CN114907269A - 一种以哌嗪为连接基团的苯并咪唑-4-羧酰胺衍生物 - Google Patents
一种以哌嗪为连接基团的苯并咪唑-4-羧酰胺衍生物 Download PDFInfo
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- CN114907269A CN114907269A CN202210741921.8A CN202210741921A CN114907269A CN 114907269 A CN114907269 A CN 114907269A CN 202210741921 A CN202210741921 A CN 202210741921A CN 114907269 A CN114907269 A CN 114907269A
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Abstract
本发明涉及一系列以哌嗪为连接基团的苯并咪唑‑4‑羧酰胺衍生物,可作为新型有效的PARP‑1抑制剂。本发明使用PARP‑1试剂盒测定法和MTT法测试了这些衍生物的PARP‑1抑制活性以及对BRCA‑1缺陷细胞(MDA‑MB‑436)和野生细胞(MCF‑7)的抑制作用。结果表明,本发明化合物对PARP‑1酶表现出较好的抑制作用和对MDA‑MB‑436癌细胞有较好的抑制增殖作用。
Description
技术领域
本发明涉及药物化学领域,具体为一种2-(4-(4-乙酰基哌嗪-1-羰基)苯基)-1H-苯并[d] 咪唑-4-羧酰胺衍生物及其作为PARP-1抑制剂用途。
背景技术
1963年,Chambon等人首次发现了PARP酶。聚ADP-核糖聚合酶(PARP)是一个由 18个亚型组成的蛋白质家族,在DNA损伤修复过程中起重要作用。它还在广泛的生物学过程中发挥重要作用,例如凋亡和转录调节,维持基因组稳定性,细胞周期进程和染色质动力学调节。PARP-1是PARP家族中数量最多,特征最丰富的成员,它参与了真核细胞的碱基切除修复(BER)途径以修复DNA单链断裂。一旦DNA受损,PARP-1将被激活,以催化烟酰胺腺嘌呤二核苷酸(NAD+)转化为烟酰胺和ADP-核糖,将ADP-核糖单元转移到核受体蛋白上并在底物上形成聚(ADP-核糖)蛋白,对DNA修复的转移过程和维持基因组稳定性至关重要。1964年,Dobzhansky在果蝇研究中首次提出了合成致死的概念。两个非致命基因突变对细胞具有致命性,而具有一个或另一个突变的细胞则不会发生凋亡。研究人员发现, BRCA-1和BRCA-2种系突变会增加患乳腺癌和卵巢癌的风险。直到2005年才确认BRCA-1 和BRCA-2的缺失在PARP抑制敏感性中起着重要作用。最近,已经证明PARP-1和BRCA1/2 是合成致死的。PARP-1抑制剂可以选择性地靶向具有缺陷的BRCA1/2基因的肿瘤细胞,该基因可以在同源重组(HR)介导的双链DNA断裂修复中表达为两种必需蛋白。因此,PARP-1 抑制剂可以用作治疗BRCA1/2缺陷型癌症的单一药物。到目前为止,市场上有几种PARP抑制剂,例如olaparib(Lynparza),rucaparib(Rubraca),niraparib(Zejula)和talazoparib(Talzenna) 等;许多抑制剂在临床试验中都是候选药物,例如fuzuopali,veliparib(ABT-888)和Fluzoparib(SHR-3162)。
目前,所有PARP-1抑制剂都模仿NAD+的结构,竞争NAD+和PARP催化活性位点的组合以抑制PARP酶。PARP-1的催化结构域通常被表征为两个亚口袋,分别为烟酰胺-核糖结合位点(NI位点)和腺嘌呤-核糖结合位点(AD位点)。已知的PARP-1抑制剂的酰胺官能团通过与Ser904和Gly863形成关键氢键而占据Ni位点,而芳香族母核与Tyr907和Tyr896 产生π-π相互作用。与NI位点相比,AD位点是一个较大的疏水口袋,可以容纳NAD+的ADP- 核糖部分。与该口袋相互作用的不同基团可以提高这些化合物的抑制活性,改善其水溶性和理化性质。Penning等人引入了碱性胺可溶基团,其中氮原子与ASP-766相互作用。通过水分子使PARP的活性位点增加其细胞通透性。Jeffrey W.Johannes等人在侧链末端修饰了一个氰基吡啶部分,并且腈的氮与Asp-1198的-NH形成氢键,结果提示是及时的。Yi Zhong等人用硫代乙内酰脲环作为连接基团与Tyr-896和Ile895形成额外的氢键。Olaparib是第一种被批准用于治疗具有BRCA基因缺陷的晚期卵巢癌的PARP-1抑制剂,修饰了苄基上的氟原子使其与Gly-894的N末端相互作用,哌嗪上的氮与Asp-766形成了良好的电荷相互作用,从而丰富了AD位点之间的构效关系并为今后的研究提供了理论基础。
尽管PARP-1抑制剂的研究已取得巨大进展,但仍存在许多缺点,例如与化学疗法药物联合使用时严重的毒性,体内副作用或不良的药效学和药代动力学性质。因此,亟需开发更有效,更安全的PARP-1抑制剂。
发明内容
