CN111056978B - 一种磺酰胺类化合物及其制备方法和应用 - Google Patents
一种磺酰胺类化合物及其制备方法和应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
一种磺酰胺类化合物及其制备方法和应用,以EGFR、VEGFR‑2和FGFR1三种激酶为靶标,以查尔酮为先导物,将查尔酮结构中的α,β‑不饱和羰基共轭结构跃迁为苄基苯基酮结构母核,去除α,β‑不饱和羰基共轭结构的母核,所设计的化合物不会与体内谷胱甘肽的硫醇发生亲电反应,最大程度上保留了查尔酮本身的药效结构特征与生物活性。在苄基苯基酮结构母核的基础上引入磺酰胺基团,合成了一系列磺酰胺类化合物。通过活性筛选发现同时抑制三种受体酪氨酸激酶的多靶标抑制剂。激酶筛选试验表明大部分化合物都具有较好激酶抑制活性,肿瘤细胞增殖试验表明大部分化合物都具有较强的肿瘤细胞增殖抑制活性,能够应用在制备抗肿瘤药物中。
Description
技术领域
本发明涉及一种磺酰胺类化合物及其制备方法和应用。
背景技术
天然产物作为新药发现的先导化合物越来越引起药学家的兴趣。查尔酮是一种重要的黄酮类活性天然产物,其结构为1,3-二苯基-2-丙烯基-1-酮,广泛存在于甘草、红花等药用植物中。研究证实查尔酮具有抗真菌、抗炎、抗肿瘤等广泛的生物活性,其中抗肿瘤活性主要是基于对受体酪氨酸激酶(Receptor Tyrosine Kinases,RTKs)的选择性抑制。RTK在肿瘤发生、发展过程中发挥关键的作用,特别体现在肿瘤细胞的恶性增殖、迁移、分化和代谢过程中。其中,EGFR、VEGFR-2和FGFR1三种RTKs的表达异常与多种肿瘤的发生、发展密切相关,这三种RTK的活性已经成为抗肿瘤药物研究的有效靶标。尤为重要的是,这三种RTKs具有高度保守的一级序列和三维结构,其配体结合位点和酪氨酸激酶催化区域也高度相似,使得设计同时针对这三种RTKs的多靶标抑制剂成为可能,也有利于解决单靶标抑制剂易出现耐药性的缺陷。
发明内容
本发明的目的在于提供一种磺酰胺类化合物及其制备方法和应用。
为实现上述目的,本发明采用如下的技术方案:
一种磺酰胺类化合物,该化合物的结构式如下:
其中,R1为4-OCH3或H,X为3-CF3、2-F、3-F、4-Br、4-OCH3、3-Cl-4-F或3-Cl-4-Cl。
本发明进一步的改进在于,R1和X具体如下:
一种如上所述的磺酰胺类化合物的制备方法,R1为4-OCH3,R2为3-Cl-4-F时,制备过程如下:
将N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺溶于无水二氯甲烷中,搅拌均匀,搅拌下加入重铬酸吡啶嗡盐,室温反应12h后过滤,柱层析分离,得到N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺。
本发明进一步的改进在于,N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺通过以下过程制得:
将N-(3-氯-4-氟苯基)-2-甲基苯磺酰胺溶于无水四氢呋喃中,在冰浴条件下滴加正丁基锂的正己烷溶液,滴加完成后,继续搅拌均匀,再加入对甲氧基苯甲醛的无水四氢呋喃溶液,冰浴条件下继续搅拌反应,待反应完全后,进行后处理,得到N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺。
