℃下搅拌反应5h,反应完毕后,向体系中依次加入DBU(15mmol)、溴代三氯甲烷(12mmol),搅拌反应3h。反应结束后,加入等体积的饱和氯化铵溶液,用二氯甲烷萃取(3×15ml),无水无水硫酸钠干燥有机层,旋干,用V石油醚/V乙酸乙酯=1:1过柱,得到硝基三噻唑化合物9,产率47%:1H NMR(400MHz,CDCl3)δ:8.22(s,1H),8.19(s,1H),8.17(s,1H),7.87(d,J=7.6Hz,1H),7.79(d,J=7.2Hz,1H),7.69(t,J=7.2Hz,1H),7.63(t,J=7.6Hz,1H),3.98(s,3H);13C NMR(100MHz,CDCl3)δ:163.5,162.9,162.7,162.0,149.6,149.3,148.9,147.7,132.4,131.1,128.3,126.7,124.6,52.7;ESI-HRMS calcd for C17H10N4NaO4S3([M+Na]+)452.9762,found452.9767.。
步骤6.室温下,化合物9(0.2mmol)溶解于5ml THF中,加入1.0mmol二氯化锡,回流直至反应结束,,体系中加入1N NaHCO3溶液,然后用乙酸乙酯萃取三次,合并有机相,加入无水硫酸钠干燥,柱色谱分离得到氨基三噻唑化合物10,产率90%:1H NMR(400MHz,inTHF-d8)δ:1H NMR(400MHz,THF)δ8.46(s,1H),8.43(s,1H),8.26(s,1H),7.73(d,J=7.6Hz,1H),7.25(t,J=7.6Hz,1H),6.91(d,J=8.4Hz,2H),6.90-6.84(m,1H),6.72(t,J=7.6Hz,1H),3.98(s,3H);13C NMR(100MHz,in THF-d8)δ:171.3,163.8,163.3,161.8,150.6,148.7,147.8,131.9,129.6,128.6,118.1,117.4,116.5,115.1,114.6,51.9;ESI-HRMS calcd forC17H12N4NaO2S3([M+Na]+)423.0020,found 423.0026.。
实施例3——二噻唑化合物5,6,7,9,10对人结肠癌细胞系HCT116、人肺癌细胞系A549的抑制活性
采用CCK-8法测定芳基衍生联噻唑化合物对HCT-116、A549癌细胞系的半数抑制浓度(IC50)。
CCK-8法是一种基于WST-8(2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐)的广泛应用于细胞毒性的快速灵敏测试方法。其原理是:该试剂中含有WST-8在电子耦合试剂的存在下,可以被细胞线粒体中的脱氢酶还原为高度水溶性的黄色甲瓒产物(formazan dye)。生成的甲瓒物的数量,颜色深浅与活细胞的数量成正比,与细胞毒性成反比。使用酶标仪在450nm波长测定OD值,可间接反映活细胞数量。
具体测定方法:
1、在培养了48小时后的96孔板(100μl细胞悬浮液/孔)中,加入10μl不同浓度的待测化合物(6个梯度浓度值);
2、培养板在培养箱中37℃孵育48小时后;向每孔中加入10μl CCK-8溶液;
3、继续在培养箱37℃孵育2小时;
4、用酶标仪测定在450nm处的吸光值。
5、计算细胞存活率%=(试验孔-空白孔)/(对照孔-空白孔)*100%
IC50半数抑制浓度(IC50)为当50%的肿瘤细胞存活时的药物浓度,根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,进而在曲线上求得对应的药物浓度。
所测得的IC50值见表1所示:
表1.实施例1、2化合物IC50表
a6次平行试验,实验结果取平均值,实验误差5-10%;
btaxol(紫杉醇)作为对照样;
实验结果表明,苯环2位的取代基种类对化合物的抑制效果有重要影响。例如,将苯环2-位的硝基由氨基替代后(5 vs 6),二噻唑类化合物对HCT116癌细胞系的抑制效果提高了约17倍,对A549癌细胞系的抑制效果也有提高了1倍;而将化合物中易水解的酯基用酰胺基替代后(6 vs 7),并未显著影响其抑制效果。将噻唑环数目从两个增加到三个(5 vs9,6 vs 10)后,化合物对癌细胞的抑制效果有了进一步提高。三噻唑化合物10对两种癌细胞的IC50值分别达到4.4μM和4.5μM。从上述结果可知:芳基衍生二噻唑、芳基衍生三噻唑类化合物对HCT-116、A549癌细胞系都有明显的抑制作用。
以上实验结果详细描述了本发明的优选实施方式,但是本发明并不限于上述实施方式中的具体细节;在本发明的芳香-联噻唑搭配构思范围内,可以对本发明的技术方案进行多种等同变换,这些变换均属于本发明保护范围。为避免不必要重复,本发明对各种在芳香-联噻唑结构上的各种可能组合方式不再另行说明;只要不违背本发明的思想,其同样应视为本发明所公开的内容。
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