CN108912098B - 一种嘧啶类化合物及应用 - Google Patents
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Abstract
一种嘧啶类化合物及应用,基于VEGFR‑2、EphB4、TIE‑2可代偿性激活的发现,以联苯芳基脲为新型先导物,分析三种受体活性位点的保守构象并寻找共性结构域;采用分子杂交的药物设计策略,构建满足共性结构域构象要求的化合物库,通过多水平活性筛选发现同时拮抗三条代偿性通路的多靶标抑制剂。该化合物能够用于制备抗血管生成药物中,具有抑制VEGFR‑2、Tie‑2和EphB4激酶活性的作以及抗细胞增殖活性的作用。三氮唑结构片段对化合物的抑制活性具有重要作用,铰链区杂环的引入可以提高小分子与受体的亲和力及抑制活性,可以作为多靶标抑制剂设计的新型药效片段。
Description
技术领域
本发明涉及一种嘧啶类化合物及应用。
背景技术
抗血管生成主要应用于包括恶性肿瘤在内的各种血管增生性疾病的治疗。旨在降低血管密度和抑制血管生成。最初假设抗血管生成抑制剂可以规避典型的药物抗性,因为其靶细胞是遗传稳定的内皮细胞。但是,多种促血管生成因子诱导的肿瘤侵袭性增加和随后获得的耐药性,所以并非所有患者都从抗血管生成治疗中受益。
为了更好地确定癌细胞的抗性,做了更加深入的研究,这使得它们能够克服抗血管生成策略。抗血管生成抑制剂的获得性耐药主要是由促血管生成因子的代偿性激活引起。促血管生成因子的代偿性激活使得肿瘤能够规避单一途径的阻断。抗血管生成抑制剂则能够诱导血管正常化并增强化疗药物的传递。另一种机制是减少缺氧以获得癌细胞最大程度的死亡。抗血管生成疗法暂时性的增加氧合和药物递送。临床和实验研究已经证明,在使用抗血管生成抑制剂的治疗后,肿瘤采用代偿性血管生成途径以及其持续生长和转移的其他适应性机制。因此,导致肿瘤生长和转移的代偿性信号通路成为肿瘤难治性的潜在原因。
Sato等研究证实:多种调控因子共同参与了血管生成过程,单一靶标药物作用后会诱发其他调控因子的代偿性激活。Wang和Sawamiphak等发现EphB4被抑制后可激活VEGFR-2,作为代偿性通路促进血管生成。此外,EphB4也可调控VEGFR-2的活性,在血管生成中发挥总调控者的作用,EphB4与VEGFR-2的表达也呈高度一致性。Erber等发现EphB4被抑制后能够代偿性上调Tie-2和VEGFR-2的表达,进而促进血管生成。Huang等证实Tie-2的促血管生成作用是VEGFR-2依赖性的,特别是当VEGFR-2被抑制时,Tie-2可作为替代性促血管生成因子被代偿性激活。这三条代偿性通路的激活均能够使血管生成调控的动态平衡再度失调,引起血管再次异常增生,进而缩短并最终关闭血管正常化的"时间窗"。
目前,虽然抗血管生成药物的研究取得了一些创新性的进展,但是还存在以下问题:①调控血管生成是一个网络,涉及多个信号通路,单靶标药物作用后,血管生成往往出现代偿性通路,导致耐药性的产生;②已发现的抗血管生成药物作用靶标选择性不高,不良反应较多;③单靶标抗血管生成药物只能作用于血管生成过程的一个环节,血管生成的多因子调控及其复杂性直接限制了单靶标药物的效果。抗血管生成药物的研究虽然用于临床的时间不长,还处于初级阶段,但对于病理性血管生成相关疾病的治疗具有确切的疗效和良好的应用前景,要成为一种应用于临床的成熟方法还需要更多的基础研究探索。
因此,血管正常化可能有助于在抗血管生成疗法期间,在某个时间段内具有改善的循环,使得化疗疗法更有效。抗血管生成抑制剂抗性的机制是高度可变的,并且取决于抗血管生成抑制剂的不同而不同。促血管生成因子如VEGFR-2,Tie-2,EphB4和FGFR的代偿性激活是可能导致反应性和耐药性差的主要机制。
发明内容
本发明的目的在于提供一种嘧啶类化合物及应用。
为实现上述目的,本发明采用如下的技术方案:
一种嘧啶类化合物,该化合物的结构式如下:
本发明进一步的改进在于,R1具体如下:
本发明进一步的改进在于,R1为Cl时,制备方法如下:
对溴苄叠氮的合成:在冰浴条件下,将对溴苄溴溶于无水DMF中,滴加第一份叠氮化钠水溶液,升至室温再滴加第二份叠氮化钠水溶液,滴加完毕后,室温反应12h,减压蒸馏,层析柱分离,得到黄色油状物,即为对溴苄叠氮;
1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑的合成:将对溴苄叠氮以及间氯苯乙炔溶于无水乙醇,然后加入L-抗坏血酸钠和五水合硫酸铜后加入水,室温搅拌12h,减压蒸馏,用层析柱分离,得白色固体,即为1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑;
