CN116589402A - 一种作为NAMPT-PDEδ双靶点抑制剂的化合物及其应用 - Google Patents
一种作为NAMPT-PDEδ双靶点抑制剂的化合物及其应用 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
本发明公开了一种作为NAMPT‑PDEδ双靶点抑制剂的化合物或其药用盐,结构通式选自以下结构的一种:本发明还公开了所述作为NAMPT‑PDEδ双靶点抑制剂的化合物或其药用盐在制备NAMPT‑PDEδ双靶点抑制剂中的应用,以及所述作为NAMPT‑PDEδ双靶点抑制剂的化合物或其药用盐在制备抗肿瘤的药物中的应用。本发明制备的化合物体外抗肿瘤活性测试表现出较强的体外抗肿瘤活性和广谱抗肿瘤的特点;NAMPT和PDEδ抑制活性表明,大部分化合物对两者均有较强的抑制作用,是针对NAMPT‑PDEδ的双靶点抑制剂,本发明化合物可以用于治疗恶性肿瘤及与分化增殖相关疾病。
Description
技术领域
本发明属于医药技术领域,具体地说,涉及一种作为NAMPT-PDEδ双靶点抑制剂的化合物及其应用。
背景技术
NAD在细胞生理过程中起着至关重要的作用,肿瘤细胞的快速增殖和更高的能量代谢等特征,使其对NAD生物合成途径的限速酶NAMPT更加敏感,因此NAMPT成为癌症治疗中热门的靶点。目前已发现的NAMPT抑制剂均能有效地、有选择性地降低肿瘤细胞内NAD水平,表现出较强的肿瘤细胞杀伤作用,且能够抑制小鼠移植瘤的生长。但大多数已报道的NAMPT小分子抑制剂存在剂量毒性问题,限制了其进一步应用。其中进入临床研究的NAMPT抑制剂有FK866和CHS828,然而这两个化合物均表现出了剂量限制性的血小板减少症、胃肠道症状等毒副作用,目前研究已处于停滞状态。因此,降低NAMPT抑制剂毒副作用已成为了NAMPT研究的重要方向。近年来,基于NAMPT的多靶点药物已成为一个研究热点,其能产生协同效应,发挥更高的药效,同时还有效降低药物副作用。因此,基于NAMPT与其具有协同抗癌活性的靶点,设计开发新型双靶点抑制剂,可能是实现细胞内多靶点平衡调节,减少毒副作用,提高抗癌疗效的有效策略。
KRAS蛋白作为一个二元分子开关,在激活状态下KRAS蛋白的三磷酸鸟苷(guanosine triphosphate,GTP)结合位点与GTP结合,将效应蛋白募集至细胞膜上,进而激活Mst1、PI3K/Akt、MAPK等下游生长增殖相关信号通路,引起细胞增殖;当KRAS蛋白处于失活状态时,KRAS-GTP复合物被水解,此时KRAS蛋白迅速与二磷酸鸟苷(guanosinediphosphate,GDP)结合形成KRAS-GDP复合物,并因此停止对下游生长增殖信号通路的激活。而癌变状态下,KRAS突变损害蛋白内在GTP酶活性,阻止其从活性形式GTP向非活性形式GDP的转化,使KRAS蛋白持续和GTP结合并持久激活下游生长增殖信号通路,从而导致细胞过度增殖和癌症的发生。近年来,针对突变型KRAS蛋白的靶向药物一直是医药领域的研究热点。然而,由于KRAS蛋白体积小、表面平坦,缺乏传统小分子药物可以结合的“深口袋”结构,且与GTP结合紧密,多年来一直没有有效药物,因此被认为是“难成药靶标”(Undruggable Target)。目前,先后有多种靶向KRAS蛋白的药物处于临床试验阶段,进展十分缓慢或面临失败。因此,研发新型广谱KRAS蛋白干预策略对癌症治疗具有重要的研究价值。
KRAS信号传导的功能主要取决于其在细胞内的位置,研究发现PDEδ在调节KRAS蛋白在细胞膜上的定位中发挥着重要作用。PDEδ是Pde6d基因编码蛋白,其疏水空腔能够结合KRAS蛋白的法尼基,增强其在细胞内的扩散,同时PDEδ能促进KRAS在细胞膜上的正确定位和富集,对维持KRAS蛋白的相关信号通路起着关键作用。因此,通过靶向抑制PDEδ,阻断KRAS-PDEδ蛋白-蛋白相互作用能够有效干扰KRAS信号的传导,广谱阻断KRAS下游的信号通路,发挥抗胰腺癌作用。例如,基于AlphaScreen筛选发现的苯二磺胺类、苯并咪唑类化合物等PDEδ小分子抑制剂均显示出高效抑制KRAS-PDEδ蛋白-蛋白相互作用的活性。然而,现有的PDEδ小分子抑制剂普遍存在细胞活性低、成药性能差等问题,进一步的结构优化仍未显著提升其代谢稳定性。此外,蛋白结合活性与抗肿瘤活性不匹配是PDEδ小分子抑制剂研究所面临的主要问题之一,尤其是到目前为止,PDEδ小分子抑制剂体内抗肿瘤药效尚未见报道。细胞活性和体内药效的提升是当前PDEδ小分子抑制剂研发的瓶颈问题。因此,通过拓展化学结构类型,研发更为高效的PDEδ抑制剂可能是治疗胰腺癌的新思路。此外,PDEδ蛋白的功能还没有研究透彻,与其他靶点间的协作机制仍有待进一步阐明,需要开发合适的工具分子辅助研究蛋白的协同功能。