本发明进一步的改进在于,N-(3-氯-4-氟苯基)-2-甲基苯磺酰胺通过以下过程制得:将氯乙酰3-氯-4-氟苯胺和三乙胺溶于无水二氯甲烷中,搅拌均匀,冰浴条件下,滴加2-甲基苯磺酰氯的无水二氯甲烷溶液,滴加完成后,升温至室温反应,待反应完全后,进行后处理,得到N-(3-氯-4-氟)-2-甲基苯磺酰苯胺。
本发明进一步的改进在于,2-甲基苯磺酰氯通过以下过程制得:在容器中加入氯磺酸,冰浴条件下,搅拌下滴加甲苯,滴加完成后,继续搅拌反应3h后于0℃放置12h,向反应混合物中加入冰水混合物,分离出有机相,冷冻,过滤得到有机相,将有机相减压蒸馏,得到2-甲基苯磺酰氯。
一种如上所述的磺酰胺类化合物在制备抗肿瘤药物中的应用。
本发明进一步的改进在于,该化合物具有抑制EGFR、VEGFR-2和FGFR1激酶活性的作用。
本发明进一步的改进在于,该化合物具有抗肿瘤细胞增殖活性的作用。
与现有技术相比,本发明具有的有益效果:本发明基于查尔酮具有抗真菌、抗炎、抗肿瘤等广泛的生物活性,其中抗肿瘤活性主要是基于对受体酪氨酸激酶(ReceptorTyrosine Kinases,RTKs)的选择性抑制。RTK在肿瘤发生、发展过程中发挥关键的作用,特别体现在肿瘤细胞的恶性增殖、迁移、分化和代谢过程中。其中,EGFR、VEGFR-2和FGFR1三种RTKs的表达异常与多种肿瘤的发生、发展密切相关,这三种RTK的活性已经成为抗肿瘤药物研究的有效靶标。尤为重要的是,这三种RTKs具有高度保守的一级序列和三维结构,其配体结合位点和酪氨酸激酶催化区域也高度相似,使得设计同时针对这三种RTKs的多靶标抑制剂有利于解决单靶标抑制剂易出现耐药性的缺陷。激酶筛选试验表明本发明中的磺酰胺类化合物中大部分化合物都具有较好激酶抑制活性,其中,R1为H,X为3-Cl-4-Cl或F时的磺酰胺化合物同时对三种激酶有较好的抑制活性。肿瘤细胞增殖试验表明本发明中的吡唑磺酰胺类化合物中大部分化合物都具有较强的肿瘤细胞增殖抑制活性,活性结果实验证实化合物R1为H,X为3-Cl-4-Cl或F时的磺酰胺化合物对3株肿瘤细胞有很强的抑制活性。构效关系分析发现:磺酰胺结构片段对化合物的抑制活性具有重要作用,可以提高化合物与受体的亲和力及抑制活性,该化合物具有抑制V EGFR、VEGFR-2和FGFR1激酶活性的作用和抗肿瘤细胞增殖活性的作用,能够应用在制备抗肿瘤药物中,作为多靶标抑制剂设计的新型药效片段。
本发明的磺酰胺类化合物(Chalcone-QZO)的设计依据是基于磺酰胺类药效团的众多生物学活性,特别是磺酰胺药效团的作用,首先采用骨架跃迁的药物分子设计策略,将查尔酮结构中的α,β-不饱和羰基共轭结构跃迁为苄基苯基酮结构母核。去除α,β-不饱和羰基共轭结构的母核,所设计的化合物不会与体内谷胱甘肽的硫醇发生亲电反应,最大程度上保留了查尔酮本身的药效结构特征与生物活性。在苄基苯基酮结构母核的基础上引入磺酰胺基团,设计了磺酰胺类化合物。
本发明将2-甲基苯磺酰氯与各种卤素取代苯胺反应生成相应的苯磺酰胺中间体;再以N-取代邻甲基苯磺酰胺为原料,利用磺酰胺基的邻位金属化作用,在无水四氢呋喃中与正丁基锂作用,再与芳香醛发生加成反应合成仲醇;仲醇再经重铬酸吡啶嗡盐氧化即可制得磺酰胺类化合物,该化合物为具有全新结构的小分子多靶标抑制剂,并通过HRMS、NMR等手段表征了目标化合物的结构。
附图说明
图1为本发明的合成路线图。其中,反应条件:(a)HSO3Cl,(b)X-Ar-NH2,CH2Cl2,Et3N,(c)i,BuLi,THF,-10℃,ii,R1-Ar-CHO,THF,0℃,(d)PDC,CH2Cl2。
具体实施方式
下面结合附图对本发明进行详细说明。
