CN112250672A - 一种核苷碱基衍生物及其制备方法和应用 - Google Patents
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract
本发明属于医药领域,涉及一种具有P300乙酰化酶选择性抑制活性的核苷碱基衍生物及其应用。该核苷碱基衍生物为具有式Ⅰ所示结构的化合物、具有式II所示结构的化合物,或它们的互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物,或其前体药物,或其药学上可接受的盐、溶剂合物或水合物。研究表明式I和式II所示化合物对P300乙酰化酶具有良好的抑制活性,对CBP表现出较好的选择性,且细胞毒作用较小,可作为探针分子以及先导化合物用于P300乙酰化酶作用机制研究和P300相关疾病药物研发。
Description
技术领域
本发明属于医药领域,更具体地,涉及一种具有P300乙酰化酶选择性抑制活性的核苷碱基衍生物及其应用。
背景技术
P300/CBP是一类重要的参与表观遗传调控的组蛋白乙酰化酶,由于P300与CBP序列存在高度的同源性,P300与CBP具有许多相似的功能,但也存在一些特异的生理作用。P300与CBP蛋白在多种细胞生命活动中发挥作用,主要包括促进组蛋白等底物蛋白乙酰化与调节多种转录因子、参与蛋白相互作用等,与细胞增殖、细胞周期、凋亡、分化、DNA损伤修复等相关。此外,P300/CBP功能失调还参与了肿瘤、糖尿病、炎症、心脏疾病等的发病机制,目前已发现P300/CBP在多种恶性肿瘤中异常表达,是抗肿瘤药物研发的潜在靶点。
“合成致死”效应是指同时抑制两种非致死性细胞通路时细胞死亡,而单独抑制其中一条通路时细胞可以存活的现象。“合成致死”策略已成为抗肿瘤药物研发的有效方法,其中最典型的例子是PARP抑制剂,后者可有效抑制BRCA突变的肿瘤细胞,自2014年第一个基于“合成致死”效应研发的PARP抑制剂Olaparib上市以来,已有另三个PARP抑制剂(瑞卡帕布Rucaparib、尼拉帕利Niraparib、他拉唑帕尼Talazoparib)成功上市用于BRCA缺失的肿瘤治疗,同时也吸引了更多基于“合成致死”策略的抗肿瘤药物研发。鉴于P300与CBP高度同源而具有功能互补性,因此单独抑制或敲除P300或CBP可能不能有效杀伤肿瘤细胞,但已有研究表明在CBP缺失的肿瘤细胞中抑制P300时可有效抑制肿瘤细胞,说明P300与CBP存在“同源合成致死”现象,P300选择性抑制剂有望成为CBP缺失的肿瘤细胞的“克星”。根据目前统计结果,CBP功能突变缺失的肿瘤主要有非小细胞肺癌(10%-15%),淋巴瘤(29%-33%),白血病(18%)以及膀胱癌(15%-27%)等,显示P300选择性靶向抗肿瘤药物具有广阔的应用前景。
已报道的P300乙酰化酶抑制剂根据结构和来源不同分为三类,包括双底物类似物、天然产物和化学合成小分子。前两类已知的P300抑制剂普遍缺乏体内活性,因此化学合成小分子成为研究重点,代表性化合物也是目前研究中常用的P300抑制剂阳性对照化合物是C646,对P300的抑制活性IC50为1.6μM;2017年,Abbvie领导的研究团队报道了新型P300抑制剂A485,其对P300/CBP的IC50值小于100nM,且能有效抑制肿瘤细胞增殖和小鼠体内肿瘤生长。然而,C646和A485对P300和CBP缺乏选择性。