研究发现,PDEδ和NAMPT在调控细胞代谢的内稳态上具有一定协同效应。KRAS蛋白突变可导致多条代谢通路改变,这是肿瘤代谢重编程的重要驱动因素,对胰腺癌的发生发展至关重要,NAD是其中关键的辅因子。由此推测同时抑制NAMPT和PDEδ两个靶点,共同促使胰腺癌细胞代谢通路趋向稳定,能够产生抗胰腺癌协同作用。基于上述理论,PDEδ抑制剂4与NAMPT抑制剂MS0开展了协同抗胰腺癌活性测试(协同指数CI<1.0),提示PDEδ和NAMPT信号通路存在协同。上述证据表明,设计PDEδ/NAMPT双靶点抑制剂有望成为研发胰腺癌治疗药物的新策略。
研究发现NAMPT抑制剂和PDEδ抑制剂均可分为头部基团、链接基团、尾部基团三部分。都具有相似的链状骨架结构特征:1)头部基团,由含氮杂环和氢键受体构成的核心基团,模拟底物结构;2)烷基或芳基连接子,结合蛋白的疏水性腔道;3)尾部基团指向蛋白表面。NAMPT抑制剂的活性必须基团在头部,尾部为活性非必须基团朝向蛋白表面一侧;同样,PDEδ抑制剂活性非必须基团指向蛋白表面,当对其进行结构改造后可起到增强活性的作用,这为构建PDEδ/NAMPT双靶点抑制剂提供了可行性依据。
发明内容
本发明的目的是提供一种作为NAMPT-PDEδ双靶点抑制剂的化合物。
本发明的第二目的是提供一种所述作为NAMPT-PDEδ双靶点抑制剂的化合物在制备NAMPT-PDEδ双靶点抑制剂中的应用。
为了实现上述目的,本发明采用的技术方案如下:
本发明的第一方面提供了一种作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐,结构通式选自以下结构的一种:
其中,X选自键、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、
R1选自
R2选自氢、卤素(氟、氯、溴、碘)、C1~C10烷氧基(如甲氧基、乙氧基、异丙氧基、正丙氧基、叔丁氧基、正丁氧基等)、C1~C10烷基(如甲基、乙基、异丙基、正丙基、叔丁基、正丁基等);
R3选自氢、卤素(氟、氯、溴、碘)、C1~C10烷氧基(如甲氧基、乙氧基、异丙氧基、正丙氧基、叔丁氧基、正丁氧基等)、C1~C10烷基(如甲基、乙基、异丙基、正丙基、叔丁基、正丁基等);
R4选自氢、卤素(氟、氯、溴、碘)、C1~C10烷氧基(如甲氧基、乙氧基、异丙氧基、正丙氧基、叔丁氧基、正丁氧基等)、C1~C10烷基(如甲基、乙基、异丙基、正丙基、叔丁基、正丁基等);
R5选自氢、卤素(氟、氯、溴、碘)、C1~C10烷氧基(如甲氧基、乙氧基、异丙氧基、正丙氧基、叔丁氧基、正丁氧基等)、C1~C10烷基(如甲基、乙基、异丙基、正丙基、叔丁基、正丁基等);
R6选自氢、卤素(氟、氯、溴、碘)、C1~C10烷氧基(如甲氧基、乙氧基、异丙氧基、正丙氧基、叔丁氧基、正丁氧基等)、C1~C10烷基(如甲基、乙基、异丙基、正丙基、叔丁基、正丁基等);
R7选自氢、卤素(氟、氯、溴、碘);
R8选自氢、卤素(氟、氯、溴、碘);
R9选自氢、卤素(氟、氯、溴、碘);
R10选自氢、卤素(氟、氯、溴、碘);
R11选自氢、卤素(氟、氯、溴、碘)。
所述药用盐是其有机酸盐或无机酸盐。
所述无机酸为盐酸、硫酸、磷酸、二磷酸、氢溴酸或硝酸;所述有机酸为乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸、鞣酸、枸橼酸、三氟醋酸、苹果酸或苯磺酸盐。
所述药用盐不含结晶水,或含一个以上结晶水。
优选的,所述作为NAMPT-PDEδ双靶点抑制剂的化合物选自以下结构的一种:
本发明的第二方面提供了一种所述作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐在制备NAMPT-PDEδ双靶点抑制剂中的应用。
本发明的第三方面提供了一种所述作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐在制备抗肿瘤的药物中的应用。
