CN110713487A - 一种新型杂环芳腙类衍生物、其药学上可接受的盐、其制备方法和应用 - Google Patents
一种新型杂环芳腙类衍生物、其药学上可接受的盐、其制备方法和应用 Download PDFInfo
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- CN110713487A CN110713487A CN201910956600.8A CN201910956600A CN110713487A CN 110713487 A CN110713487 A CN 110713487A CN 201910956600 A CN201910956600 A CN 201910956600A CN 110713487 A CN110713487 A CN 110713487A
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Abstract
Description
技术领域
本发明涉及医药技术领域,具体涉及新型杂环芳腙类衍生物、用于防治肿瘤的新型杂环芳腙类衍生物、其药学上可接受的盐及其制备方法和应用。
背景技术
癌症是人致死率极高的疾病,很多种类的癌症都无法实现治愈,因此,抗肿瘤药物一直是药物、化学、光学或跨学科技术领域的研究重点和热点。目前,具有抗癌活性的药物或潜在药物很多,临床上所使用的抗癌药物,大多是干扰或阻断细胞的增殖过程,一般称为细胞毒药物,根据其作用原理化疗药物大致分为如下4类。(1)抑制DNA合成:通过阻碍脱氧嘌呤核苷或脱氧嘧啶核苷的合成、互换、还原而干扰DNA的合成,大部分的抗代谢类药物如MTX、6 桵P、6-TG、5-FU,HU、Ara-C等居于此类。(2)直接破坏DNA结构成与 DNA结合:此类药物大多为烷化剂和抗癌抗生素。如HN2、CTX、TSPA、CLB、 BUS等烷化剂,通过烷化作用与DNA交叉联结,从而破坏DNA的结构和功能、 BLM、MMC、ADM、DNR、ACD等抗癌抗生素和PDD、亚硝脲类药物亦有类似烷化剂的作用,可使DNA链断裂,直接破坏DNA。PCB可使DNA链解聚。 (3)抑制蛋白质的合成:如门冬酰胺酶,能分解门酰驶酶,肿瘤细胞与正常的细胞不同,本身不能合成门冬相互理解胺,必须从细胞外摄取,门冬酰胺酶能造成外源性门冬酰胺缺乏,从而抑制了蛋白质的合成。(4)抑制有丝分裂:如 VCR、VLB、VDS、NVB、VPl6、VM26等植物类抗癌药与细胞的微管蛋白结合,促进微管解聚使其不能形成纺锤体,抑制细胞分裂。紫杉醇为新型的有丝分裂抑制剂,促进微管装配抑制微管解聚,是目前唯一促进微管聚合新型的抗癌药。
目前,关于利用肿瘤铁蛋白降解起到抗肿瘤作用且毒副作用小的药物很少见。而本申请且具有降解肿瘤铁蛋白的作用和较佳的抗癌活性。且本申请人通过将设计多靶结构的新型化合物并通过化学原理用于未来肿瘤细胞药物的开发中,意义重大。
发明内容
本发明针对现有技术的缺陷提供了一种新型杂环芳腙类衍生物、其药学上可接受的盐、其制备方法和应用,本发明旨在寻找一类结构新颖、抗肿瘤活性强的新型药物。
本发明的目的是通过以下技术方案来实现:
本发明的一个发明点为提供一种新型杂环芳腙类衍生物或其药学上可接受的盐,所述噻唑芳腙类衍生物包括结构通式Ⅰ以及该结构通式Ⅰ的光学异构体;
在上述结构通式Ⅰ中,
R代表芳烃、杂环或同时具有芳烃和杂环的取代基;
R1为杂环;
上述杂环均指杂环本身或连接有取代基的杂环。
进一步地,R2和R3中至少一个为杂环;R’为芳烃。X代表S;Z代表N
进一步地,R2和R3中至少一个为吡啶环,该吡啶环包括吡啶环本身以及带有取代基的吡啶环。
R6、R7和R8各自独立的为H、卤原子、硝基、氨基、酰胺、羟基、醚、羧基、酮、饱和烃或不饱和烃等。
进一步地,R8为H、卤原子、甲基、甲氧基或硝基。
进一步地,若R4为O时,则R6为H、卤原子、硝基或醚,更优选为H或卤原子;若R5为O时,则R7为H、卤原子、硝基或醚,更优选为H或卤原子;即,若R2或R3为苯环时,苯环上的取代基为H、卤原子、硝基或醚,优选为H 或卤原子。