本发明的目的在于提供一种2-(4-(4-乙酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑 -4-羧酰胺衍生物,其能够有效地抑制PARP-1,同时对于BRCA-1缺陷细胞(MDA-MB-436)具有良好的抑制增殖作用。
本发明的第一个方面,是提供一类通式14化合物及其药学上可接受的盐:
其中:R选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C3-C10环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基;所述C3-C10环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基任选被一个或多个R’取代;
所述R’独立地选自卤素、硝基、-CN、C1-C3烷基。
优选地,R选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C3-C10环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基;所述C3-C10环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基任选被一个或多个R’取代;
所述R’独立地选自卤素、C1-C3烷基。
更优选地,R选自甲基、环丙基、苯基、5-6元杂芳基;所述环丙基、苯基、5-6元杂芳基任选被一个或多个R’取代;
所述R’选自氯、溴、甲基。
本发明的另一方面提供一种制备式14化合物的方法,其合成路线如下:
其中:各步骤的试剂和反应条件如下:(a)NH3(aq);(b)NaClO,NaOH,65℃;(c)SOCl2,60℃; (d)NH3·H2O,0℃;(e)Raney Ni,N2H4·H2O,60℃;(f)NaHSO3,H2O,CH3OH,60℃;(g)LiOH, H2O,40℃;(h)HBTU;(i)HCl,CH2Cl2;(j)HBTU;
R的选择范围如前所述。
本发明通过12个步骤的化学反应合成了一系列2-(4-(4-乙酰基哌嗪-1-羰基)苯基)-1H- 苯并[d]咪唑-4-羧酰胺衍生物(14)。关键中间体邻二氨基苯甲酰胺(6)是由市售的3-硝基邻苯二甲酸酐(1)为原料进行合成的。首先,通过氨基开环,霍夫曼重排反应和酰胺化反应将3-硝基邻苯二甲酸酐(1)转化为2-氨基-3-硝基苯甲酰胺(5)。然后,以甲醇作为溶剂,在雷尼镍(RaneyNi)催化下,用80%水合肼将其还原为邻二氨基苯甲酰胺(6)。中间体(6) 与4-甲酰基苯甲酸甲酯(7)的醛基进行环化反应,然后在碱性条件下高产率地水解为相应的羧酸(9)。此外,将N-Boc-哌嗪(10)与含有不同基团的羧酸(11a-11r)缩合,然后脱BOC 保护,得到中间体(13a-13r)。最后,将中间体(9)和中间体(13a-13r)进一步缩合,以合理的收率获得一系列目标化合物(14a-14r)。本文总共合成了18种目标化合物,并通过1HNMR,13C NMR,熔点和MALDI-TOF质谱法对其结构进行了表征。化合物的具体合成路线和关键点也显示在方案1中。
本发明的另一方面提供一种药物组合物,其包含式14所示的化合物或其药学上可接受的盐,以及药学上可接受的载体。
本发明另一方面涉及一种式14化合物在制备PARP-1抑制剂中的用途。
本发明另一方面涉及一种式14化合物在制备治疗乳腺癌药物中的用途;
优选地,所述乳腺癌是由MDA-MB-436细胞组成的。
定义:
“烷基”是指仅仅由碳和氢原子组成,不含有不饱和度,可为C1-6烷基。在一些实施方案中,烷基具有1至6或1至4个碳原子。代表性饱和直链烷基包括但不限于-甲基、-乙基、-正丙基、-正丁基、-正戊基和-正己基;而饱和支链烷基包括但不限于-异丙基、-仲丁基、-异丁基、-叔丁基、-异戊基、2-甲基丁基、3-甲基丁基、2-甲基-戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基-丁基等。烷基通过单键连接于母体分子。除非在说明书中另外陈述,否则烷基任选被一个或多个独立地包括以下的取代基取代:酰基、烷基、烯基、炔基、烷氧基、烷基芳基、环烷基。在一非限制性实施方案中,取代的烷基可选自氟甲基、二氟甲基、三氟甲基、2-氟乙基、3-氟丙基、羟基甲基、2-羟基乙基、3-羟基丙基、苯甲基和苯乙基。
“烷氧基”是指“烷基”通过氧原子与母体分子相连,其中“烷基”具有如上所述的定义。
“卤代烷基”是指其中所有氢原子部分或全部被选自氟代基、氯代基、溴代基和碘代基的卤素置换的烷基。在一些实施方案中,所有氢原子都各自被氟代基置换。在一些实施方案中,所有氢原子都各自被氯代基置换。卤代烷基的实例包括-CF3、-CF2CF3、-CF2CF2CF3、-CFCl2、 -CF2Cl等。
环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基