所述肿瘤选自胰腺癌、结直肠癌、肺癌等。
所述肿瘤的细胞选自MiaPaca-2人胰腺癌细胞、HCT116人结肠癌细胞、A549人肺癌细胞。
本发明选用CCK8法进行活性测试,NAMPT抑制剂(MS0)、PDEδ抑制剂(化合物4)作为阳性对照药。药理实验表明本发明的化合物或其药用盐,对3种肿瘤细胞株(MiaPaca-2人胰腺癌细胞、HCT116人结肠癌细胞,A549人肺癌细胞)的体外抗肿瘤活性结果显示,大部分化合物对三种肿瘤细胞株均表现出了中等以上的细胞抗增殖活性,大部分化合物较阳性药物MS0和化合物4活性均有明显提升。
本发明的化合物经酶抑制活性和体外抗肿瘤活性试验发现,本发明的化合物对NAMPT和PDEδ蛋白均具有很强的抑制活性,而且具有较强的体外抗肿瘤活性,部分化合物对MiaPaca-2、HCT116、A549细胞具有很好的抑制活性,且表现出优于阳性药化合物4和MS0的抑制活性。
体外抗肿瘤活性测试表明,本发明制备的化合物表现出较强的体外抗肿瘤活性和广谱抗肿瘤的特点。NAMPT和PDEδ抑制活性表明,大部分化合物对两者均有较强的抑制作用,是NAMPT和PDEδ的双靶点抑制剂,例如化合物A6、B5、B14。本发明探索了NAMPT和PDEδ两个靶点抑制剂的设计、合成、抗肿瘤活性研究,本发明制备的化合物或其药用盐具有全新的结构骨架,作为抗肿瘤及分化和增殖相关的药物开发,具有进一步研究的价值。因此,本发明制备的化合物或其药用盐可以用于制备多靶点抗肿瘤药物。
由于采用上述技术方案,本发明具有以下优点和有益效果:
本发明制备的化合物体外抗肿瘤活性测试表现出较强的体外抗肿瘤活性和广谱抗肿瘤的特点;NAMPT和PDEδ抑制活性表明,大部分化合物对两者均有较强的抑制作用,是针对NAMPT-PDEδ的双靶点抑制剂,本发明化合物可以用于治疗恶性肿瘤及与分化增殖相关疾病。本发明制备的化合物B5具有优异的分子水平抑制活性(NAMPT IC50值为3.41nM,PDEδIC50值为0.5nM),在三种不同的肿瘤细胞株上也表现出优越的生长抑制活性(IC50均在10nM以下)。
附图说明
图1是化合物B5的体内抗肿瘤效力结果示意图。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
以下实施例所涉化合物的化学结构式、1H-NMR和MS数据详见表1。其中表1、2、3中的编号A1-A8,B1-B19与说明书的保持一致。
表1.本发明化合物的结构式和核磁质谱数据
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实施例1
N-(4-(N-(4-氯苄基)-N-环戊基氨磺酰基)苯基)烟酰胺(化合物A1)的制备
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第一步,制备中间体I:N-(4-氯苄基)环戊胺
将对氯苯甲醛(1.41g,10mmol)溶于超干20mL甲醇中,加入环戊胺(0.85g,10mmol),加入无水硫酸钠(4.2g,30mmol),室温下反应12小时。反应完毕,于冰水浴中加入NaBH4(0.19g,5mmol),转移至室温反应2h,TLC监测反应完全。将反应液倒入水(20mL)中,用乙酸乙酯(50mL×3)萃取,有机相合并后经无水硫酸钠干燥,减压蒸除溶剂,浓缩得淡黄色油状体1.9g,即中间体I;无需进一步纯化直接进行下一步,收率91%。
第二步,制备中间体II:N-(4-氯苄基)-N-环戊基-4-硝基苯磺酰胺
将中间体I(1.91g,9.1mmol)溶于20mL二氯甲烷中,加入对硝基苯磺酰氯(1.68g,7.6mmol)、TEA(2.5mL,18.2mmol),室温下搅拌反应2h。反应完毕,加入DCM(100mL×2)萃取,合并有机相后水洗(200mL×1),饱和食盐水(200mL×1)洗,无水硫酸钠干燥,过滤,剩余物拌样,硅胶柱层析(PE/EA=4/1)进行纯化,得到淡黄色固体2.6g中间体II,收率86%。1HNMR(600MHz,DMSO-d6)δ:8.40(d,2H,J=8.9Hz),8.15(d,2H,J=8.8Hz),7.37-7.44(m,4H),4.41(s,2H),1.15-1.54(m,8H).13C NMR(150MHz,DMSO-d6)δ:150.3,145.8,138.7,132.0,129.1,128.7,125.1,59.7,46.7,29.1,23.3.