5-(4-(4-(3-氯苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶的合成:反应瓶中加入1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑,5-嘧啶硼酸,碳酸铯以及[1,1'-双(二苯基磷)二茂铁]二氯化钯,并加入1,4-二氧六环和水,在氮气保护下于100℃反应12h,冷却至室温,经过层析柱分离,得到白色固体,即为5-(4-(4-(3-氯苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶。
一种嘧啶类化合物在制备抗血管生成药物中的应用。
本发明进一步的改进在于,该化合物具有抑制VEGFR-2、Tie-2和EphB4激酶活性的作用。
本发明进一步的改进在于,该化合物具有抗血管内皮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VEGFR-2、EphB4、TIE-2可代偿性激活的发现,以联苯芳基脲为新型先导物,分析三种受体活性位点的保守构象并寻找共性结构域;采用分子杂交的药物设计策略,构建满足共性结构域构象要求的化合物库,通过多水平活性筛选发现同时拮抗三条代偿性通路的多靶标抑制剂。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,其中有R1为-CH3的嘧啶化合物对三种激酶有较好的抑制活性。细胞增殖试验表明大部分化合物都具有较强的细胞增殖抑制活性,活性结果实验证实R1为-CH3的嘧啶化合物对人脐静脉内皮细胞有很强的抑制活性。构效关系分析发现:三氮唑结构片段对化合物的抑制活性具有重要作用,铰链区杂环的引入可以提高小分子与受体的亲和力及抑制活性,可以作为多靶标抑制剂设计的新型药效片段。分子模建显示R1为-CH3的嘧啶化合物与三种受体酪氨酸激酶活性位点的氨基酸残基均有氢键相互作用,与活性口袋有较好的空间场与立体场的匹配性。
进一步的,利用酰化、Suzuki偶联、点击化学等反应合成目标化合物,该化合物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。
具体实施例方式
下面结合附图对本发明进行详细说明。
参见图1,本发明的吡唑类化合物的结构式为:
表1本发明的化合物的具体结构
表1中的R1中的数字是表示R1基团在苯环上的位置。
参见图1,本发明的具体的制备过程如下:
化合物对溴苄叠氮(3)的合成:在冰浴条件下,将对溴苄溴(2)2.00g(8.00mmol)溶于20mL无水DMF中,缓慢滴加叠氮化钠(叠氮化钠的量为0.78g(11.99mmol))的水溶液,升至室温再缓慢滴加用叠氮化钠(叠氮化钠的量为0.78g(11.99mmol))的水溶液,滴加完毕后,撤去冰浴,室温反应过夜,即12h。反应结束后,用乙酸乙酯萃取2~3次,萃取的有机相依次用饱和NaHCO3溶液(60mL×3),饱和NaCl洗涤(60mL×3),无水Na2SO4干燥,过滤,减压蒸出溶剂,用层析柱分离(石油醚:乙酸乙酯体积比=40:1),得到黄色油状物,即为对溴苄叠氮(3)1.45g,产率约为85.1%。
化合物1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑(4)的合成:在100ml反应瓶中,将1.20g(5.63mmol)对溴苄叠氮(3)以及0.78g(5.63mmol)间氯苯乙炔(1)溶于30ml无水乙醇,然后加入0.45g(2.25mmol)L-抗坏血酸钠以及0.29g(1.13mmol)五水合硫酸铜后再加入3mL水,室温搅拌过夜,即12h。减压蒸馏除去溶剂,用层析柱分离(石油醚:乙酸乙酯体积比=3:1),得白色固体,即为1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑(4)1.31g,产率约为66.7%。