“环烷基”是指由碳、氢形成的饱和碳环的基团,例如C3-C10环烷基、C3-C8环烷基、C3-C6 环烷基,包括并不限于环丙基、环丁基、环戊基。环烷基通过单键连接于母体分子。除非在说明书中另外陈述,否则环烷基任选被一个或多个独立地包括以下的取代基取代:卤素、烷基、烯基、炔基、烷氧基、烷基芳基、环烷基。
“杂环烷基”是指环烷基的环上,有一个或多个环碳原子被杂原子取代,所述杂原子例如可以是N、O、S等。
“芳基”包括单环芳基(如苯基)和多环芳基,多环芳基例如萘、蒽、菲、联苯基等。
在某些实施方案中,药学上可接受的形式是药学上可接受的盐,药学上可接受的盐在本领域中是熟知的。药学上可接受的盐的实例是诸如盐酸、氢溴酸、磷酸、硫酸、高氯酸、乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸、乙酸、丙酸、乙醇酸、丙酮酸、草酸、乳酸、三氟乙酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸等。
“药学上可接受的载体”包括任何和所有溶剂、分散介质、包覆剂、抗细菌剂和抗真菌剂、等张剂和吸收延迟剂等。药学上可接受的载体或赋形剂不破坏公开的化合物的药理学活性,并且在以足以递送治疗量的化合物的剂量施用时是无毒的。药物活性物质的所述介质和试剂的使用在本领域中是熟知的。
与现有技术相比,本发明的有益效果是:
(1)本发明提供了一类新的具有PARP-1抑制活性的2-(4-(4-乙酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺衍生物,拓宽了现有的PARP-1抑制化合物的范围,可作为先导化合物继续优化;
(2)本发明化合物具有选择性抑制PARP-1,可作为选择性和/或靶向药物,具有良好的开发前景。
附图说明
图1为本发明化合物14q与PARP-1(PDB ID:5WS1)的分子对接。;
图2为本发明化合物14q的1H NMR谱图。
图3为本发明化合物14q的13C NMR谱图。
图4为本发明化合物14q的MALDI-TOF MS质谱图。
具体实施方式
除非另有说明,否则所有化学药品和试剂(试剂级)均购自标准商业供应商,无需进一步纯化即可使用。熔点(未校正)在ZRD-1全自动熔点仪上测定。在Brukerultraflextreme质谱仪上测量MALDI-TOF MS,并使用指示的溶剂和内标(TMS)在BrukerAV-400型光谱仪上记录1H NMR光谱。元素分析是在Perkin Elmer 2400CHN上完成的。化学位移的值以δ值(ppm) 和偶合常数(J)以赫兹(Hz)表示。峰重数通常描述如下:s,单峰;d,双峰;t,三胞胎;q,四重奏;m,多重。
实施例1:2-(4-(4-乙酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14a)
步骤a:2-氨基甲酰基-3-硝基苯甲酸(2)
在室温下,将2.0065g(0.01mol)的3-硝基邻苯二甲酸酐溶于30mL干燥的四氢呋喃中,搅拌3-4h。缓慢滴加2mL氨水,直到溶液从透明悬浮液变为白色悬浮液,然后在室温下继续搅拌4h。将悬浮液过滤并干燥,得到1.9654g的白色固体,产率为96.0%。
步骤b:2-氨基-3-硝基苯甲酸(3)
将35mL NaClO溶液滴加到1.994g(0.009mol)的2-氨基甲酰基-3-硝基苯甲酸(2),NaOH 4.0013g(0.1mol)的混合物中,在冰浴下剧烈搅拌2h。将反应加热至65℃。约3小时后,反应完成并产生橙红色固体。将固体溶解在10mL蒸馏水中,然后通过浓硫酸将溶液的 pH调节至4。将悬浮的固体过滤并干燥以获得1.3691g的亮黄色固体,产率为80.8%。
步骤c-d:2-氨基-3-硝基苯甲酰胺(5)
将1.3691g(0.0075mol)的2-氨基-3-硝基苯甲酸(3)加入3mL SOCl 2中,并在60℃下搅拌2h。在高真空下蒸发掉过量的SOCl 2。将残余物溶于10mL四氢呋喃中,然后滴加至6-8mL 氨水中,在冰浴下搅拌1-2h。将悬浮液过滤并用MeOH(10mL×3)洗涤,得到1.2803g黄色固体,产率为94.2%。
步骤e:2,3-二氨基苯甲酰胺(6)
将2-氨基-3-硝基苯甲酰胺(5)1.2803g(0.007mol),加入半汤匙雷尼镍和2ml80%水合肼,溶于40mL无水乙醇溶液中,60℃反应2h。过滤并浓缩后,将粗产物通过硅色谱法纯化(二氯甲烷:甲醇=30∶1),得到0.7920g的浅黄色固体,产率为74.8%。
步骤f:4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)苯甲酸甲酯(8)
将3-二氨基苯甲酰胺(6)0.7920g(0.005mol),4-甲酰基苯甲酸甲酯(7)0.8346g(0.005mol), NaHSO31.0231g(0.01mol)和2mL蒸馏水添加到40mL无水乙醇溶液中,在60℃反应1-2h。将悬浮液过滤并用甲醇(20mL×3)洗涤,得到0.9583g白色固体,产率为65.0%。
步骤g:4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)苯甲酸(9)