第三步,制备中间体III:4-氨基-N-(4-氯苄基)-N-环戊基苯磺酰胺
将中间体II(2.6g,6.5mmol)溶于30mL DCM/MeOH(2:1)中,加入Pd/C(0.7g,0.6mmol),在1atm氢气条件下室温搅拌过夜。待反应结束后,反应液经硅藻土过滤,用50mL甲醇冲洗滤层,滤液合并,减压蒸除溶剂,浓缩得白色固体2g中间体III,收率90%,无需进一步纯化直接进行下一步。1H NMR(600MHz,DMSO-d6)δ:7.46(d,2H,J=8.7Hz),7.39(s,4H),6.62(d,2H,J=8.7Hz),6.01(s,2H),4.24(s,2H),4.05-4.16(m,1H),1.31-1.43(m,6H),1.13-1.17(m,2H).13C NMR(150MHz,DMSO-d6)δ:153.37,139.95,131.63,129.40,129.07,128.51,125.12,113.30,59.21,46.28,28.97,23.43.
第四步,制备化合物A1:
将烟酸(0.074g,0.4mmol)溶于5mL的草酰氯以制备酰氯。反应过夜后,将多余的草酰氯旋干,固体溶于2mL DMF,加入DIPEA(0.058g,0.48mmol)、中间体III(0.1g,0.3mmol),室温反应2h。反应完成后,用EtOAc(3×100mL)萃取,合并的有机相用盐水洗涤,用无水Na2SO4干燥,过滤,减压浓缩。残余物用MeOH/DCM(0-10%)快速柱色谱纯化,得到白色固体14mg即化合物A1,收率33.7%。
实施例2
将实施例1中第四步所使用的烟酸替换成3-吡啶乙酸,其他同实施例1,获得化合物A2,收率44.2%。
实施例3
将实施例1中第四步所使用的烟酸替换成3-吡啶丙酸,其他同实施例1,获得化合物A3,收率53.5%。
实施例4
将实施例1中第四步所使用的烟酸替换成3-吡啶氧基乙酸,其他同实施例1,获得化合物A4,收率40.6%。
实施例5
将实施例1中第四步所使用的烟酸替换成3-吡啶丙烯酸,其他同实施例1,获得化合物A5,收率45.2%。
实施例6
将实施例1中第四步所使用的烟酸替换成2-(吡啶-3-基)环丙烷羧酸,其他同实施例1,获得化合物A6,收率37.5%。
实施例7
将实施例1中第四步所使用的烟酸替换成噻吩并[2,3-b]吡啶-2-甲酸,其他同实施例1,获得化合物A7,收率33.5%。
实施例8
将实施例1中第四步所使用的烟酸替换成噻吩并[2,3-c]吡啶-2-甲酸,其他同实施例1,获得化合物A8,收率48.8%。
实施例9
N-(4-氯苄基)-N-环丙基-4-(3-(吡啶-3-基甲基)脲基)苯磺酰胺(B1)的制备
将实施例1中第一步所使用的环戊胺替换成环丙烷,其他按照实施例1中第一步至第三步制备获得中间体IIIa,收率78.4%。
第一步,制备中间体IVa:(4-(N-环戊基-N-(4-氯苄基)氨磺酰基)苯基)氨基甲酸苯酯
将中间体IIIa(0.36g,1.0mmol)溶于20mL THF中,加入氯甲酸苯酯(0.18g,1.2mmol),室温反应4h。反应完毕,EA/水萃取(100mL×2),合并有机相,拌样硅胶柱层析(PE/EA=3/1)分离纯化,得到白色固体0.46g中间体IVa,收率95%。1H NMR(600MHz,DMSO-d6)δ:10.73(s,1H),7.86(d,2H,J=8.9Hz),7.73(d,2H,J=8.7Hz),7.39-7.47(m,6H),7.26-7.31(m,3H),4.33(s,2H),4.17-4.23(m,1H),1.44-1.47(m,4H),1.33-1.36(m,2H),1.13-1.18(m,2H).13C NMR(600MHz,DMSO-d6)δ:152.08,150.74,143.26,139.52,133.93,131.78,129.97,129.82,129.09,128.90,128.61,126.18,122.39,118.66,115.68,59.36,46.43,28.95,23.37HRMS(ESI):m/z calcd.for C25H25ClN2O4S 484.1224,found483.1156.[M-H]-.