化合物5-(4-(4-(3-氯苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶(MD1)的合成与结构表征:反应瓶中加入1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑(4)1.20g(3.44mmol),5-嘧啶硼酸(5)0.60g(4.82mmol),碳酸铯1.43g(10.35mmol)以及[1,1'-双(二苯基磷)二茂铁]二氯化钯0.25g(0.34mmol)四种反应试剂,并加入30mL 1,4-二氧六环和10mL水,在氮气保护下于100℃反应过夜,即12h。冷却至室温,用乙酸乙酯萃取3-4次,萃取的有机相依次用饱和NaHCO3溶液(60mL×3),饱和NaCl洗涤(60mL×3),无水Na2SO4干燥,旋干,经过层析柱分离(石油醚:乙酸乙酯=15:1),得到白色固体,即为5-(4-(4-(3-氯苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶(MD1)0.34g,产率28%,m.p.=176-178℃。HRMS(ESI)[M+H]+:m/z=347.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.15(s,2H),8.81(s,1H),7.93(s,1H),7.86(d,J=8.0Hz,3H),7.50(dd,J=23.7,7.9Hz,3H),7.40(d,J=8.0Hz,1H),5.75(s,2H).13C NMR(101MHz,DMSO)δ157.92,155.28,145.90,137.06,134.22,133.23,133.20,131.39,129.44,128.21,127.94,125.29,124.18,122.94,53.24.
化合物MD2~MD8的合成同上,5-嘧啶硼酸与含不同取代基的中间体4通过Suzuki偶联反应得到目标化合物。
化合物5-4-(4-(2-氟苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶(MD2)的合成与结构表征:产率23%,m.p.=152-154℃。HRMS(ESI)[M+H]+:m/z=345.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.14(s,2H),8.62(d,J=3.8Hz,1H),8.18–8.11(m,1H),7.85(d,J=8.3Hz,2H),7.57–7.52(m,2H),7.45–7.38(m,1H),7.38–7.30(m,2H),5.78(s,2H).13C NMR(101MHz,DMSO)δ157.88,155.26,137.26,134.13,133.20,130.26,130.17,129.37,127.90,127.81,127.77,125.49,125.46,124.63,124.51,118.83,118.70,116.63,116.41,53.01.
化合物5-(4-(4-苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶(MD3)的合成与结构表征:产率30%,m.p.=147-149℃。HRMS(ESI)[M+H]+:m/z=313.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.15(s,2H),8.71(s,1H),7.86(dd,J=7.7,3.3Hz,4H),7.53(d,J=8.2Hz,2H),7.45(t,J=7.6Hz,2H),7.34(t,J=7.4Hz,1H),5.74(s,2H).13C NMR(101MHz,DMSO)δ157.91,155.27,147.24,137.27,134.16,133.22,131.14,129.42,129.35,128.44,127.93,125.68,122.17,53.13.
化合物5-(4-(4-(对甲苯基)-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶(MD4)的合成与结构表征:产率18%,m.p.=203-205℃。HRMS(ESI)[M+H]+:m/z=327.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.15(s,2H),8.64(s,1H),7.85(d,J=8.3Hz,2H),7.75(d,J=8.1Hz,2H),7.52(d,J=8.2Hz,2H),7.26(d,J=8.0Hz,2H),5.72(s,2H),2.33(s,3H).13CNMR(101MHz,DMSO)δ157.92,155.28,147.30,137.74,137.30,134.15,133.23,129.97,129.37,128.38,127.93,125.62,121.73,53.10,21.34.