目前研究P300或CBP特异的生理功能常用基因沉默/敲除或化学小分子抑制剂的方法,然而生物敲除的方法会导致蛋白整体缺失,引起细胞内蛋白组整体改变,不能有效研究蛋白特定区域的具体功能;由于目前已知的蛋白特定区域的小分子抑制剂缺乏P300和CBP选择性,这制约了P300与CBP特异生理功能的研究,成为P300生理功能基础研究亟需解决的关键技术问题。
发明内容
本发明的目的之一是提供一类具有P300乙酰化酶抑制活性的核苷碱基衍生物。
具体地,本发明的第一方面提供一种核苷碱基衍生物,该核苷碱基衍生物为具有式Ⅰ所示结构的化合物、具有式II所示结构的化合物,或它们的互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物,或其前体药物,或其药学上可接受的盐、溶剂合物或水合物:
其中,
Base为核苷碱基,所述核苷碱基选自取代的或非取代的胞嘧啶、尿嘧啶、腺嘌呤、鸟嘌呤、5-氮杂胞嘧啶、5-氟代胞嘧啶、5-甲基胞嘧啶;
L为C1-C6亚烷基或具有式III所示结构的基团;
n=1、2、3或4;
R为氢或C1-C6烷基。
根据本发明,所述药学上可接受的盐可以为无机酸盐或有机酸盐;优选地,所述无机酸盐选自下述任意一种无机酸形成的盐:盐酸、硫酸和磷酸;优选地,所述有机酸盐选自下述任意一种有机酸形成的盐:乙酸、三氟乙酸、丙二酸、柠檬酸和对甲苯磺酸。
根据本发明,优选地,所述核苷碱基上的取代基选自C1-C5的烷基、C1-C5的烷氧基、C2-C5的烯基、C2-C5的炔基、卤素、羟基、硝基、三氟甲基、三氟甲氧基、氨基、丙烯酰胺基、氰基。
具体地,所述核苷碱基衍生物选自以下所示化合物中的至少一种:
本发明上述核苷碱基衍生物可通过本领域常规的有机合成方法制得,例如,制备方法可包括以下步骤:
1)核苷碱基与式IV所示化合物发生亲核取代反应,得到式V所示化合物;
2)式V所示化合物与式VI所示化合物发生Click反应,得到式I所示化合物;或式V所示化合物与式VII所示化合物发生Click反应,得到式II所示化合物。
式IV、式V、式VI、式VII中的L、R、n与式I或式II中对应的L、R、n定义相同。
所述步骤1)的反应在有机溶剂中进行,所述有机溶剂选自二甲基甲酰胺、二甲基乙酰胺、氯仿、二氯甲烷、丙酮、四氢呋喃、乙腈等中的一种或多种。一般加入碱以促进反应的发生,所述碱选自三乙胺、二异丙基乙基胺、氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、碳酸钠、甲醇钠等中的一种或多种。
所述步骤2)中式VI与式VII所示叠氮化合物可由相应的溴代衍生物与叠氮化钠反应得到,或商业购买得到。所述Click反应选用常规Click反应所用催化剂,优选五水硫酸铜与抗坏血酸钠;反应温度为25-80℃,反应时间为3-12小时;反应溶剂选自DMF、DMSO、水、叔丁醇、乙腈等中的一种或多种。
此外,式I或式II所示化合物中,当R=H时,亦可由R=烷基的对应化合物在碱性条件下水解得到。
经过高分辨质谱,核磁共振,熔点等测试,证明所制备的化合物正确无误,为通式Ⅰ和通式II所示化合物。
本发明的第二方面提供一种药物组合物,其包含作为活性成分的上述核苷碱基衍生物以及可药用辅料。
用式Ⅰ和式II所示化合物或其药学上可接受的盐制备的预防和/或治疗P300相关疾病药物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明的第三方面提供上述核苷碱基衍生物和/或药物组合物在下述至少一个方面中的应用:
1)制备P300乙酰化酶抑制剂;
2)制备真核生物肿瘤细胞增殖抑制剂;
3)制备预防和/或治疗P300相关疾病的药物。