以查尔酮为新型先导化合物,基于肿瘤发生过程中具有关键作用的三种RTKs(EGFR/VEGFR-2/FGFR1)为多靶标,首先利用计算机工具分析查尔酮分子结构特征,精确解析受体活性位点的三维结构,并模拟查尔酮与三种受体活性位点的结合模式;分析三种RTKs高度保守的活性构象及与共同底物(ATP)的作用模式,寻找其共有结构特征元素;采用生物电子等排和原位装配等药物设计策略引入不同取代基作为新型铰链区结合基团,将药效片段库中作用于同一结构域的片段组合优化,以期满足共性结构域对抑制剂的构象要求;设计能够满足三种受体酪氨酸激酶活性位点对抑制剂药效团共同构象要求的衍生物;针对查尔酮结构中α,β-不饱和共轭双键的代谢缺陷,基于多聚药理学的原理构建同时靶向EGFR/VEGFR-2/FGFR1的抑制剂化合物库,合成结构多样性的不含α,β-共轭双键查尔酮衍生物作为多靶标抑制剂,以期能够同时抑制三种肿瘤相关RTKs的活性,在活性筛选的基础上利用计算机工具进行构效关系研究,用于指导新一轮的化合物的设计与合成,并通过活性筛选发现理化性质改善、生物活性提高的新型查尔酮衍生物类抗肿瘤药物。
本发明的磺酰胺类化合物(Chalcone-QZO)的设计依据是基于磺酰胺类药效团的众多生物学活性,特别是磺酰胺药效团的作用,首先采用骨架跃迁的药物分子设计策略,将查尔酮结构中的α,β-不饱和羰基共轭结构跃迁为苄基苯基酮结构母核。去除α,β-不饱和羰基共轭结构的母核,所设计的化合物不会与体内谷胱甘肽的硫醇发生亲电反应,最大程度上保留了查尔酮本身的药效结构特征与生物活性。在苄基苯基酮结构母核的基础上引入磺酰胺基团,设计了磺酰胺类化合物。
参见图1,本发明的磺酰胺类化合物的结构式为:
其中,,R1为4-OCH3或H,X为3-CF3、2-F、3-F、4-Br、4-OCH3、3-Cl-4-F或3-Cl-4-Cl。
表1本发明的磺酰胺化合物具体结构
表1中的X中的数字是表示X基团在苯环上的位置。
参见图1,本发明中R1为4-OCH3,R2为3-Cl-4-F时,具体的制备过程如下:
2-甲基苯磺酰氯的合成:在三颈瓶中加入氯磺酸,冰浴条件下,搅拌下缓慢滴加甲苯,滴加完成后,继续搅拌反应3h,待反应完全后0℃放置过夜,向反应混合物中加入冰水混合物,分离出有机相,并用冰水洗涤两次;在-10~-20℃条件下放置5h,可析出白色的结晶,过滤出固体后得到有机相。将有机相减压蒸馏,收集1mmHg条件下96~98℃的馏分,得到的油状物即为2-甲基苯磺酰氯。具体过程如下:
在150mL三颈瓶中加入22.1mL氯磺酸(330.17mmol),冰浴条件下,搅拌下缓慢滴加甲苯12.2mL(110.31mmol),滴加完成后,继续搅拌反应3h,TLC监测反应进程,待反应完全后0℃放置过夜,向反应混合物中加入500g冰水混合物,分离出有机相,并用冰水洗涤两次;在-10~-20℃条件下放置5h,可析出白色的结晶(为对甲基苯磺酰氯),过滤出固体后得到有机相。将有机相减压蒸馏,收集1mmHg条件下96~98℃的馏分,得到油状的邻甲基苯磺酰氯10.05g,产率72.04%。
N-(3-氯-4-氟苯基)-2-甲基苯磺酰胺的合成:室温条件下将氯乙酰3-氯-4-氟苯胺和三乙胺溶于无水二氯甲烷中,搅拌使其溶解。冰浴条件下,缓慢滴加2-甲基苯磺酰氯的无水二氯甲烷溶液,滴加完成后,撤去冰浴,反应混合物升温至室温反应。待反应完全后,依次用盐酸、蒸馏水、饱和氯化钠水溶液洗涤。有机相用无水硫酸钠干燥,石油醚/乙酸乙酯重结晶得到白色固体即为N-(3-氯-4-氟)-2-甲基苯磺酰苯胺。具体过程如下:
室温条件下将0.88g(6.80mmol)氯乙酰3-氯-4-氟苯胺和1.1mL(6.81mmol)三乙胺溶于15.5mL无水二氯甲烷中,搅拌使其溶解。冰浴条件下,缓慢滴加0.73mL(5.01mmol)邻甲基苯磺酰氯的无水二氯甲烷溶液,滴加完成后,撤去冰浴,反应混合物升温至室温反应。TLC监测反应进程,待反应完全后,依次用2mol/L盐酸、蒸馏水、饱和氯化钠水溶液洗涤。有机相用无水硫酸钠干燥,石油醚/乙酸乙酯重结晶得0.48g产物,产率96.24%。
N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺的合成:将化合物N-(3-氯-4-氟苯基)-2-甲基苯磺酰胺溶于无水四氢呋喃中,在冰浴条件下缓慢滴加正丁基锂的正己烷溶液,滴加完成后,继续搅拌10min,再向反应混合物中缓慢加入的对甲氧基苯甲醛的无水四氢呋喃溶液。冰浴条件下反应混合物继续搅拌反应。待反应完全后,加入饱和的氯化铵水溶液充分搅拌,乙酸乙酯提取后,用饱和食盐水洗涤有机相,无水硫酸钠干燥。柱层析分离纯化得油状物即为N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺。具体过程如下:
将化合物N-(3-氯-4-氟苯基)-2-甲基苯磺酰胺(0.60g,2.03mmol)溶于10mL无水四氢呋喃中,在冰浴条件下缓慢滴加1.80mL的2.5mol/L的正丁基锂的正己烷溶液,滴加完成后,继续搅拌10min,再向反应混合物中缓慢加入的对甲氧基苯甲醛(0.30g,2.04mmol)的无水四氢呋喃溶液。冰浴条件下反应混合物继续搅拌反应。TLC监测反应进程,待反应完全后,加入饱和的NH4Cl水溶液充分搅拌,乙酸乙酯提取后,用饱和食盐水洗涤有机相,无水Na2SO4干燥。柱层析分离纯化得油状物0.72g(产率87.80%)。EI-MS:m/z:435.0(M+H);1H-NMR(300MHz,DMSO-d6):δ3.82(s,3H),6.72-6.77(m,2H),6.84-6.89(m,1H),7.50-7.58(m,4H),7.66-7.72(m,4H),7.75-7.82(m,3H).
N-(3-氯-4-氟苯基)-2-(2-氧代-2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA8)的合成:将N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺溶于无水二氯甲烷中,搅拌使其溶解。室温下搅拌下加入重铬酸吡啶嗡盐,室温反应过夜后过滤,柱层析分离得到白色固体即为N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺。具体过程如下:
将N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)乙基)苯磺酰胺(0.22g,5.01mmol)溶于5mL无水二氯甲烷中,搅拌使其溶解。室温下搅拌下加入PDC(0.63g,1.67mmol),室温反应过夜后过滤,柱层析分离得到目标化合物0.21g,产率76.70%,熔点:128-129℃。ESI-MS m/z 433,(M+H),1H-NMR(400MHz,CDCl3):δ3.84(s,3H),4.90(s,2H),6.77(dd,J=9.0,19.0Hz,2H),7.02(dd,J=9.0,18.8Hz,1H),7.12-7.15(m,2H),7.19-7.23(m,2H),7.35(d,J=7.8Hz,2H),7.50-7.52(m,1H),7.89(d,J=8.0Hz,2H),8.12(d,J=8.0Hz,1H).