化合物5-(4-(4-(间甲苯基)-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶(MD5)的合成与结构表征:产率25%,m.p.=165-167℃。HRMS(ESI)[M+H]+:m/z=327.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.15(s,2H),8.68(s,1H),7.89–7.83(m,2H),7.73–7.61(m,2H),7.55–7.51(m,2H),7.33(t,J=7.6Hz,1H),7.15(d,J=7.5Hz,1H),5.73(s,2H),2.36(s,3H).13C NMR(101MHz,DMSO)δ157.92,155.28,147.34,138.57,137.27,134.17,133.22,131.05,129.38,129.32,129.08,127.93,126.25,122.84,122.10,53.13,21.55.
化合物5-4-(4-(三氟甲基)苯基)-1H-1,2,3-三唑1-基)甲基)苯基)嘧啶(MD6)的合成与结构表征:产率37%,m.p.=194-196℃。HRMS(ESI)[M+H]+:m/z=381.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.15(s,2H),8.89(s,1H),8.10(d,J=8.1Hz,2H),7.84(dd,J=16.1,8.3Hz,4H),7.55(d,J=8.2Hz,2H),5.77(s,2H).13C NMR(101MHz,DMSO)δ157.93,155.28,145.86,137.05,135.10,134.25,133.20,129.45,127.96,126.44,126.40,126.22,123.46,123.40,53.26.
化合物3-(1-(4-(嘧啶-5-基)苄基)-1H-1,2,3-三唑-4-基)苯胺(MD7)的合成与结构表征:产率36%,m.p.=180-182℃。HRMS(ESI)[M+H]+:m/z=328.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.15(s,2H),8.53(s,1H),7.85(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.08(dd,J=16.2,8.5Hz,2H),6.94(d,J=7.7Hz,1H),6.53(d,J=8.7Hz,1H),5.71(s,2H),5.19(s,2H).13C NMR(101MHz,DMSO)δ157.91,155.28,149.58,147.91,137.38,134.13,133.24,131.58,129.88,129.35,127.91,121.70,114.14,113.52,110.95,53.03.
化合物N-(3-(1-(4-(嘧啶-5-基)苄基)-1H-1,2,3-三唑-4-基)苯基)环丙烷甲酰胺(MD8)的合成与结构表征:在冰浴条件下,将化合物3-(1-(4-(嘧啶-5-基)苄基)-1H-1,2,3-三唑-4-基)苯胺(MD7)0.2g(0.60mmol)溶于10ml无水二氯甲烷,缓慢滴加无水三乙胺0.15ml(1.08mmol),搅拌30分钟后,再缓慢加入0.10ml(1.20mmol)环丙甲酰氯的二氯甲烷溶液,滴加完毕,撤去冰浴,室温反应过夜,即12h。用二氯甲烷萃取3-4次,萃取的有机相依次用饱和NaHCO3溶液(60mL×3),饱和NaCl洗涤(60mL×3),无水Na2SO4干燥,旋干,经过层析柱分离(石油醚:乙酸乙酯体积比=15:1),得到白色固体(MD8)0.20g,产率:83%,m.p.=210-212℃。HRMS(ESI)[M+H]+:m/z=395.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.20(s,1H),9.15(s,2H),8.65(s,1H),8.17(t,J=1.9Hz,1H),7.85(d,J=8.3Hz,2H),7.54(d,J=8.2Hz,3H),7.48(d,J=7.8Hz,1H),7.35(t,J=7.9Hz,1H),5.73(s,2H),1.80(s,1H),0.82(s,4H).13C NMR(101MHz,DMSO)δ172.29,157.93,155.31,147.20,140.42,137.29,134.20,133.26,131.56,129.87,129.44,127.96,122.18,120.47,118.99,116.12,53.13,15.07,7.75.