将4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)苯甲酸甲酯(8)添加到40mL甲醇溶液中。然后用LiOH水溶液将溶液的pH调节至12,在40℃水浴中搅拌过夜。使用高真空除去溶剂。将固体溶解在蒸馏水中,然后用柠檬酸水溶液将溶液的pH调节至7,得到0.8260g白色固体,产率为92.0%。
步骤h-i:13a-13r
将具有不同取代基的羧酸11a-11r(0.005mol),HBTU 1.8239g(0.005mol)和无水碳酸钾1.3672g(0.01mol)添加到40mL丙酮溶液中,在室温下反应0.5h。然后将N-Boc-哌嗪0.9328g (0.005mol)加入溶液中,并将混合物在室温搅拌过夜。将固体溶解在30mL二氯甲烷中,加浓盐酸脱Boc保护基,然后通过1M NaOH溶液将溶液的pH调节至3。过滤并浓缩后,将粗产物通过硅色谱法纯化(二氯甲烷:甲醇=20∶1),得到中间体13a-13r。
步骤j:2-(4-(4-乙酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14a)
将4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)苯甲酸(9)0.1438g(0.0005mol),HBTU 0.1886g (0.0005mol)和无水碳酸钾0.1346g(0.001mol)加入40mL丙酮溶液,室温下反应0.5h。然后加入13a(0.005mol),并将混合物在环境温度下搅拌过夜。过滤并浓缩后,将粗产物通过硅色谱法纯化(二氯甲烷:甲醇=40∶1),得到0.0546g白色粉末,产率为27.92%。
白色粉末,产率27.92%;mp 251.5-253.3℃;1H NMR(400MHz,DMSO-d6),δ(ppm):13.56(s, 1H),9.35(s,1H),8.35(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.85(s,1H),7.80(d,J=8.0Hz, 1H),7.68(d,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),3.61(s,8H),2.08(s,3H);MALDI-TOF MS: m/z,calcd.For C21H21N5O3[M+H+]391.164,found392.132.Elemental analysis:(Calc.for C, 64.44;H,5.41;N,17.89;O,12.26.Found C,64.43;H,5.42;N,17.91;O,12.24).
实施例2:2-(4-(4-新戊酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14b)
白色粉末,产率30.12%;mp 265.7-266.9℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.60(s, 1H),9.39(s,1H),8.37(d,J=8.0Hz,2H),7.95(d,J=8.0Hz,1H),7.90(s,1H),7.83(d,J=8.0Hz, 1H),7.69(d,J=8.0Hz,2H),7.44(t,J=8.0Hz,1H),3.68(s,2H),3.42(s,6H),1.47(s,9H); MALDI-TOF MS:m/z,calcd.For C24H27N5O3[M+H+]449.206,found450.182.Elemental analysis:(Calc.for C,64.13;H,6.05;N,15.58;O,14.24.Found C,64.14;H,6.05;N,15.56;O, 14.25).
实施例3:2-(4-(4-(环丙烷羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14c)
白色粉末,产率32.90%;mp 274.5-276.1℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.56(s, 1H),9.36(s,1H),8.35(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.84(s,1H),7.79(d,J=8.0Hz, 1H),7.69(d,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),3.75(s,3H),3.61(s,4H),0.79(s,4H); MALDI-TOF MS:m/z,calcd.For C23H23N5O3[M+H+]417.180,found418.172.Elemental analysis:(Calc.for C,66.17;H,5.55;N,16.78;O,11.50.Found C,66.18;H,5.56;N,16.77;O, 11.49).