第二步,制备化合物B1:
将中间体IVa(0.33g,0.7mmol)溶于20mL1,4-二氧六环中,加入三乙胺(0.21g,2.1mmol)、3-吡啶甲胺(0.09g,0.86mmol),70℃下反应4h。反应完毕,EA/水萃取(100mL×2),饱和氯化钠(100mL×2)反洗,合并有机相,无水硫酸钠干燥,减压浓缩,柱层析纯化(DCM/MeOH=100:5),得到黄色固体141mg即化合物B1,收率42%。
实施例10
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按照实施例9中第一步配比,将中间体IIIa替换为中间体III,制备获得中间体IVb,收率90.2%。
将实施例9中第二步所使用的中间体IVa替换成中间体IVb,其他与实施例9相同,获得化合物B2,收率45.6%。
实施例11
将实施例10中所使用的3-吡啶甲胺替换成3-吡啶乙胺,其他与实施例10相同,获得化合物B3,收率36.2%。
实施例12
将实施例10中所使用的3-吡啶甲胺替换成3-吡啶丙胺,其他与实施例10相同,获得化合物B4,收率26.9%。
实施例13
将实施例1中第一步所使用的对氯苯甲醛替换成对甲氧基苯甲醛,其他按照实施例1中第一步至第三步制备获得中间体IIIc,收率88%。
按照实施例9中第一步配比,将中间体IIIa替换为中间体IIIc,制备获得中间体IVc,收率90%。
将实施例9中第二步所使用的中间体IVa替换成中间体IVc,其他与实施例9相同,获得化合物B5,收率45.8%。
实施例14
将实施例13中所使用的3-吡啶甲胺替换成3-吡啶乙胺,其他与实施例13相同,获得化合物B6,收率34.5%。
实施例15
将实施例13中所使用的3-吡啶甲胺替换成3-吡啶丙胺,其他与实施例13相同,获得化合物B7,收率30.8%。
实施例16
将实施例1中第一步所使用的对氯苯甲醛替换成对氟苯甲醛,其他按照实施例1中第一步至第三步制备获得中间体IIId,收率86%。
按照实施例9中第一步配比,将中间体IIIa替换为中间体IIId,制备获得中间体IVd,收率90%。
将实施例9中第二步所使用的中间体IVa替换成中间体IVd,其他与实施例9相同,获得化合物B8,收率32.5%。
实施例17
将实施例16中的3-吡啶甲胺替换成3-吡啶乙胺,其他同实施例16,获得化合物B9,收率24.6%。
实施例18
将实施例16中的3-吡啶甲胺替换成3-吡啶丙胺,其他同实施例16,获得化合物B10,收率17.8%。
实施例19
将实施例1中第一步所使用的环戊胺替换成环己胺,其他按照实施例1中第一步至第三步制备获得中间体IIIe,收率82%。
按照实施例9中第一步配比,将中间体IIIa替换为中间体IIIe,制备获得中间体IVe,收率95%。
将实施例9中第二步所使用的中间体IVa替换成中间体IVe,其他与实施例9相同,获得化合物B11,收率35.4%。
实施例20
将实施例19中的3-吡啶甲胺替换成3-吡啶乙胺,其他同实施例19,获得化合物B12,收率33.5%。
实施例21
将实施例19中的3-吡啶甲胺替换成3-吡啶丙胺,其他同实施例19,获得化合物B13,收率19.6%。
实施例22
将实施例1中第一步所使用的对氯苯甲醛替换成对甲氧基苯甲醛,其他按照实施例1中第一步至第三步制备获得中间体IIIf,收率78%。
按照实施例9中第一步配比,将中间体IIIa替换为中间体IIIf,制备获得中间体IVf,收率93%。
将实施例9中第二步所使用的中间体IVa替换成中间体IVf,其他与实施例9相同,获得化合物B14,收率35.7%。
实施例23
将实施例22中的3-吡啶甲胺替换成3-吡啶乙胺,其他同实施例22,获得化合物B15,收率35.4%。
实施例24
将实施例22中的3-吡啶甲胺替换成3-吡啶丙胺,其他同实施例22,获得化合物B16,收率25.7%。
实施例25
将实施例1中第一步所使用的对氯苯甲醛替换成对氟苯甲醛,其他按照实施例1中第一步至第三步制备获得中间体IIIg,收率90%。