本发明的嘧啶类化合物的构效关系如下:
VEGFR-2/Tie-2/EphB4抑制活性:
表2嘧啶类系列化合物对VEGFR-2/Tie-2/EphB4抑制活性IC50(nM)
comp | R<sub>1</sub> | VEGFR-2 | Tie-2 | EphB4 |
MD2 | 2-F | 7.63 | 47.54 | 0.25 |
MD3 | H | 10.87 | 51.86 | 0.32 |
MD4 | 4-CH<sub>3</sub> | 11.06 | 25.74 | 3.30 |
MD5 | 3-CH<sub>3</sub> | 2.57 | 13.71 | ND |
MD7 | 3-NH<sub>2</sub> | 55.95 | 210 | ND |
ND=未测定
由表2可以看出,大部分化合物对VEGFR-2、Tie-2和EphB4具有同时抑制作用。对VEGFR-2的抑制活性来说,化合物MD2(IC50=7.63nM)和MD5(IC50=2.57nM)抑制活性在10nM以下,抑制活性在10~60nM之间的有两个,分别是MD4(IC50=11.06nM)和MD7(IC50=55.95nM)。对Tie-2来说,MD3(IC50=51.86nM),MD4(IC50=11.06nM)和MD5(IC50=13.71nM)抑制活性在10~60nM之间。对EphB4来说,抑制活性在10nM以下的化合物有3个,分别是化合物MD2(IC50=0.25nM),MD3(IC50=0.32nM)和MD4(IC50=3.30nM),且化合物MD2(IC50=0.25nM)和MD3(IC50=0.32nM)的抑制活性与阳性药索拉菲尼的抑制活性相当。化合物MD4对三种激酶显示有较好的抑制活性。活性结果显示,取代基类型和位置的不同都对生物活性影响较大。嘧啶系列化合物中苯环上取代基团为对位甲基时对三种激酶具有较好的抑制活性。
抗血管内皮细胞增殖活性:
表3嘧啶类系列化合物对人脐静脉内皮细胞抑制活性IC50(μM)
测定化合物对人脐静脉内皮细胞(EA.hy926)的抗增殖活性。从表3可以看出,大部分化合物具有较好的抗细胞增殖活性,部分化合物具有比阳性药更好的抑制活性。化合物MD1(IC50=7.83μM)和MD4(IC50=1.01μM)较索拉菲尼具有更高的抑制活性,化合物MD2(IC50=7.83μM),MD3(IC50=35.53μM),MD6(IC50=46.84μM),MD7(IC50=30.21μM)和MD8(IC50=17.26μM)抑制活性在10~50μM之间,与索拉菲尼抑制活性相当。化合物MD4(IC50=1.01μM)对细胞的抗增殖活性最强且对VEGFR-2/Tie-2/EphB4三种激酶均显示较好的抑制活性。
对于嘧啶类化合物,主要通过在右侧苯环引入不同取代基和取代位置的不同,探讨对活性结果的影响。活性结果显示,取代基类型和位置的不同都对生物活性影响较大。化合物MD4(IC50=1.01μM)对细胞的抗增殖活性最强且对VEGFR-2/Tie-2/EphB4三种激酶均显示较好的抑制活性,值得开展深入的活性筛选研究。
Claims (6)
3.根据权利要求1所述的一种嘧啶类化合物,其特征在于,R1为Cl时,制备方法如下:
对溴苄叠氮的合成:在冰浴条件下,将对溴苄溴溶于无水DMF中,滴加第一份叠氮化钠水溶液,升至室温再滴加第二份叠氮化钠水溶液,滴加完毕后,室温反应12h,减压蒸馏,层析柱分离,得到黄色油状物,即为对溴苄叠氮;
1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑的合成:将对溴苄叠氮以及间氯苯乙炔溶于无水乙醇,然后加入L-抗坏血酸钠和五水合硫酸铜后加入水,室温搅拌12h,减压蒸馏,用层析柱分离,得白色固体,即为1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑;
5-(4-(4-(3-氯苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶的合成:反应瓶中加入1-(4-溴苄基)-4-(3-氯苯基)-1H-1,2,3-三唑,5-嘧啶硼酸,碳酸铯以及[1,1'-双(二苯基磷)二茂铁]二氯化钯,并加入1,4-二氧六环和水,在氮气保护下于100℃反应12h,冷却至室温,经过层析柱分离,得到白色固体,即为5-(4-(4-(3-氯苯基-1H-1,2,3-三唑-1-基)甲基)苯基)嘧啶。
4.一种如权利要求1-2中任意一项所述的嘧啶类化合物在制备抗血管生成药物中的应用。
5.根据权利要求4所述的应用,其特征在于,该化合物具有抑制VEGFR-2、Tie-2和EphB4激酶活性的作用。
6.根据权利要求4所述的应用,其特征在于,该化合物具有抗血管内皮细胞增殖活性的作用。
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