磺酰胺类化合物SFA1~14熔点、质谱及氢谱解析数据如下:
化合物N-(3-氯-4-氟苯基)-2-(2-氧代-2-苯基乙基)苯磺酰胺(SFA1)
产率78.00%,熔点150-152℃。EI-MS:m/z:404(M+H),1H-NMR(400MHz,CDCl3):δ4.92(s,2H),6.92(d,J=8.0Hz,2H),7.00(s,1H,NH),7.20-7.25(m,1H),7.32(d,J=7.8Hz,2H),7.35-7.42(m,2H),7.42-7.46(m,1H),7.65(d,J=7.8Hz,1H).
化合物2-(2-氧代-2苯基乙基)-N-(3-三氟甲基-苯基)-苯磺酰胺(SFA2)
产率72.21%,熔点178-180℃。EI-MS:m/z:420(M+H),1H-NMR(400MHz,CDCl3):δ4.93(s,2H),6.92(d,J=8.0Hz,2H),7.03(s,1H,NH),7.21-7.26(m,1H),7.33(d,J=7.8Hz,2H),7.37-7.43(m,3H),7.47-7.52(m,1H),7.66(d,J=7.8Hz,1H).
化合物N-(3,4-二氯苯基)-2-(2-氧代-2-苯基乙基)苯磺酰胺(SFA3)
产率67.04%,熔点144-146℃。EI-MS:m/z:420(M+H),1H-NMR(400MHz,CDCl3):δ4.92(s,2H),6.95(d,J=8.0Hz,2H),7.01(s,1H,NH),7.21-7.26(m,1H),7.33(d,J=7.8Hz,2H),7.37-7.44(m,2H),7.47-7.52(m,1H),7.67(d,J=7.8Hz,1H).
化合物N-(4-甲氧基苯基)-2-(2-氧代-2-苯基乙基)苯磺酰胺(SFA4)
产率71.90%,熔点178-180℃。EI-MS:m/z:420(M+H),1H-NMR(400MHz,CDCl3):δ4.93(s,2H),6.94(d,J=8.0Hz,2H),7.23-7.25(m,2H),7.35(d,J=7.8Hz,2H),7.38-7.44(m,4H),7.49-7.54(m,3H).
化合物N-(4-溴苯基)-2-(2-氧代-2-苯基乙基)苯磺酰胺(SFA5)
产率63.31%,熔点198-200℃。EI-MS:m/z:430(M+H),1H-NMR(400MHz,CDCl3):δ4.90(s,2H),6.99(d,J=8.0Hz,2H),7.15(d,J=7.8Hz,2H),7.28-7.33(m,3H),7.39-7.45(m,3H),7.49-7.54(m,2H).
化合物N-(2-氟苯基)-2-(2-氧代-2-苯基乙基)苯磺酰胺(SFA6)
产率68.17%,熔点142-144℃。EI-MS:m/z:370(M+H),1H-NMR(400MHz,CDCl3):δ4.89(s,2H),6.95-7.18(m,5H),7.25-7.30(m,3H),7.38-7.42(m,3H),7.48-7.52(m,2H).
化合物N-(3-氟苯基)-2-(2-氧代-2-苯基乙基)苯磺酰胺(SFA7)
产率67.31%,熔点155-157℃。EI-MS:m/z:370(M+H),1H-NMR(400MHz,CDCl3):δ4.91(s,2H),6.94-7.19(m,5H),7.23-7.28(m,3H),7.34-7.40(m,3H),7.45-7.50(m,2H).