本发明的另一个发明点为提供一种新型杂环芳腙类衍生物的制备方法,上述的杂环芳腙类衍生物的制备流程如下所示:
Step1:化合物1与化合物2反应生成化合物3;
Step2:化合物3与化合物4反应生成终产物杂环芳腙类衍生物;其中化合物4中的R”为芳烃或杂环。对于此处的R2、R3同以上所有自然段中所限定的取代基,故这里不再重复限定。
所述化合物4为R8同以上自然段中所限定的取代基,故这里不再重复限定。
在以上Step1中,化合物1和化合物2溶解在有机溶剂中,然后在含有化合物1和化合物2的有机溶剂中加入催化剂,反应生成化合物3;所述有机溶剂优选为乙醇或无水乙醇;所述催化剂优选为冰醋酸;此步骤中的温度优选为 40-100℃,更优选为60-80℃;
在以上Step2中,化合物3与化合物4在溶剂中进行反应生产终产物,此处的溶剂优选为乙醇;此步骤中的温度优选为常温,常温通常指10-30℃。
本发明的又一个发明点为提供一种用于制备肿瘤的新型杂环芳腙类衍生物或其药学上可接受的盐,所述杂环芳腙类衍生物为以上任一自然段中所述的化合物Ⅰ或其药学上可接受的盐。
本发明的最后一个发明点为提供一种以上任一自然段中所述的新型杂环芳腙类衍生物或其药学上可接受的盐在作为制备治疗肿瘤药物的应用。
本发明提供了一种新型杂环芳腙类衍生物、其药学上可接受的盐、其制备方法和应用,其主要具有的有益效果为:
本发明将杂环与芳腙结合形成了一种新型的化合物,其具优异的抗癌活性,且毒副作用小,其合成简单、方便,具有较好的应用于工业生产中。
具体地,该化合物通过在腙的一侧加入噻唑等杂环、另一侧的碳原子上引入至少一个吡啶基团,这几个部分均为不同领域中的药物活性基团,本发明人极有新意的选择了这几个基团并将其通过特定的连接关系连接成为一个整体,形成了一种新的药物。这三者相互作用使得该化合物通过体内代谢或免疫的途径能够靶向癌细胞,与癌细胞进行较好的作用实现将癌细胞杀灭的作用。腙的碳原子上的另一个基团优选为吡啶环或芳环,可增加与癌细胞靶向作用的成功率,从而增加抗癌活性或效率;噻吩环的使用不仅能够增加抗癌活性,而且其与该化合物的其它几个重要基团配合也具有一定的降低毒性等作用,噻吩环上加入芳环有助于抑制癌细胞的生长,从而增加控制癌细胞生长的作用;吡啶环的邻位与腙连接,有助于将整体活性提升,毒性降低。
更重要的是,通过研究发现,本申请的化合物还能显著激活溶酶体功能,有利于铁蛋白自噬的发生与进行;同时能够显著诱导活性氧的产生,并能被ROS 的清除剂清除,该化合物该能显著降解肿瘤铁蛋白的表达,即可引起铁蛋白自噬的发生进而引起芬顿反应的发生,从而起到抗肿瘤作用,且通过该途径的本申请化合物来治疗肿瘤的毒副作用小。
本申请的制备方法新颖、简单,仅通过两步便能得到目标化合物,在这工业应用中具有极大的优势,因为,步数越多整体产率越低、原料和中间体用量越多、成本越大、时间越长、不确定性越大,故本申请的成本低、时间短,应用佳。
总之,本申请化合物中的各个取代基基团均对降解肿瘤铁蛋白有着辅助增强的作用,本申请通过一种特别的机理实现了抗肿瘤的作用,毒副作用小,且本申请首次设计了多靶结构的新型化合物并通过化学拼合原理用于未来肿瘤细胞药物的开发中对该类药物的研究意义重大。
附图说明
图1a为本发明实施例所述的化合物PhcY的细胞活性图。
图1b为本发明实施例所述的化合物PhcY的细胞活性图。
图1c为本发明实施例所述的化合物PhcY的细胞活性图。
图2a为本发明实施例所述的化合物PhcY诱导溶酶体功能图。
图2b为本发明实施例所述的化合物PhcY诱导溶酶体功能图。
图3a为本发明实施例所述的化合物PhcY诱导活性氧产生图。
图3b为本发明实施例所述的化合物PhcY诱导活性氧产生图。
图3c为本发明实施例所述的化合物PhcY诱导活性氧产生图。
图4a为本发明实施例所述的化合物PhcY对铁蛋白的影响图。
图4b为本发明实施例所述的化合物PhcY对铁蛋白的影响图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明具体实施例对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