所述真核生物为哺乳动物;所述肿瘤细胞为癌细胞;所述癌细胞优选为白血病癌细胞、乳腺癌细胞、肝癌细胞、胰腺癌细胞、肺癌细胞、脑癌细胞、卵巢癌细胞、子宫癌细胞、睾丸癌细胞、皮肤癌细胞、胃癌细胞、鼻咽癌细胞、结肠癌细胞、膀胱癌细胞或直肠癌细胞;进一步优选为携带CBP突变或缺失的肿瘤细胞。
所述白血病癌细胞优选为人慢性粒细胞白血病(CML)细胞系K562,所述淋巴瘤细胞优选为人组织细胞淋巴瘤细胞U937,所述肺癌细胞优选为人肺癌细胞NCI-H520,所述人脑胶质瘤细胞优选为U251,所述黑色素癌细胞具体为A375,所述胶质母细胞瘤细胞优选为人胶质母细胞瘤细胞A172和人脑星形胶质母细胞瘤细胞U-118MG,所述宫颈癌细胞优选为人宫颈癌细胞系Hela,所述鼻咽癌细胞优选为鼻咽癌细胞株CNE-2,所述肝癌细胞优选为人肝癌细胞株HepG2,所述乳腺癌细胞优选为人乳腺癌细胞MCF-7和MDA-MB-231。
本发明式Ⅰ和式II所示化合物或其药学上可接受的盐也可用于制备预防和/或治疗P300相关疾病的药物。所述P300相关疾病包括但不限于肿瘤、肥厚性心脏病、糖尿病、非酒精性脂肪肝、逆转录病毒感染疾病。
用式Ⅰ和式II所示化合物或其药学上可接受的盐制备的P300乙酰化酶抑制剂、真核生物肿瘤细胞增殖抑制剂以及预防和/或治疗P300相关疾病的药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。
需要的时候,在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式,然而应该理解,可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
下述实施例中所述实验方法,如无特殊说明,均为有机合成与生物测试的常规方法;所述试剂和生物材料,如无特殊说明,均从商业途径获得。
实施例1化合物J1的合成
实施例1A
4-氨基-1-(4-乙炔基苄基)嘧啶-2(1H)-酮
将胞嘧啶(1eq)、4-乙炔基苄溴(1.2eq)、无水碳酸铯(1.5eq)溶于无水DMF中,室温下反应过夜。TLC确认胞嘧啶反应完全后加入水,并以DCM萃取。除去有机相中溶剂后得标题化合物。可通过在乙醚中重结晶或通过柱色谱分离进一步纯化。1H NMR(400MHz,DMSO-d6)δ7.69(d,J=7.2Hz,1H),7.44(d,J=8.2Hz,2H),7.24(d,J=8.1Hz,2H),7.09(d,J=31.1Hz,2H),5.67(d,J=7.2Hz,1H),4.85(s,2H),4.18(s,1H).13C NMR(101MHz,DMSO)δ166.50,156.23,146.51,139.49,132.31,128.20,121.15,94.24,83.78,81.28,51.62.
实施例1B
4-叠氮基丁酸乙酯
将4-溴丁酸乙酯(1eq)溶于DMF中,加入叠氮化钠(3eq),由室温缓慢升温至80℃并在此温度下反应过夜。之后加入乙酸乙酯,过滤除去过量的叠氮化钠,加入水并以乙酸乙酯萃取。有机相经水、饱和食盐水洗涤后用无水硫酸钠干燥。过滤并用旋转蒸发仪旋除溶剂得到标题化合物。1H NMR(400MHz,Chloroform-d)δ4.15(q,J=7.1Hz,2H),3.36(t,J=6.7Hz,2H),2.41(t,J=7.2Hz,2H),2.00–1.82(m,2H),1.27(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.73,60.61,50.69,31.23,24.31,14.25.