化合物N-(3-氯-4-氟苯基)-2-(2-羟基-2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA8)
产率76.59%,熔点:128-129℃。ESI-MS m/z 433,(M+H),1H-NMR(400MHz,CDCl3):δ3.84(s,3H),4.90(s,2H),6.77(dd,J=9.0,19.0Hz,2H),7.02(dd,J=9.0,18.8Hz,1H),7.12-7.15(m,2H),7.19-7.23(m,2H),7.35(d,J=7.8Hz,2H),7.50-7.52(m,1H),7.89(d,J=8.0Hz,2H),8.12(d,J=8.0Hz,1H).
化合物2-(2-(4-甲氧基苯基)-2-氧乙基)-N-(3-三氟甲基)苯基)-苯磺酰胺(SFA9)
产率53.87%,熔点181-183℃。EI-MS:m/z:450(M+H),1H-NMR(400MHz,CDCl3):δ3.81(s,3H),4.92(s,2H),7.02-7.10(m,4H),7.15(d,J=7.8Hz,2H),7.18(s,1H),7.58-7.69(m,3H),7.91(d,J=8.0Hz,2H).
化合物N-(3,4-二氯苯基)-2-(2-羟基-2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA10)
产率70.07%,熔点:145-147℃。ESI-MS m/z 483,(M+H),1H-NMR(400MHz,CDCl3):δ3.85(s,3H),4.91(s,2H),6.78(dd,J=9.0,19.0Hz,2H),7.04(dd,J=9.0,18.8Hz,1H),7.15-7.19(m,2H),7.25-7.29(m,2H),7.38(d,J=7.8Hz,2H),7.59-7.63(m,1H),7.92(d,J=8.0Hz,2H),8.10(d,J=8.0Hz,1H).
化合物N-(4-甲氧基苯基)-2-(2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA11)
产率79.31%,熔点132-134℃。EI-MS:m/z:412(M+H),1H-NMR(400MHz,CDCl3):δ3.84(s,3H),4.92(s,2H),6.75-7.03(m,4H),7.14(d,J=7.8Hz,2H),7.52-7.66(m,3H),7.80-7.87(m,1H),7.88(d,J=8.0Hz,2H).
化合物N-(4-溴苯基)-2-(2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA12)
产率68.10%,熔点196-197℃。EI-MS:m/z:460(M+H),1H-NMR(400MHz,CDCl3):δ3.85(s,3H),4.94(s,2H),6.78-7.07(m,4H),7.16(d,J=7.8Hz,2H),7.54-7.68(m,3H),7.84-7.91(m,1H),7.90(d,J=8.0Hz,2H).
化合物N-(2-氟苯基)-2-(2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA13)
产率69.90%,熔点152-153℃。EI-MS:m/z:400(M+H),1H-NMR(400MHz,CDCl3):δ3.83(s,3H),4.91(s,2H),6.78-7.10(m,4H),7.15(d,J=7.8Hz,2H),7.54-7.69(m,3H),7.80-7.85(m,1H),7.90(d,J=8.0Hz,2H).
化合物N-(3-氟苯基)-2-(2-(4-甲氧基苯基)-2-氧乙基)苯磺酰胺(SFA13)
产率66.10%,熔点161-163℃。EI-MS:m/z:400(M+H),1H-NMR(400MHz,CDCl3):δ3.84(s,3H),4.92(s,2H),6.77-7.05(m,4H),7.12(d,J=7.8Hz,2H),7.50-7.65(m,3H),7.81-7.86(m,1H),7.89(d,J=8.0Hz,2H).