实施例4:2-(4-(4-苯甲酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14d)
白色粉末,产率27.87%;mp 243.8-244.9℃;1H NMR(400MHz,DMSO-d6),δ(ppm):9.39(s, 1H),8.37(d,J=8.0Hz,2H),7.95(d,J=4.0Hz,1H),7.87(s,1H),7.82(d,J=8.0Hz,1H),7.71 (d,J=4.0Hz,2H),7.54(d,J=4.0Hz,5H),7.43(t,J=8.0Hz,1H),3.77(s,8H);MALDI-TOF MS:m/z,calcd.For C26H23N5O3[M+H+]453.180,found454.126.Elemental analysis:(Calc.for C,68.86;H,5.11;N,15.44;O,10.58.Found C,68.86;H,5.13;N,15.41;O,10.60).
实施例5:2-(4-(4-(1H-咪唑-2-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺 (14e)
白色粉末,产率26.54%;mp 288.2-289.8℃;1H NMR(400MHz,DMSO-d6),δ(ppm):9.74(s, 1H),8.63(s,1H),8.38(d,J=8.0Hz,2H),7.97(s,1H),7.74(t,J=8.0Hz,2H),7.65(d,J=8.0Hz, 1H),7.61(s,1H),7.59(s,2H),7.52(s,1H),7.18(t,J=8.0Hz,1H),3.77(s,8H);MALDI-TOF MS:m/z,calcd.For C23H21N7O3[M+H+]443.170,found444.136.Elemental analysis:(Calc.for C,62.29;H,4.77;N,22.11;O,10.86.Found C,62.25;H,4.87;N,22.06;O,10.82).
实施例6:2-(4-(4-(1-甲基-1H-咪唑-5-羰基)哌嗪-1羰基)苯基)-1H-苯并[d]咪唑-4- 羧酰胺(14f)
白色粉末,产率32.43%;mp 285.5-286.4℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.57(s, 1H),9.36(s,1H),8.35(d,J=8.0Hz,2H),7.93(d,J=8.0Hz,1H),7.84(s,1H),7.80(d,J=8.0 Hz,1H),7.70(s,3H),7.68(s,1H),7.41(t,J=8.0Hz,1H),3.71(s,6H),3.47(s,2H),1.26(s,3H); MALDI-TOF MS:m/z,calcd.For C24H23N7O3[M+H+]457.186,found 458.130.Elemental analysis:(Calc.for C,63.01;H,5.07;N,21.43;O,10.49.Found C,63.00;H,5.08;N,21.46;O, 10.46).
实施例7:2-(4-(4-吡啶基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14g)
白色粉末,产率29.47%;mp 264.2-265.7℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.60(s, 1H),9.38(s,1H),8.65(d,J=8.0Hz,1H),8.37(d,J=8.0Hz,2H),8.00(s,1H),7.94(d,J=8.0Hz, 1H),7.89(s,1H),7.82(d,J=8.0Hz,1H),7.72(s,2H),7.68(d,J=8.0Hz,1H),7.55(s,1H),7.43 (t,J=8.0Hz,1H),3.83(s,4H),3.60(s,4H);MALDI-TOF MS:m/z,calcd.For C25H22N6O3[M+Na+]454.175,found 477.136.Elemental analysis:(Calc.for C,66.07;H,4.88;N, 18.49;O,10.56.Found C,66.05;H,4.87;N,18.50;O,10.58).
实施例8:2-(4-(4-烟酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14h)
白色粉末,产率28.41%;mp 268.1-269.8℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.61(s, 1H),9.36(s,1H),8.69(d,J=4.0Hz,2H),8.35(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.92 (d,J=8.0Hz,1H),7.87(s,1H),7.80(d,J=4.0Hz,1H),7.68(d,J=8.0Hz,2H),7.50(t,J=8.0 Hz,1H),7.40(m,2H),3.73(s,8H);MALDI-TOF MS:m/z,calcd.For C25H22N6O3[M+H+] 454.175,found 455.124.Elemental analysis:(Calc.forC,66.07;H,4.88;N,18.49;O,10.56. Found C,66.07;H,4.87;N,18.49;O,10.57).
实施例9:2-(4-(4-异烟酰酰基哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14i)
白色粉末,产率35.64%;mp 266.6-267.6℃;1H NMR(400MHz,DMSO-d6),δ(ppm):13.56(s, 1H),9.36(s,1H),8.72(s,2H),8.34(s,2H),7.93(d,J=8.0Hz,1H),7.86(s,1H),7.80(d,J=8.0Hz, 1H),7.68(d,J=4.0Hz,2H),7.46(s,2H),7.41(t,J==8.0Hz,1H),3.72(s,4H),3.54(s,2H),3.42 (s,2H);MALDI-TOF MS:m/z,calcd.For C25H22N6O3[M+H+]454.175,found 455.157. Elemental analysis:(Calc.for C,66.07;H,4.88;N,18.49;O,10.56.Found C,66.03;H,4.89;N, 18.47;O,10.61).