实施例1(化合物J1)
4-(4-(4-((4-氨基-2-氧代嘧啶-1(2H)-基)甲基)苯基)-1H-1,2,3-三唑-1-基)
由实施例1A和实施例1B合成。反应条件为有机合成工艺中常用的Click反应所采用的反应条件。具体地,将实施例1A(1eq)、实施例1B(1.2eq)溶于水和叔丁醇的混合溶液(体积比1:1)中,加入抗坏血酸钠(0.1eq)和五水硫酸铜(0.02eq),在氮气保护下于60℃反应4h。经薄层色谱法(TLC)确认实施例1B反应完全后加入适量的水,过滤得标题化合物。以水洗涤进一步纯化化合物或以柱色谱分离纯化化合物。
实施例2化合物J9的合成
实施例2A
4-氨基-1-(丙-2-炔-1-烷)嘧啶-2(1H)-酮
将胞嘧啶(1eq)、3-溴丙炔(3eq)溶于无水DMF中,加入无水碳酸铯(2eq),加热至80℃并反应过夜。反应结束后加入水并以乙酸乙酯萃取。有机相经水、饱和食盐水洗涤后以无水硫酸镁干燥。除去有机相的溶剂后以色谱柱分离得标题化合物。1H NMR(400MHz,DMSO-d6)δ7.52(d,J=7.7Hz,1H),6.64(d,J=7.8Hz,1H),4.77(d,J=2.5Hz,2H),3.49(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO)δ166.55,155.61,145.26,94.61,79.96,75.79,37.84.
实施例2B
将6-溴己酸乙酯(1eq)溶于DMF中,加入叠氮化钠(3eq),由室温缓慢升温至80℃并在此温度下反应过夜。之后加入乙酸乙酯,过滤除去过量的叠氮化钠,加入水并以乙酸乙酯萃取。有机相经水、饱和食盐水洗涤后用无水硫酸钠干燥。过滤并用旋转蒸发仪旋除溶剂得到标题化合物。1H NMR(400MHz,DMSO-d6)δ4.05(q,J=7.1Hz,2H),3.31(t,J=6.8Hz,2H),2.29(t,J=7.3Hz,2H),1.60–1.47(m,4H),1.38–1.27(m,2H),1.18(t,J=7.1Hz,3H).13CNMR(101MHz,DMSO)δ173.26,60.18,51.05,33.91,28.46,26.16,24.52,14.64.
实施例2(化合物J9)
6-(4-((4-氨基-2-氧代嘧啶-1(2H)-基)甲基)-1H-1,2,3-三唑-1-基)己酸乙酯
将实施例2A(1eq)、实施例2B(1.2eq)溶于水和叔丁醇的混合溶液(体积比1:1)中,加入抗坏血酸钠(0.1eq)和五水硫酸铜(0.02eq),在氮气保护下于60℃反应4h。经薄层色谱法(TLC)确认实施例2B反应完全后加入适量的水,过滤得标题化合物。以水洗涤进一步纯化化合物或以柱色谱分离纯化化合物。
实施例3化合物J19的合成
4-(4-(4-((4-氨基-2-氧代嘧啶-1(2H)-基)甲基)苯基)-1H-1,2,3-三唑-1-基)丁酸
参考实施例1,由实施例1A与4-叠氮丁酸反应得到。或者,由对应的酯(J19对应的羧酸乙酯为实施例1的J1)水解得到,具体地,将化合物J1(1eq)与氢氧化锂(2eq)加入到水、乙醇、四氢呋喃的混合溶液中,加热至80℃反应两小时。经薄层色谱法(TLC)确认J1反应完全后加入适量的水,过滤得标题化合物。以水洗涤进一步纯化化合物或以柱色谱分离纯化化合物。
实施例4化合物的表征
参考实施例1-实施例3,使用常规化学合成方法制备化合物J1-J48,并使用核磁共振,高分辨质谱,熔点等对化合物进行表征,结果如下表1。
表1
实施例5
P300/CBP乙酰化酶抑制活性试验。
使用同位素标记的方法测试化合物J1-J48对P300和CBP乙酰化酶的抑制活性。反应体系包括P300(或CBP),生物素标记的底物肽以及同位素标记的乙酰辅酶A([3H]Ac-CoA)。室温下预先将一定浓度的化合物与乙酰化酶P300(或CBP)混合,之后加入底物肽和乙酰辅酶A,孵育后停止反应并转移至包被有链霉亲和素的384孔板中,孵育反应后以洗涤孔板,测试放射性,数据使用GraphPad Prism 5.0处理得到浓度-抑制曲线,并拟合出IC50值。