下面为本发明磺酰胺类化合物的药理活性如下:
对EGFR、VEGFR-2和FGFR1三种RTKs抑制活性:
表2磺酰胺类化合物对EGFR、VEGFR-2和FGFR1的抑制活性IC50(nM)
由表2可以看出,在对EGFR抑制活性中,化合物SFA3的活性结果最好(IC50=21.99nM),这个化合物的结构特征是结构母核为苯磺酰胺结构,末端苯胺为3-氯-4-氯苯胺;对于VEGFR-2的抑制结果,共有3个化合物对VEGFR-2有高效的抑制活性(IC50小于20nM),分别是SFA3(IC50=15.17nM),SFA6(IC50=12.55nM)和SFA9(IC50=17.54nM);对于FGFR1抑制活性结果,共有2个化合物对FGFR1有高效的抑制活性(IC50小于20nM),分别是SFA3(IC50=14.44nM),和SFA6(IC50=13.29nM)。从整体活性结果显示,SFA3和SFA6具有较好的三靶标抑制活性,说明对于磺酰胺系列化合物来讲,末端3,4-二氯苯胺和2-氟苯胺结构有利于提高对三个RTKs的抑制活性。
在化合物激酶抑制活性筛选的基础上,进行了肿瘤细胞增殖抑制活性筛选。药理筛选试验表明大多数的化合物对肿瘤细胞有体外增殖抑制活性。在乳腺癌细胞(MCF-7),非小细胞肺癌细胞(A549),白血病细胞(K562)上进行试验时,发现具有肿瘤细胞增殖抑制活性。
表3磺酰胺类化合物肿瘤细胞增殖抑制活性IC50(μM)
磺酰胺类化合物对MCF-7、A549和K562三种肿瘤细胞均具有一定程度的增殖抑制活性,从整体结果来看,化合物结构中的甲氧基对于化合物的抗肿瘤活性影响不大。对MCF-7细胞抑制活性最好的化合物是SFA2,其结构特征为末端苯胺3-三氟甲基苯胺。对A549细胞抑制活性最好的化合物是SFA13,其末端苯胺为2-氟苯胺,同时化合物SFA2对A549细胞的抑制活性也较好,二者的IC50值分别为15.8μM和17.2μM;对K562细胞抑制活性最好的化合物是SFA12,其结构中末端苯胺为4-溴苯胺,抑制活性IC50值为12.7μM。活性筛选结果显示磺酰胺类化合物作为具有潜在抗肿瘤活性的候选化合物,验证了磺酰胺结构作为抗肿瘤化合物结构母核的有效性。磺酰胺结构母核可以作为抗肿瘤化合物设计的新型结构母核,对于这一类化合物,末端苯胺上的3,4-二氯和三氟甲基等卤素取代基有利于抗肿瘤活性。
本发明中化合物QZ3和QZ6对EGFR、VEGFR-2和FGFR1三种激酶和MCF-7、A549和K562三种肿瘤细胞均显示较好的抑制活性。
本发明以在肿瘤发生、发展过程中发挥关键作用的EGFR、VEGFR-2和FGFR1三种激酶为靶标,以查尔酮为先导物,基于磺酰胺类药效团的众多生物学活性,特别是磺酰胺药效团的作用,首先采用骨架跃迁的药物分子设计策略,将查尔酮结构中的α,β-不饱和羰基共轭结构跃迁为苄基苯基酮结构母核。去除α,β-不饱和羰基共轭结构的母核,所设计的化合物不会与体内谷胱甘肽的硫醇发生亲电反应,最大程度上保留了查尔酮本身的药效结构特征与生物活性。在苄基苯基酮结构母核的基础上引入磺酰胺基团,设计并合成了一系列磺酰胺类化合物。通过活性筛选发现同时抑制三种受体酪氨酸激酶的多靶标抑制剂。激酶筛选试验表明大部分化合物都具有较好激酶抑制活性,肿瘤细胞增殖试验表明大部分化合物都具有较强的肿瘤细胞增殖抑制活性,该类化合物具有抑制EGFR、VEGFR-2和FGFR1激酶活性的作用和抗肿瘤细胞增殖活性的作用,能够应用在制备抗肿瘤药物中。
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