实施例10:3-(4-(4-(4-甲基-1,2,3-噻二唑-5-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d] 咪唑-4-羧酰胺(14j)
白色粉末,产率33.45%;mp 256.0-257.7℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.56(s, 1H),9.35(s,1H),8.34(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.85(s,1H),7.79(d,J=8.0Hz, 1H),7.69(s,2H),7.40(t,J=8.0Hz,1H),3.80(s,8H),2.68(s,3H);MALDI-TOF MS:m/z,calcd. For C23H21N7O3S[M+H+]475.142,found 476.133.Elementalanalysis:(Calc.for C,58.09;H, 4.45;N,20.62;O,10.09;S,6.74.Found C,58.08;H,4.39;N,20.73;O,10.12;S,6.68).
实施例11:2-(4-(4-(2-溴噻唑-4-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14k)
白色粉末,产率27.96%;mp 270.9-272.3℃;1H NMR(400MHz,DMSO-d6),δ(ppm):9.36(s, 1H),8.35(d,J=8.0Hz,2H),8.21(s,1H),7.92(d,J=4.0Hz,1H),7.84(s,1H),7.80(d,J=8.0 Hz,1H),7.69(d,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),3.77(s,6H),3.50(s,2H);MALDI-TOF MS:m/z,calcd.For C23H19BrN6O3S[M+H+]538.042,found539.000.Elemental analysis:(Calc. for C,51.21;H,3.55;Br,14.81;N,15.58;O,8.90;S,5.94.Found C,51.22;H,3.54;Br,14.80;N, 15.53;O,8.90;S,6.01).
实施例12:2-(4-(4-(4-(噻唑-5-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14l)
白色粉末,产率34.52%;mp 259.3-260.8℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.57(s, 1H),9.36(s,1H),9.28(s,1H),8.35(d,J=8.0Hz,2H),8.26(s,1H),7.92(d,J=8.0Hz,1H),7.85 (s,1H),7.79(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),3.78(s,8H); MALDI-TOF MS:m/z,calcd.For C23H20N6O3S[M+Na+]460.131,found 483.089.Elemental analysis:(Calc.for C,59.99;H,4.38;N,18.25;O,10.42;S,6.96.Found C,60.00;H,4.38;N, 18.26;O,10.41;S,6.95).
实施例13:3-(4-(4-(1-甲基-1H-吡咯-2-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑 -4-羧酰胺(14m)
白色粉末,产率28.95%;mp 259.7-261.4℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.56(s, 1H),9.36(s,1H),8.35(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.85(s,1H),7.79(d,J=8.0Hz, 1H),7.69(d,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),6.94(s,1H),6.39(s,1H),6.07(s,1H),3.71 (s,8H);MALDI-TOF MS:m/z,calcd.For C25H24N6O3[M+H+]456.191,found 457.148. Elemental analysis:(Calc.for C,65.78;H,5.30;N,18.41;O,10.51.Found,65.77;H,5.32;N, 18.40;O,10.51).
实施例14:2-(4-(4-(4-溴-1H-吡咯-2-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4- 羧酰胺(14n)
白色粉末,产率32.13%;mp 264.8-266.3℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.56(s, 1H),11.90(s,1H),9.36(s,1H),8.36(d,J=8.0Hz,2H),7.93(d,J=8.0Hz,1H),7.85(s,1H), 7.80(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),7.08(s,1H),6.67(s,1H), 3.76(s,6H),3.51(s,2H);MALDI-TOF MS:m/z,calcd.ForC24H21BrN6O3[M+H+]520.0859, found 521.036.Elemental analysis:(Calc.for C,55.29;H,4.06;Br,15.33;N,16.12;O,9.21. Found C,55.30;H,4.06;Br,15.27;N,16.14;O,9.23).
实施例15:2-(4-(4-(呋喃-2-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14o)
白色粉末,产率36.66%;mp 253.3-254.6℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.59(s, 1H),9.37(d,J=4.0Hz,1H),8.36(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.89(s,1H),7.87 (d,J=4.0Hz,1H),7.80(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),7.08 (d,J=4.0Hz,1H),6.68(s,1H),3.77(s,6H),3.51(s,2H);13C NMR(151MHz,DMSO)δ169.06, 166.57,158.98,151.57,147.20,145.42,141.88,137.81,135.85,130.61,128.41,127.43,123.63, 123.14,123.06,116.43,115.68,111.87,40.38,40.24,40.10,39.82,39.68,39.55.MALDI-TOF MS: m/z,calcd.For C24H21N5O4[M+H+]443.159,found 444.098.Elemental analysis:(Calc.for C, 65.00;H,4.77;N,15.79;O,14.43.Found C,65.00;H,4.78;N,15.75;O,14.47).