化合物对P300和CBP抑制活性测试结果如表2所示,同等条件下,P300阳性对照化合物C646对P300的抑制活性IC50为0.76μM。由表2可知,除J16、J29、J40、J48活性较弱外(IC50>10μM),大部分化合物对P300具有良好的酶抑制活性,有一些化合物对P300的IC50<1μM,同时对CBP几乎没有抑制作用(10μM条件下抑制率<50%),即相对于CBP显示了良好的P300选择性抑制活性,典型的代表性化合物包括J1、J23、J35等。J32(IC50=0.18μM)和J45(IC50=0.12μM)表现出优异的P300酶抑制活性,但这两个化合物在10μM时对CBP抑制率>50%。
化合物对P300乙酰化酶的构效关系初步讨论如下:
(1)化合物J1-J4都是胞嘧啶衍生物,随着链长依次增长,对P300酶活性依次降低,即活性与链长负相关;
(2)化合物J4-J8以及J11为不同碱基衍生物,链长相同,化合物J4与J11活性相近,强于后续化合物J6>J8>J5>J7;
(3)J9,J10以及J12-J15,碱基不用,连接链中没有苯环结构,活性顺序为J12>J13>J10>J14>J15>J09;
(4)化合物J12,J16-J18都是氮杂胞嘧啶的衍生物,活性顺序为J18≥J12>J17>J16,其活性与链长正相关,因此可知不同碱基改变链长后无固定的活性变化趋势;
(5)J11,J19-J21仍是氮杂胞嘧啶衍生物,连接链中含苯环结构,活性顺序为J21≥J11>J20>J19,链长与前三者活性正相关,因此可知相同碱基衍生物,不同连接链其活性变化趋势也不相同;
(6)J22-J25系列为胞嘧啶衍生物,活性顺序为J23>J22>J25>J24,链长与活性非线性相关;将酯水解为酸后,J22>J19,J23>J20,而J24<J21,J25<J11,此外需要注意的是J23-J25在甲醇中溶解性较差;
(7)J26-J31系列活性顺序为J27>J30>J26>J31>J28>J29;
(8)J32-J37系列活性顺序为J32>J36>J35>J33>J34>J37,连接链相比J26-J31系列多了一个苯环,P300乙酰化酶抑制活性提高;相比J4-J8及J11系列,连接链中乙撑基替换为苯基,活性也提高;
(9)J43-J48系列,活性顺序为J45>J44>J47>J46>J43>J48,相比于J26-J31系列,酯水解为酸后只有J43、J48活性相比于J26、J31活性下降;其他J44>J27,J45>J28,J46>J29,J47>J30,即转换后活性上升;
(10)J38-J42系列活性顺序为J39>J41>J38>J42>J40,相比J32,J35-J37,只有J39水解后活性提高(J39>J34),其它化合物活性降低(J38<J32,J40<J35,J41<J36,J42<J37)。此外,化合物J04活性比J32弱,但水解产物J25活性强于化合物J38。
表2化合物J1-J48的P300、CBP乙酰化酶抑制活性
实施例6
MTT法细胞增殖抑制活性测试
测试部分化合物的细胞毒性。体外细胞增殖抑制实验采用MTT法,所测试的肿瘤细胞包括人结直肠癌细胞HCT116,乳腺癌细胞HCC1937、T47D、MDA-MB-231,肝癌细胞HepG2,肺癌细胞H520以及正常乳腺细胞MCF-10A。首先测试了部分化合物在10μM浓度下对细胞增殖的抑制率,并对抑制活性较强的化合物和细胞系进行了IC50测试。
测试的具体步骤包括(a)样品准备:将化合物配制成5mM的DMSO溶液,并以DMSO梯度稀释得到一系列不同浓度的样品溶液;(b)铺板:取对数期细胞,通过血球计数板计数,将肿瘤细胞以每孔6×103-8×103个的密度接种于96孔板中,每孔培养基体积为99μL;(c)加药:铺板后12-16h加药(待细胞贴壁后加药)。每孔加入1μL待测化合物溶液,使化合物终浓度为设定的浓度值,每个浓度设置4个复孔,IC50测试时设置8个浓度梯度。同时设置两个阳性药组(分别加入HDAC抑制剂SAHA或DNMT抑制剂SGI-1027)、对照组(加入1μL DMSO)和空白组(加入1μL DMSO);(d)MTT处理:化合物与细胞共培养48h或72h后往实验组和对照组中加入MTT的PBS溶液(5mg/mL,10μL/孔),继续于培养箱中无菌培养4h;(e)后处理与OD值测试:将96孔板离心并吸除培养基(贴壁细胞无须离心),加入DMSO(100μL/孔)并将96孔板在微量振荡器上振荡5分钟后使用酶标仪测试490nm处OD值,最后根据OD值计算出不同浓度下化合物对肿瘤细胞增殖的抑制率(Inh%),进而通过绘制浓度-抑制率曲线求得IC50值。抑制率计算公式为:Inh%=(对照组OD490-实验组OD490)/(对照组OD490-空白组OD490)×100%。