在本申请的权利要求书和说明书中,“杂环”的表述均指杂环本身或连接有取代基的杂环。本发明所用试剂和原料均市售可得或可按文献方法制备。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。
本申请实施例的合成路线如下:
下面以实施例的方式列举一些主要目标化合物以及其合成过程和谱图数据等。
实施例1:5-(4-氯苯基)-2-(2-(二(吡啶-2-基)亚甲基)肼基)噻唑
制备方法:在通风橱中,在干燥条件下,在25mL单口圆底烧瓶中,将10mmol 的二吡啶酮和10.25mmol的氨基硫脲加至10ml无水乙醇中,之后向其中滴加两点冰醋酸催化剂,在80℃搅拌反应约4h后,TLC跟踪反应,反应结束后,静置待其冷却后,析出的固体过滤烘干后用无水乙醇溶解重结晶,重结晶得白色晶体,即为中间体。
取上述中间体0.25mmol置于25mL单口圆底烧瓶中,加5ml乙醇溶解,再加入α-溴代-4-氯苯乙酮,加入磁子,室温下搅拌反应,TLC跟踪反应,约4h 后结束反应,过滤,乙醇洗涤,得到黄色固体,将得到的固体溶于无水乙醇重结晶提纯得到黄色粉末状目标化合物,即终产物。两步综合产率89%。
目标化合物的确认数据:1H NMR(600MHz,DMSO-d6)δ12.81(s,1H),8.96 (s,8H),8.60(s,7H),8.24(q,J=7.7,7.3Hz,10H),8.12(t,J=7.6Hz,9H),8.02(d, J=7.6Hz,8H),7.86(d,J=8.1Hz,15H),7.83–7.73(m,15H),7.58(d,J=6.3Hz, 7H),7.54–7.34(m,20H)。
施例2:2-(2-(二(吡啶-2-基)亚甲基)肼基)-5-(3,4-二氯苯基)噻唑
制备方法同实施例1,仅将实施例1中的α-溴代-4-氯苯乙酮换为α-溴代-3,4- 二氯苯乙酮代替便可,得到黄色粉末状目标化合物。两步综合产率85%。目标化合物的确认数据:1H NMR(600MHz,DMSO-d6)δ8.93(d,J=5.2Hz,1H),8.60 (d,J=5.0Hz,1H),8.15(t,J=7.8Hz,1H),8.10–8.03(m,2H),7.98(d,J=8.0Hz, 1H),7.84(d,J=8.2Hz,1H),7.76–7.69(m,2H),7.67(d,J=9.1Hz,2H),7.57– 7.51(m,1H).
实施例3:4-(2-氯苯基)-2-(2-(二(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代-2-氯苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮便可,得到黄色粉末状目标化合物。两步综合产率82%。目标化合物的确认数据:1H NMR(600MHz,DMSO-d6)δ14.14(s,1H),8.90(d,J=5.1Hz,1H), 8.60(d,J=4.8Hz,1H),7.99(q,J=6.9,6.4Hz,2H),7.96–7.89(m,2H),7.86(d,J =7.8Hz,1H),7.65(s,1H),7.62(d,J=8.0Hz,1H),7.58(dd,J=7.6,5.0Hz,1H), 7.50–7.43(m,2H),7.38(dd,J=8.0,2.1Hz,1H).
实施例4:2-(2-(二(吡啶-2-基)亚甲基肼基)-4-(4-氟苯基)噻唑
制备方法同实施例1,以α-溴代-4-氟苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮便可,得到黄色粉末状目标化合物。两步综合产率80%。目标化合物的确认数据为:1H NMR(600MHz,DMSO-d6)δ8.96(d,J=5.1Hz,1H),8.60(d,J= 5.0Hz,1H),8.19(t,J=7.2Hz,1H),8.07(t,J=7.8Hz,1H),8.01(d,J=8.0Hz, 1H),7.94–7.87(m,2H),7.79(d,J=8.1Hz,1H),7.73(t,J=6.5Hz,1H),7.54(dd, J=7.5,5.0Hz,1H),7.47(s,1H),7.26(t,J=8.9Hz,2H).