实施例16:3-(4-(4-(3-甲基呋喃-2-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4- 羧酰胺(14p)
白色粉末,产率28.65%;mp 252.2-253.7℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.58(s, 1H),9.36(s,1H),8.35(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.87(s,1H),7.80(d,J=8.0Hz, 1H),7.73(s,1H),7.69(d,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),6.54(s,1H),3.70(d,J=32.0 Hz,6H),3.49(s,2H),2.19(s,3H);13C NMR(151MHz,DMSO)δ169.02,166.56,160.15,151.58, 143.73,142.68,141.88,137.83,135.84,130.59,128.41,127.41,126.82,123.62,123.14,123.07, 115.67,114.96,40.38,40.25,40.11,39.83,39.69,39.55,11.39.MALDI-TOF MS:m/z,calcd.For C25H23N5O4[M+H+]457.175,found 458.138.Elemental analysis:(Calc.for C,65.64;H,5.07;N, 15.31;O,13.99.Found C,65.66;H,5.08;N,15.33;O,13.93).
白色粉末,产率36.71%;mp 270.8-273.1℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.57(s, 1H),9.36(s,1H),8.36(d,J=8.0Hz,2H),7.93(d,J=8.0Hz,1H),7.85(s,1H),7.80(d,J=8.0Hz, 1H),7.70(d,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),7.16(d,J=4.0Hz,1H),6.73(d,J=4.0Hz, 1H),3.76(s,6H),3.52(s,2H);13C NMR(151MHz,DMSO)δ169.06,166.56,157.89,151.57, 148.88,141.88,137.79,135.84,130.61,128.41,127.42,124.96,123.63,123.15,123.07,118.73, 115.67,113.97,40.38,40.24,40.11,39.83,39.69,39.55.MALDI-TOF MS:m/z,calcd.For C24H20BrN5O4[M+H+]521.069,found522.036.Elemental analysis:(Calc.for C,55.19;H,3.86; Br,15.30;N,13.41;O,12.25.Found C,55.20;H,3.85;Br,15.30;N,13.42;O,12.23).
实施例18:2-(4-(4-(5-氯呋喃-2-羰基)哌嗪-1-羰基)苯基)-1H-苯并[d]咪唑-4-羧酰胺(14r)
白色粉末,产率30.60%;mp 268.5-269.9℃;1HNMR(400MHz,DMSO-d6),δ(ppm):13.60(s, 1H),9.39(s,1H),8.37(d,J=8.0Hz,2H),7.95(d,J=8.0Hz,1H),7.90(s,1H),7.83(d,J=8.0Hz, 1H),7.69(d,J=8.0Hz,2H),7.44(t,J=8.0Hz,1H),3.68(s,2H),3.42(s,6H),1.47(s,9H); MALDI-TOF MS:m/z,calcd.For C24H20ClN5O4[M+H+]477.120,found478.059.Elemental analysis:(Calc.for C,60.32;H,4.22;Cl,7.42;N,14.65;O,13.39.Found C,60.33;H,4.20;Cl, 7.44;N,14.62;O,13.41).