化合物J1-J38对细胞增殖的抑制作用如表3所示,所测试化合物在10μM浓度下处理细胞72h,对HCC1937、HepG2、MCF-10A几乎没有抑制作用。在HCT116中,只有J31在10μM浓度下对细胞增殖抑制率>50%,其他化合物对HCT116增殖影响很小。在肺癌细胞H520中,有4个化合物J30、J31、J32和J34对细胞有较强的增殖抑制活性,IC50分别为11.21μM,7.85μM,12.23μM和23.22μM。可见大部分化合物毒副作用较小,可作为选择性P300乙酰化酶分子探针研究P300作用机制,揭示P300催化底物乙酰化调节细胞命运的分子基础,为原创性抗肿瘤药物研发提供理论支撑。
表3化合物在10μM、72h条件下对细胞增殖的抑制率
注:*IC50,μM。
此外,还测试了化合物J16-J38对乳腺癌细胞T47D和MDA-MB-231的抑制活性(结果见表4),在10μM浓度下处理细胞72小时,在MDA-MB-231细胞中,只有化合物J35抑制率>50%,J34抑制率为45%,接近50%;在T47D中,化合物J27-J32都具有较明显的抑制活性。由此可知,化合物对不同的肿瘤细胞具有不同的抑制作用,同一种肿瘤细胞对不同化合物响应性也不同。综合细胞增殖抑制实验的结果,化合物J1对所测试细胞系几乎都没有细胞毒作用,适合作为研究生物机制用的探针分子;化合物J31和J32对肿瘤细胞T47D、H520具有较强的增殖抑制活性,可作为抗肿瘤苗头化合物用于后续药物发现和药物作用机制研究。
表4化合物J16-J38在10μM、72h条件下的细胞增殖抑制率
由以上研究结果可以看出,式I所示化合物和式II所示化合物对P300乙酰化酶具有良好的抑制活性,对CBP表现出较好的选择性,且细胞毒作用较小,可作为探针分子以及先导化合物用于P300乙酰化酶作用机制研究和P300相关疾病药物研发。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。
Claims (10)
2.根据权利要求1所述的核苷碱基衍生物,其中,所述药学上可接受的盐为无机酸盐或有机酸盐。
3.根据权利要求2所述的核苷碱基衍生物,其中,所述无机酸盐选自下述任意一种无机酸形成的盐:盐酸、硫酸和磷酸;
所述有机酸盐选自下述任意一种有机酸形成的盐:乙酸、三氟乙酸、丙二酸、柠檬酸和对甲苯磺酸。
4.根据权利要求1所述的核苷碱基衍生物,其中,所述核苷碱基上的取代基选自C1-C5的烷基、C1-C5的烷氧基、C2-C5的烯基、C2-C5的炔基、卤素、羟基、硝基、三氟甲基、三氟甲氧基、氨基、丙烯酰胺基、氰基。
6.一种药物组合物,其包含作为活性成分的如权利要求1-5中任意一项所述的核苷碱基衍生物以及可药用辅料。
7.根据权利要求6所述的药物组合物,其中,所述药物组合物的剂型形式选自注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂。
8.权利要求1-4中任意一项所述的核苷碱基衍生物和/或权利要求6或7所述的药物组合物在下述至少一个方面中的应用:
1)制备P300乙酰化酶抑制剂;
2)制备真核生物肿瘤细胞增殖抑制剂;
3)制备预防和/或治疗P300相关疾病的药物。
9.根据权利要求8所述的应用,其中,所述真核生物为哺乳动物;所述肿瘤细胞为癌细胞;所述癌细胞优选为白血病癌细胞、乳腺癌细胞、肝癌细胞、胰腺癌细胞、肺癌细胞、脑癌细胞、卵巢癌细胞、子宫癌细胞、睾丸癌细胞、皮肤癌细胞、胃癌细胞、鼻咽癌细胞、结肠癌细胞、膀胱癌细胞或直肠癌细胞;进一步优选为携带CBP突变或缺失的肿瘤细胞;