实施例5:2-(2-(二(吡啶-2-基)亚甲基)肼基)-4-(3-氟苯基)噻唑
制备方法同实施例1,以α-溴代-3-氟苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮便可,得到黄色粉末状目标化合物。两步综合产率76%。目标化合物的确认数据为:1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),8.89(d,J=4.5Hz, 1H),8.60(d,J=4.3Hz,2H),8.00(q,J=7.1,6.1Hz,2H),7.93(d,J=7.9Hz,1H), 7.74(d,J=7.8Hz,1H),7.69(d,J=8.4Hz,1H),7.65-7.60(m,3H),7.57(s,0H), 7.49-7.43(m,2H).
实施例6:4-(4-溴苯基)-2-(2-(二(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代-4-溴苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮便可,得到黄色粉末状目标化合物。两步综合产率83%。目标化合物的确认数据为:1H NMR(600MHz,DMSO-d6)δ9.04–8.96(m,1H),8.61(dt,J= 5.0,1.3Hz,1H),8.29–8.21(m,1H),8.11(tt,J=7.7,1.7Hz,1H),8.03(dd,J=7.8, 1.4Hz,1H),7.86–7.77(m,5H),7.63–7.60(m,2H),7.57–7.53(m,2H).
实施例7:2-(2-(二(吡啶-2-基)亚甲基)肼基)-4-(3-硝基苯基)噻唑
制备方法同实施例1,以α-溴代-3-硝基苯乙酮代替实施例1中的α-溴代-4- 氯苯乙酮便可,得到黄色粉末状目标化合物。两步综合产率86%。目标化合物的确认数据为:1HNMR(600MHz,DMSO-d6)δ8.93(d,J=4.9Hz,1H),8.68(s, 1H),8.60(d,J=4.8Hz,1H),8.34(d,J=7.8Hz,1H),8.17(d,J=8.2Hz,1H),8.02 (dt,J=15.7,7.8Hz,2H),7.95(d,J=8.0Hz,1H),7.82(s,1H),7.72(t,J=8.0Hz, 1H),7.68–7.57(m,2H),7.49(t,J=6.2Hz,1H).
实施例8:(E)-2-(2-((4-氯苯基)(吡啶-2-基)亚甲基)肼基)-4-(4-氟苯基)噻唑
目标化合物的确认数据为:1HNMR(600MHz,DMSO-d6)δ13.41(s,1H), 8.90(s,1H),8.01(s,1H),7.90(t,J=6.8Hz,2H),7.59(t,J=6.3Hz,1H),7.53(s, 4H),7.48–7.39(m,2H),7.24(t,J=8.5Hz,2H).
实施例9:(E)-2-(2-((4-氯苯基)(吡啶-2-基)亚甲基)肼基)-4-(3-硝基苯基)噻唑
制备方法同实施例1,以α-溴代-3-硝基苯乙酮代替实施例1中的α-溴代-4- 氯苯乙酮,同时将2-(4-氯苯甲酰基)吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率86%。目标化合物的确认数据为:1H NMR (600MHz,DMSO-d6)δ14.12(s,1H),8.90(d,J=4.9Hz,1H),8.60(d,J=4.8Hz, 1H),8.10–8.06(m,1H),7.99(tt,J=7.7,2.2Hz,2H),7.92(d,J=7.9Hz,1H),7.62 (d,J=8.0Hz,1H),7.60–7.56(m,1H),7.54(s,1H),7.50–7.44(m,1H),7.31(ddd, J=8.2,7.2,1.8Hz,1H),7.12(dd,J=8.3,1.1Hz,1H),7.02(td,J=7.4,1.1Hz,1H).