实施例19活性测试
PARP-1酶抑制活性
PARP-1抑制试验是由盛兆生物技术有限公司(中国上海)在外包中进行的。我们使用市售的PARP-1化学发光分析试剂盒(BPS Bioscience,目录号80551,美国加利福尼亚州圣地亚哥)来测量化合物的抑制活性(14a-14r)。操作过程与说明相同。首先,将5×组蛋白混合物添加到384孔板中,并在4℃下孵育过夜。然后,在各种浓度的抑制剂和含有PARP-1酶的 PARP缓冲液之间发生核糖基化反应。用链霉亲和素-HRP处理该板,然后加入ELISA混合溶液。使用链霉亲和素-HR催化的显色反应确定附着在组蛋白上的生物素化底物的含量,该反应可间接反映不同干预条件下PARP-1的活性。
在固定浓度为500nM的条件下体外筛选化合物14a-14r的PARP-1酶抑制活性,然后选择PARP-1抑制率>50%的化合物进一步测定IC50值,结果显示在表1中,在该化合物中,14k(IC50=25nM),14q(IC50=23nM)和14r(IC50=43nM)显示出优异的PARP-1酶活性,与对照Veliparib(IC50=61nM)Olaparib(IC50=15nM)相当。与14h相比,14g和14i 均具有优异的PARP-1酶抑制活性,这可能是由于相邻和对位的电子云密度相对较低。此外,与其他杂环化合物相比,呋喃环取代的衍生物14o-14r表现出更好的PARP-1抑制活性,尤其是14q和14r含卤素原子(Br,Cl)。促进抑制作用的可能原因是呋喃环具有最大的电负性,并且π电子的离域度较小,可以通过静电力与疏水口袋中的氨基相互作用。此外,我们注意到,每个被卤素原子取代的化合物,例如14k,14n,14q和14r,均显示出合理的抑制活性。可能的原因是,当取代的卤素原子与AD位点结合时,疏水力可能会增加。这暗示着在苯并咪唑的侧链中引入强电负性基团或卤素原子可能会改善其抑制活性。
细胞抗增值实验
采用噻唑基蓝四唑溴化物(MTT)方法进行14a–14r的抗增殖活性评估。每孔约8×103个细胞被置于96孔微培养板(Costar)的孔中并生长24小时。与半稀释的抑制剂(128、64、 32、16、8、4、2、1μM)孵育48小时后,将细胞培养物与20μL MTT溶液(5mg/mL)每孔在黑暗中孵育4小时在37℃。然后小心地去除上清液,并加入150μL DMSO,摇动10分钟以溶解甲瓒晶体。用WellscanMK-2酶标仪测量490nm处的吸光度。该测定独立进行了三次。
采用MTT法评价了所有目标化合物对具有天然BRCA-1突变的人乳腺癌MDA-MB-436细胞和野生型人乳腺癌MCF-7细胞的增殖抑制作用,结果列于表1。除了化合物14n,对野生型MCF-7细胞都没有生长抑制作用。IC50值在36.69-95.83μM之间的呋喃衍生物14o-14r 与对照Olaparib(IC50=19.5μM)表现出相似的作用,并且其抗BRCA-1突变的细胞抑制活性明显强于野生型细胞,表明这些化合物可以选择性地杀死BRCA-1突变细胞。我们发现化合物14k与化合物14q相比显示出相似的酶活性。但是,它对BRCA-1突变型MDA-MB-436 细胞没有明显的增殖抑制作用。因此,化合物14q可能是对PARP-1酶和BRCA-1缺陷细胞具有高活性的有前途的先导化合物。
表1对PARP-1酶的抑制活性和对MDA-MB-436细胞和MCF-7细胞的抗肿瘤活性
a数值是来自三个独立剂量反应曲线的平均值。
bND,不确定。尚未确定在500nM浓度下抑制率<50%的化合物的IC50值。
分子模拟
分子对接实验由SYBYL-X 2.0执行。本发明使用从RCSB蛋白质数据库(PDB)中检索到的与2取代的苯并咪唑-4-羧酰胺抑制剂(PDB ID:5WS1)配合使用的PARP-1受体的3D 结构。在该实验中选择的配体是化合物14q。通过消除水分子并优化受体和配体的能量来优化蛋白质的对接(分子对接图见附图1)。苯并咪唑是PARP-1的活性位点,烯烃甲酰胺位于 Ni位置,酰胺结构可通过分子内氢键或环形成限制其构象,并具有与Gly-863和Ser-904的关键氢键,富电子的苯并咪唑环与Tyr-907效应之间存在π-π共轭物;另外,苯并咪唑环上的 -NH与Glu-988具有水介导的氢键。当14q的侧链伸入疏水口袋时,一方面,哌嗪上的氮原子可与Asp-766形成氢键相互作用,另一方面,呋喃环上的氯原子可能具有一定的疏水力疏水口袋这两个因素可能对PARP-1抑制活性的增强起主要作用。
Claims (9)
2.如权利要求1所述的式14化合物或其药学上可接受的盐,R选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C3-C10环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基;所述C3-C10环烷基、C3-C10杂环烷基、C6-C10芳基、C6-C10杂芳基任选被一个或多个R’取代;
所述R’独立地选自卤素、C1-C3烷基。
3.如权利要求1或2所述的式14化合物或其药学上可接受的盐,R选自甲基、环丙基、苯基、5-6元杂芳基;所述环丙基、苯基、5-6元杂芳基任选被一个或多个R’取代;
所述R’选自氯、溴、甲基。
6.一种药物组合物,其包含权利要求1-4任一项所述的式14所示的化合物或其药学上可接受的盐,以及药学上可接受的载体。
7.权利要求1-4任一项所述的式14所示的化合物或其药学上可接受的盐在制备PARP-1抑制剂中的用途。
8.权利要求1-4任一项所述的式14所示的化合物或其药学上可接受的盐在制备治疗乳腺癌药物中的用途。
9.如权利要求8所述用途,其特征在于,所述乳腺癌是由MDA-MB-436细胞组成的。
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