按照实施例9中第一步配比,将中间体IIIa替换为中间体IIIg,制备获得中间体IVg,收率92%。
将实施例9中第二步所使用的中间体IVa替换成中间体IVg,其他与实施例9相同,获得化合物B17,收率34.2%。
实施例26
将实施例25中的3-吡啶甲胺替换成3-吡啶乙胺,其他同实施例25,获得化合物B18,收率29.5%。
实施例27
将实施例25中的3-吡啶甲胺替换成3-吡啶丙胺,其他同实施例25,获得化合物B19,收率25.3%。
实施例28:本发明化合物的体外抑酶活性测试
1.目标化合物NAMPT蛋白抑制活性
(1)原理:NAMPT蛋白催化烟酰胺NAM转化为产物烟酰胺单核苷酸NMN;在检测反应中,经过两步化学反应,NMN被转化为有荧光的衍生物,在激发波长382nm、发射波长445nm处可检测到最大荧光信号。
(2)材料准备
a.测试液:牛血清蛋白(BSA,Kingmorn)+Tris-HCl(pH 7.5)+MgCl2(生工)
ATP溶液(100mM,生工)PRPP溶液(40mM,源叶)DTT溶液(2mM,生工)
b.化合物梯度稀释溶液
c.NAM溶液(0.2μM,生工);d.20%苯乙酮2M KOH 88%甲酸。
(3)酶活性测定方法
a)在96孔板中加入新鲜配制的测试液20μL,以及0.5μL的各浓度梯度化合物溶液,于室温静置5min;
b)再向96孔板中加入4.5μL的NAM溶液,空白对照组加入双蒸水;混匀后于37℃反应15min;
c)反应毕,在95℃加热1min后迅速放于冰上冷却以终止酶反应;
d)在终止的酶反应液中,加入20%苯乙酮和2M KOH各10μL,快速离心后,在涡旋混合仪上混匀,于0℃反应10min;
e)再加入45μL的88%甲酸,于37℃作用10min;
f)冷却后,于90μL的反应体系中取85μL转移到黑色平底96孔荧光板中;
g)用酶标仪测定激发光382nm、发射光445nm处的荧光值,用GraphPad Prism 9软件计算化合物对NAMPT的抑制活性。
2.化合物-探针竞争性抑制PDEδ测试
(1)实验材料:
PDEδ蛋白,缓冲液(PBS+charps+DMSO),96孔黑色板。
(2)实验方法:
基于荧光偏振检测方法(The Flruorescence Polarization,FP assay)对获得化合物进行了竞争性蛋白结合测试:
a.荧光标记的Atorvastatin的蛋白结合常数KD1的测试:将荧光标记的Atorvastatin溶解于DMSO,用PBS缓冲液(0.05%Chaps)稀释至24nM(0.5%DMSO),加入到梯度稀释的PDEδ蛋白中,室温避光孵育3小时,荧光各向异性值用Biotek Synergy酶标仪读取(ex:485nm,em:535nm)。蛋白结合常数根据荧光各向异性值用Mathematica 7(WolframResearch Inc.)拟合得到曲线。
b.进行化合物活性测定(KD2):选择文献报道的Deltazinone作为阳性对照,选择蛋白浓度为40nM,探针为25nM,然后将化合物半倍稀释,50μL化合物加入到50μL的蛋白探针混合液中,过夜30℃振荡孵育13h,荧光值及各项异性值检测使用Biotek Synergy H2酶标仪(485nm波长激发,528nm波长检测)。
(3)结果计算:数据拟合使用Mathamatica 9软件9(Wolfram Research Inc.)进行拟合。
实验结果表明,本发明的大部分化合物都表现出良好的NAMPT和PDEδ抑制活性,均在纳摩尔级,结果如表1所示,制备的酰胺类A系列分子大多数对NAMPT和PDEδ的抑制活性较差。如A1对NAMPT无活性,但碳链长度的延长改善了对NAMPT的抑制活性(化合物A3 vs A2)。此外,环戊烷替换为环丙烷或者环己烷,对NAMPT和PDEδ的活性同时丧失,由此表明,环烷烃的大小对PDEδ的活性影响较大。后保持吡啶环与酰胺键之间的碳原子数目大于3,替换不同的吡啶杂环酸,结果显示活性下降。