实施例10:(E)-2-(2-((4-氯苯基)(吡啶-2-基)亚甲基)肼基)-4-(3-氟苯基)噻唑
制备方法同实施例1,以α-溴代-3-氟苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮,同时将2-(4-氯苯甲酰基)吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率87%。目标化合物的确认数据为:1H NMR (600MHz,DMSO-d6)δ13.33(s,1H),8.94(dt,J=4.9,1.4Hz,1H),8.12(td,J= 7.8,1.8Hz,1H),7.71(dt,J=7.8,1.2Hz,1H),7.69–7.64(m,2H),7.56(s,1H), 7.55–7.54(m,1H),7.54–7.51(m,4H),7.45(td,J=8.0,6.2Hz,1H),7.17–7.11 (m,1H).
实施例11:(E)-4-(2-((4-氯苯基)(吡啶-2-基)亚甲基)肼基)-4-(2-氯苯基)噻唑
制备方法同实施例1,以α-溴代-2-氯苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮,同时将2-(4-氯苯甲酰基)吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率85%。目标化合物的确认数据为:1H NMR (600MHz,DMSO-d6)δ8.90(d,J=5.0Hz,1H),8.01(td,J=7.8,1.8Hz,1H),7.92 (t,J=1.9Hz,1H),7.84(d,J=7.8Hz,1H),7.63–7.57(m,2H),7.53(d,J=1.4Hz, 4H),7.46–7.41(m,2H),7.39–7.33(m,1H).
实施例12:(E)-4-(3-氯苯基)-2-(2-(苯基(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代-3-氯苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮,同时将2-(4-氯苯甲酰基)吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率90%。目标化合物的确认数据为:1H NMR (600MHz,DMSO-d6)δ13.57(s,1H),8.91(d,J=4.9Hz,1H),8.06(d,J=8.1Hz, 2H),8.02(td,J=7.8,1.8Hz,1H),7.87(d,J=8.4Hz,2H),7.75(s,1H),7.60(dd,J =7.7,4.9Hz,1H),7.54–7.51(m,2H),7.49–7.46(m,3H),7.43(d,J=8.0Hz, 1H).
实施例13:(E)-4-(3-硝基苯基)-2-(2-(苯基(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代-3-硝基苯乙酮代替实施例1中的α-溴代-4- 氯苯乙酮,同时将2-苯甲酰基吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率91%。目标化合物的确认数据为:1H NMR (600MHz,DMSO-d6)δ8.96–8.71(m,1H),8.04–7.97(m,1H),7.80(d,J=8.3 Hz,2H),7.59(dd,J=7.5,5.0Hz,1H),7.54–7.50(m,2H),7.47(d,J=7.1Hz,2H), 7.42(d,J=8.0Hz,1H),7.26(s,1H),7.01–6.84(m,2H).
实施例14:(E)-4-苯基-2-(2-(苯基(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮,同时将2-苯甲酰基吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率85%。目标化合物的确认数据为:1H NMR(600MHz, DMSO-d6)δ13.40(s,1H),8.90(d,J=5.0Hz,1H),8.01(td,J=7.8,1.8Hz,1H), 7.92(t,J=1.9Hz,1H),7.84(d,J=7.8Hz,1H),7.62–7.56(m,2H),7.53(d,J= 1.4Hz,4H),7.46–7.41(m,2H),7.38–7.32(m,1H).
实施例15:(E)-4-(4-氯苯基)(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代-4-氯苯乙酮代替实施例1中的α-溴代-4-氯苯乙酮,同时将2-苯甲酰基吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率86%。目标化合物的确认数据为:1H NMR(600 MHz,DMSO-d6)δ8.97(d,J=4.9Hz,1H),8.07(td,J=7.8,1.8Hz,1H),7.95(d,J =8.2Hz,3H),7.69–7.62(m,1H),7.60–7.55(m,5H),7.55–7.51(m,4H),7.48 (dt,J=8.0,1.1Hz,1H).
实施例16:(E)-5-(2-甲氧基苯基)-2-(2-(苯基(吡啶-2-基)亚甲基)肼基)噻唑
制备方法同实施例1,以α-溴代-2-甲氧基苯乙酮代替实施例1中的α-溴代-4- 氯苯乙酮,同时将2-苯甲酰基吡啶酮替代实施例1中二吡啶酮便可,得到黄色粉末状目标化合物。两步综合产率81%。目标化合物的确认数据为:1H NMR (600MHz,DMSO-d6)δ8.93(d,J=4.9Hz,1H),8.68(s,1H),8.60(d,J=4.8Hz, 1H),8.34(d,J=7.8Hz,1H),8.17(d,J=8.2Hz,1H),8.02(dt,J=15.7,7.8Hz, 2H),7.95(d,J=8.0Hz,1H),7.82(s,1H),7.72(t,J=8.0Hz,1H),7.68–7.57(m, 2H),7.49(t,J=6.2Hz,1H).