所述白血病癌细胞优选为人慢性粒细胞白血病细胞系K562,所述淋巴瘤细胞优选为人组织细胞淋巴瘤细胞U937,所述肺癌细胞优选为人肺癌细胞NCI-H520,所述人脑胶质瘤细胞优选为U251,所述黑色素癌细胞具体为A375,所述胶质母细胞瘤细胞优选为人胶质母细胞瘤细胞A172和人脑星形胶质母细胞瘤细胞U-118MG,所述宫颈癌细胞优选为人宫颈癌细胞系Hela,所述鼻咽癌细胞优选为鼻咽癌细胞株CNE-2,所述肝癌细胞优选为人肝癌细胞株HepG2,所述乳腺癌细胞优选为人乳腺癌细胞MCF-7和MDA-MB-231。
10.根据权利要求8所述的应用,其中,所述P300相关疾病选自肿瘤、肥厚性心脏病、糖尿病、非酒精性脂肪肝、逆转录病毒感染疾病。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011085039A2 (en) * | 2010-01-05 | 2011-07-14 | The Johns Hopkins University | Use of histone acetyltransferase inhibitors as novel anti-cancer therapies |
CN102548975A (zh) * | 2009-07-07 | 2012-07-04 | 安瑟生物科技私人有限公司 | 组蛋白去乙酰化酶抑制剂 |
CN106883217A (zh) * | 2017-04-01 | 2017-06-23 | 清华大学深圳研究生院 | 一种核苷碱基异羟肟酸衍生化合物及其制备方法与应用 |
CN107750249A (zh) * | 2015-04-20 | 2018-03-02 | 塞尔森瑞科有限责任公司 | 异噁唑基取代的苯并咪唑 |
CN107750251A (zh) * | 2015-04-20 | 2018-03-02 | 塞尔森瑞科有限责任公司 | 异噁唑基取代的咪唑并吡啶 |
KR20180071889A (ko) * | 2016-12-20 | 2018-06-28 | 충북대학교 산학협력단 | 신규한 n-히드록시벤즈아미드 및 이의 용도 |
-
2020
- 2020-10-21 CN CN202011133175.1A patent/CN112250672B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102548975A (zh) * | 2009-07-07 | 2012-07-04 | 安瑟生物科技私人有限公司 | 组蛋白去乙酰化酶抑制剂 |
WO2011085039A2 (en) * | 2010-01-05 | 2011-07-14 | The Johns Hopkins University | Use of histone acetyltransferase inhibitors as novel anti-cancer therapies |
CN107750249A (zh) * | 2015-04-20 | 2018-03-02 | 塞尔森瑞科有限责任公司 | 异噁唑基取代的苯并咪唑 |
CN107750251A (zh) * | 2015-04-20 | 2018-03-02 | 塞尔森瑞科有限责任公司 | 异噁唑基取代的咪唑并吡啶 |
KR20180071889A (ko) * | 2016-12-20 | 2018-06-28 | 충북대학교 산학협력단 | 신규한 n-히드록시벤즈아미드 및 이의 용도 |
CN106883217A (zh) * | 2017-04-01 | 2017-06-23 | 清华大学深圳研究生院 | 一种核苷碱基异羟肟酸衍生化合物及其制备方法与应用 |
Non-Patent Citations (1)
Title |
---|
刘文娟: "《药物化学》", 28 February 2013, 中国医药科技出版社 * |
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