大多数的B类系列目标分子对NAMPT和PDEδ均表现出优良的双靶抑制活性。延长碳链长度,结果显示化合物对NAMPT抑制活性逐渐增大,(例如,化合物B2<B3<B4);当改变取代环的大小,环变小则对NAMPT抑制活性显著下降,改用环己基取代时则变现出PDEδ抑制活性下降,而改变碳链长度对活性无明显影响。
表1.目标化合物NAMPT和PDEδ抑制活性
实施例29:本发明化合物的体外抗肿瘤活性测试
采用了CCK8法测试了本发明合成化合物的体外抗肿瘤活性。
(1)实验材料:细胞株(人胰腺癌MiaPaca-2细胞,人结肠癌HCT116细胞,人肺癌A549细胞)、培养基(DMEM高糖培养基,F12K培养基,cytiva)、磷酸盐缓冲液(PBS,cytiva)、青霉素-链霉素混合液(双抗,cytiva)、CCK8测试盒(翊圣)、胎牛血清(FBS,雅酶)、马血清(Kingmorn)。
(2)仪器:Gen5操作软件,Bioteck Synergy2多功能酶标仪。
(3)培养基配制备:
MiaPaca-2细胞培养基:90%DMEM+9.75%FBS+1%双抗+0.25%马血清
HCT116细胞培养基:90%DMEM+10%FBS+1%双抗
A549细胞培养基:90%F12K+10%FBS+1%双抗(0.25%马血清)
CCK8测试液配制:90%DMEM基础培养基+10%CCK-8测试盒试剂
(4)实验方法:
a)观察培养皿中的细胞状态,将处于生长对数期的细胞用0.25%的胰酶消化,吹打收集,离心后弃上清,加入新鲜培养基2-4mL,吹打均匀,细胞计数仪进行计数。
b)按照6000个/孔的数量接种细胞于96孔板中,周围一圈加入PBS(100μL);放置于细胞孵育箱中37℃、5%CO2条件下培养24h;
c)加入配制好的不同浓度的待测化合物(100μL),并设置三复孔;
d)放置于细胞孵育箱中培养48-72h,吸除培养基,加入配制好的CCK8测试液(100μL);
e)在37℃下孵育15-30min后,用酶标仪测试样品在452nm处的OD值;
表2.目标化合物体外抗肿瘤活性结果IC50(μM)
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实验结果显示,本发明的化合物具有广谱抗肿瘤活性,其IC50值在0.001-10μM之间,与联合给药组相比,大多数化合物表现出优越或相当的抗增殖活性,且体外抗肿瘤活性与化合物对NAMPT-PDEδ抑制活性基本保持一致。
分析本发明制备的化合物的活性数据,初步进行总结:(1)本发明制备的化合物对MiaPaca-2和A549细胞整体活性好于HCT116(2)相比酰胺的A系列化合物,含有脲基的B类化合物活性更佳,(3)本发明制备的化合物中,当酰胺键与吡啶环距离小于3个碳原子时,活性几乎丧失;(4)当非活性必需基团疏水环替换为不同大小的环,其活性依次为五元环≈六元环>三元环;(5)当取代基为吸电子(氟取代、氯取代时,其活性略弱于给电子基团(甲氧基);此外,改变脲基团与吡啶基团的距离时,其活性无明显区别。
综合以上结果,化合物B5具有较好的分子水平抑制活性(NAMPT IC50值为3.41nM,PDEδIC50值为0.5nM),同样表现出优越的肿瘤细胞生长抑制活性。鉴于化合物B5表现出的均衡高效的双靶点抑制效应和优秀的体外抗肿瘤活性,选择化合物B5进行后续的生物活性评价。
实施例30优选化合物的体内抗肿瘤活性