实施例17
制备方法同实施例1,仅以α-溴代-2-羟基苯乙酮代替实施例1中的α-溴代-4- 氯苯乙酮便可,产率84%。1H NMR(600MHz,DMSO-d6)δ14.28–13.29(m,1H), 8.89(dd,J=5.0,1.7Hz,1H),8.60(dd,J=5.1,1.7Hz,1H),8.02–7.95(m,2H), 7.93(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.69(dt,J=10.6,2.2Hz,1H), 7.64–7.61(m,2H),7.59–7.56(m,1H),7.47(ddd,J=11.8,8.3,5.7Hz,2H),7.15 (td,J=8.5,2.7Hz,1H).13C NMR(151MHz,DMSO-d6)δ163.82,162.22,155.81, 148.91,148.68,138.01,137.82,131.17,131.12,126.90,124.79,124.06,123.48, 122.15,114.94,114.80,112.73,112.58,107.35,56.49,19.04.ESI-MS(m/z):375.1 (M+H+).ESI-HRMS(m/z):calcd forC20H13N5SF(M+H+),375.0954; found,375.0945.
实施例18
制备方法同实施例1,仅以α-溴代-3-甲基苯乙酮代替实施例1中的α-溴代-4- 氯苯乙酮,同时将2-苯甲酰基吡啶酮替代实施例1中二吡啶酮便可,产率80%。1H NMR(600MHz,DMSO-d6)δ11.09(s,1H),8.76(s,2H),7.70(s,2H),7.59(s, 1H),7.54–7.35(m,8H),7.28(s,1H),7.19(d,J=7.8Hz,2H).13C NMR(151MHz, DMSO)δ150.99,150.42,129.65,129.34,129.11,126.85,125.87,124.33,120.92, 21.24.ESI-MS(m/z):371.1(M+H+).ESI-HRMS(m/z):calcd forC22H19N4S(M +H+),371.1325;found,371.1315.
实施例19
下面以实施例2中的目标化合物[2-(2-(二(吡啶-2-基)亚甲基)肼基)-5-(3,4-二氯苯基)噻唑](PhcY)为例来对其活性进行测试。
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定噻唑腙类衍生物对人乳腺癌细胞(MCF-7)的半数抑制浓度(IC50)。
细胞培养和细胞系
人的乳腺癌细胞细胞系来自上海细胞库,U87,T24,HEPG2,L929来自美国ATCC公司。细胞的培养条件为37℃、10%FBS的DMEM以及5%CO2,每48 小时换液一次。PBS、胰蛋白酶、胎牛血清及DMEM培养基均购自于美国Gbioc 公司
细胞增值测试和克隆形成
细胞活力用MTT测定。以每孔2500细胞的浓度铺96孔板,每孔体积100ul 在37℃、增湿的5%CO2条件下培养24小时;之后用化合物处理细胞,每孔加入一定浓度的药物100ul,处理之后,在37℃、增湿的5%CO2条件下培养72 小时;72小时之后将培养基全部吸掉,每孔加入浓度为1mg/ml,体积为50ul 的MTT,在37℃、增湿的5%CO2条件下孵育4小时,之后将MTT溶液全部吸走,加入每孔体积100ul的DMSO,最后用MTT测定OD550。细胞增殖率=[(OD 处理组-OD空白组)]/(OD对照组-OD空白组)]100%。
克隆形成实验中在6孔板中以每孔1000细胞的密度进行铺板,在37℃、增湿的5%CO2条件下培养24小时后,将原培养基吸走,加入一定化合物浓度的培养基2ml,在37℃、增湿的5%CO2条件下培养2周的时间,每隔3天进行一次带有化合物浓度培养基的更换。
蛋白印迹
用从碧云天购买的PIPA强型裂解液裂解培养的细胞,获得细胞中的蛋白后用BCA分析试剂盒测定蛋白浓度。所有的蛋白提取物100℃煮沸5min变性,用12.5%的SDS-PAGE在80V下电泳1h,120V下电泳40分钟左右是蛋白质分离。之后蛋白在PVDF膜300mA恒流条件下作用90分钟,使其充分印迹。之后用5%的脱脂奶粉在室温下封闭一小时,加入一抗过夜;第二天用TBST每 10min洗涤一次,洗6次,加入二抗室温孵育半小时,用TBST每10min洗涤一次,洗3次,然后通过增强的化学发光法进行检测。最后用化学发光成像仪分析吸光度。
(1)化合物的抗肿瘤活性评价。
利用细胞活力测定技术(MTT法),对实施例2中化合物(PhcY)的抗肿瘤活性进行评价,发现该化合物(PhcY)对乳腺癌细胞系具有很强的生长抑制作用,如图1(包括1a、1b、1c)所示。本发明人通过对几十种本申请中保护的化合物进行测试,并通过机理、推理等总结并研究,基本确定了取代基3.4二氯苯基对杂环芳腙类化合物的活性有影响,即具有较大的提升活性的良好作用。
实施例2中目标化合物的IC50在85nM,活性效果较好。
(2)药物诱导溶酶体功能激活:
本发明人又对实施例2中的化合物是否诱导溶酶体功能的活化进行评估,检测结果表明该化合物能显著激活溶酶体功能,有利于铁蛋白自噬的发生与进行,并且自噬抑制剂能反转溶酶体的功能,参见图2(包括2a、2b)。
(3)活性氧的检测:
本发明人对该药物PhcY(即实施例2中的目标化合物)的诱导活性氧(ROS) 的产生进行检测,采用DCF-DA-活性氧探针进行检测,研究结果显示该药物能显著诱导活性氧的产生,并能被ROS的清除剂清除。由此可知,本药物具有通过ros的诱导起到抗肿瘤作用,参见图3(包括3a、3b、3c)。
(4)对细胞内铁蛋白表达进行评估:
采用western bolt对细胞内铁蛋白的表达进行评估,结果显示该化合物能显著的降低铁蛋白的表达,预示铁蛋白的含量变化可能是由于铁蛋白在溶酶体降解,进而释放铁离子,导致芬顿反应的发生进而产生大量ROS进而对肿瘤细胞起到杀伤作用,参见图4(包括4a、4b)。由此可进一步说明,本申请的化合物还可通过利用肿瘤铁蛋白降解起到抗肿瘤作用且毒副作用小。
最后应说明的是:以上所述的各实施例仅用于说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分或全部技术特征进行等同替换;而这些修改或替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.一种新型杂环芳腙类衍生物或其药学上可接受的盐,其特征在于:所述噻唑芳腙类衍生物包括结构通式Ⅰ以及该结构通式Ⅰ的光学异构体;
在上述结构通式Ⅰ中,
R代表芳烃、杂环或同时具有芳烃和杂环的取代基;
R1为杂环。
2.根据权利要求1所述的新型杂环芳腙类衍生物或其药学上可接受的盐,其特征在于:结构通式Ⅰ为其中,R2、R3各自独立的为芳烃或杂环;R’代表芳烃或杂环;X为O、S、N中的一种;Z为O、S、N中的一种。
3.根据权利要求2所述的新型杂环芳腙类衍生物或其药学上可接受的盐,其特征在于:R2和R3中至少一个为杂环;R’为芳烃;X代表S;Z代表N。
4.根据权利要求3所述的新型杂环芳腙类衍生物或其药学上可接受的盐,其特征在于:R2和R3中至少一个为吡啶环。
6.根据权利要求5所述的新型杂环芳腙类衍生物或其药学上可接受的盐,其特征在于:R8为H、卤原子、甲基、甲氧基或硝基;
若R4为O时,则R6为H、卤原子、硝基或醚;若R5为O时,则R7为H、卤原子、硝基或醚。
9.一种用于制备肿瘤的新型杂环芳腙类衍生物或其药学上可接受的盐,其特征在于:所述杂环芳腙类衍生物为权利要求1-6中任一项所述的化合物Ⅰ或其药学上可接受的盐。
10.一种根据权利要求1~6中任一项所述的新型杂环芳腙类衍生物或其药学上可接受的盐在作为制备治疗肿瘤药物的应用。
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