根据体外抗肿瘤实验结果及化合物的结构特点,选择人胰腺癌MiaPaca-2细胞作为裸鼠移植瘤模型,以化合物B5作为研究对象,MS0、化合物4及MS0和化合物4两者联合用药作为阳性对照药。设置空白Control组、B5高剂量组(30mg/kg)、B5低剂量组(20mg/kg)、PDEδ抑制剂化合物4组(20mg/kg)、NAMPT抑制剂MS0组(10mg/kg)、及化合物4和MS0联合组(化合物420mg/kg、化合物MS010mg/kg)。裸鼠从上海圆创生物科技有限公司购买获得(重18~20g)。将MiaPaca-2细胞悬液皮下植入小鼠的右腋下区域。当植入的肿瘤长出并体积达到约100-300mm3时开始给药,将小鼠随机分组(每组6只)。将化合物B5悬浮于0.5%羧甲基纤维素中,以20mg/kg和30mg/kg的给药剂量,连续腹腔注射给药21天。此外每天腹膜内处理MS0(10mg/kg),化合物4(20mg/kg),化合物4+MS0或B5(20mg/kg,30mg/kg)21天,空白Control组小鼠接受0.5%羧甲基纤维素给药。通过卡尺测量长度和宽度来监测肿瘤体积,并使用以下公式计算TV=1/2×a×b2。其中a是肿瘤长度,b是宽度。在给药过程每2天监测肿瘤体积和体重。给药后第21天处死小鼠,取出各组肿瘤并记录分析。
实验结果如图1所示,图1是化合物B5的体内抗肿瘤效力结果示意图。其中,A是MiaPaca-2细胞体内异种移植小鼠模型的构建结果示意图,说明了MiaPaca-2胰腺癌异种移植模型的成功构建;B是MiaPaca-2胰腺癌异种移植裸鼠生长曲线示意图,结果显示每日腹膜内注射剂量为20mg/kg B5,使肿瘤生长抑制(TGI)达到59.4%,与空白Control组相比,该抗肿瘤活性优于单独使用10mg/kg MS0(TGI:13.0%)或20mg/kg化合物4(TGI:26.8%),并且优于化合物4和MS0联合组(TGI:44.1%)。值得注意的是,当化合物B5以30mg/kg(TGI:65.9%)的剂量给药时,抗肿瘤作用进一步增强,显著抑制了肿瘤的大小和重量;C是治疗期间小鼠体重的变化示意图,结果显示各组没有明显的体重减轻,证明化合物没有对小鼠产生明显的不良反应;D是所有组的主要器官(心脏,肝脏,脾脏,肺和肾脏)及肿瘤重量变化结果示意图,实验结果显示化合物B5给药组能够显著降低肿瘤重量并且对其他主要器官无明显影响;E是肿瘤组织解剖图片示意图。数据作为平均值表示±SD,n=3。*P<0.05和**P<0.01,与对照组相比。综上,化合物B5作为有效的NAMPT-PDEδ双重抑制剂对胰腺肿瘤表现出有效的抗肿瘤能力,并且没有明显毒性。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (6)
1.一种作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐,其特征在于,结构通式选自以下结构的一种:
其中,X选自键、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、
R1选自
R2选自氢、卤素、C1~C10烷氧基、C1~C10烷基;
R3选自氢、卤素、C1~C10烷氧基、C1~C10烷基;
R4选自氢、卤素、C1~C10烷氧基、C1~C10烷基;
R5选自氢、卤素、C1~C10烷氧基、C1~C10烷基;
R6选自氢、卤素、C1~C10烷氧基、C1~C10烷基;
R7选自氢、卤素;
R8选自氢、卤素;
R9选自氢、卤素;
R10选自氢、卤素;
R11选自氢、卤素。
2.根据权利要求1所述的作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐,其特征在于,所述作为NAMPT-PDEδ双靶点抑制剂的化合物选自以下结构的一种:
3.一种所述作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐在制备NAMPT-PDEδ双靶点抑制剂中的应用。
4.一种所述作为NAMPT-PDEδ双靶点抑制剂的化合物或其药用盐在制备抗肿瘤的药物中的应用。
5.根据权利要求4所述的应用,其特征在于,所述肿瘤选自胰腺癌、结直肠癌、肺癌。
6.根据权利要求4所述的应用,其特征在于,所述肿瘤的细胞选自MiaPaca-2人胰腺癌细胞、HCT116人结肠癌细胞、A549人肺癌细胞。
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