CN110862383A - 组蛋白乙酰转移酶p300小分子抑制剂及其药用组合物及其应用 - Google Patents
组蛋白乙酰转移酶p300小分子抑制剂及其药用组合物及其应用 Download PDFInfo
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Abstract
本发明属药物化学领域,涉及组蛋白乙酰转移酶p300小分子抑制剂,尤其是具有式(Ⅰ)结构的化合物或者其药学上可接受的盐;经实验显示,所述的化合物能抑制组蛋白乙酰转移酶p300的活性,显著降低细胞内组蛋白乙酰化水平且效果强于原p300代表性小分子抑制剂C646,对前列腺癌细胞、恶性血液肿瘤细胞、乳腺癌细胞等肿瘤细胞具有显著的抑制作用,抑制强度较原化合物C646有提升;且所述式(Ⅰ)结构的化合物能克服原p300小分子抑制剂C646存在的含有潜在毒性基团、溶解性差等缺陷,提高了化合物的类药性。
Description
技术领域
本发明属于药物化学领域,涉及组蛋白乙酰转移酶p300小分子抑制剂。本发明所涉及的化合物能够抑制组蛋白乙酰转移酶p300的活性,显著降低细胞内组蛋白乙酰化水平且效果强于原p300代表性小分子抑制剂C646,对前列腺癌细胞、恶性血液肿瘤细胞、乳腺癌细胞等肿瘤细胞具有显著的抑制作用,抑制强度较原化合物C646有所提升。且本发明所公开的化合物克服了原p300小分子抑制剂C646存在的含有潜在毒性基团、溶解性差等缺陷,提高了化合物的类药性。
背景技术
现有技术公开了组蛋白和其他蛋白质的可逆乙酰化反应是细胞调节的一种主要机制,这种共价修饰是细胞生物学中的一种重要调节方式。通常,组蛋白的高乙酰化是活跃转录的标志,组蛋白赖氨酸乙酰化与基因激活相关,而低乙酰化则与转录抑制相关,组蛋白赖氨酸脱乙酰化与基因抑制和沉默相关[1]。蛋白赖氨酸残基的乙酰化由组蛋白乙酰转移酶(HATs)催化,乙酰基-Lys裂解由组蛋白脱乙酰酶(HDAC)进行。这些酶和相关的乙酰化事件已经涉及多种生理和疾病过程[2]。
研究表明组蛋白乙酰基转移酶及其复合体除具有调控基因转录起始的功能外,还参与了细胞周期调控、DNA复制、修复以及染色体组装等许多重要的生理过程[3]。
研究表明,组蛋白乙酰化会影响细胞分化、基因表达、血管重塑、神经元可塑性、炎症或代谢等生理过程。研究还发现,细胞中某些癌基因和抑癌基因的乙酰化状态相关与某些恶性肿瘤的发生发展密切相关[4,5,6]。
组蛋白乙酰转移酶(HAT)家族中p300蛋白作为一特殊的转录辅因子本身具有组蛋白乙酰化转移酶活性,所以它具有调节染色体结构的功能[3];同时p300还是多细胞生物中特有的乙酰化酶,多细胞生物所特有的细胞分化、信号转导都与其密切相关[7]。研究显示,p300参与了包括增殖、分化、凋亡等生理进程,同时,p300作为转录调节因子,也参与了许多信号依赖的转录事件。有研究报道许多病毒癌蛋白如,腺病毒EIA、SV40大T抗原等,都能特异性地靶向p300[8]。p300与病毒癌蛋白形成复合物后导致细胞生长失去控制,增强DNA合成,抑制细胞分化。近期的研究结果表明[9],p300基因的改变导致许多人类癌症的形成。目前业内对p300的功能研究主要倾向于其乙酰化的作用方面,即对转录因子以及组蛋白的乙酰化,是涉及许多基因调控途径和蛋白质乙酰化事件的转录共激活因子[10];调控p300活性有助于治疗癌症、艾滋病、肺部疾病、阿尔茨海默病、神经变性疾病、真菌感染、甲型流感等疾病[11]。
目前,对p300蛋白中乙酰转移酶结构域的抑制剂包括一些天然产物[13-16]、双底物类似物[17]和小分子[6,12],这些抑制剂中最为经典和有效的是一种通过高通量筛选而得到的新型吡唑啉酮类p300小分子抑制剂——C646[12];对接表明小分子C646可以插入到p300HAT晶体结构的Lys-CoA结合口袋中,是一种竞争性p300抑制剂,C646通过其两端的硝基和羧基与周围p300蛋白上的氨基酸残基形成氢键而发挥作用,与p300结合的Ki值为400nM,且对p300较其他乙酰转移酶(AANAT,Gcn5,PCAF,Sas,MOZ,Rtt109)有选择性;进一步实验结果显示[12],C646能够抑制小鼠成纤维细胞系中组蛋白H3和H4乙酰化,并在体外抑制黑素瘤和肺癌细胞生长,但与其共晶中配体Lys-CoA(Ki=20nM)相比,C646抑制活性仍较弱;且C646中发挥抑制作用的硝基和羧基在体内具有潜在毒性;C646还存在溶解性差的明显缺陷,在除DMSO之外的所有常见溶剂中不溶[17],这些因素都影响了其进一步的开发应用。因此,寻找类药性好、抑制活性高的p300小分子抑制剂依然是该领域的重要课题。下述参考文献因被本发明引用,其内容包含在本发明中。
参考文献:
[1].Esteller.M,et al.“Epigenetics provides a new generation ofoncogenes and tumour-suppressor genes”.Br.J.Cancer 94:179–183
[2].S.D.Furdas,et al.“Small Molecule Inhibitors of HistoneAcetyltransferases as Epigenetic Tools and Drug Candidates”.Arch.Pharm.Chem.Life Sci.2012,345,7–21
[3].Beverley M.Dancy,Philip A.Cole.“Protein Lysine Acetylation byp300/CBP”Chem.Rev.2015,115,2419-2452
[4].L.Ellis,P.W.Atadja,R.W.Johnstone,“Epigenetics in cancer:Targetingchromatin modifications”.Mol Cancer Ther 2009,8,1409–1420.
[5].M.Esteller,et al.“Molecular Origins of Cancer:Epigenetics inCancer”N Engl J Med 2008,358,1148–1159.
[6].Loren M.Lasko,Clarissa G.Jakob,P.A.Cole,Saul H.Rosenberg,MichaelR.Michaelides,Albert Lai&Kenneth D.Bromberg.“Discovery of a selectivecatalytic p300/CBP inhibitor that targets lineage-specific tumours”Nature2017,550,128–132.
[7].Arany,Z.;Sellers,W.R.;Livingston,D.M.;Eckner,R.“E1A-associatedp300and CREB-associated CBP belong to a conserved family of coactivators”Cell1994,77,799.
[8].Eckner,R.;Ewen,M.E.;Newsome,D.;Gerdes,M.;DeCaprio,J.A.;Lawrence,J.B.;Livingston,D.M.“Molecular cloning and functional analysis of theadenovirus E1A-associated 300-kD protein(p300)reveals a protein withproperties of a transcriptional adaptor.”Genes Dev.1994,8,869.
[9].Teufel DP,Freund SM,Bycroft M,Fersht AR."Four domains of p300eachbind tightly to a sequence spanning both transactivation subdomains of p53".Proceedings of the National Academy of Sciences of the United States ofAmerica.104(17):7009–14.
[10].Spiegelman BM,Heinrich R."Biological control through regulatedtranscriptional coactivators".Cell.119(2):157–67.
[11].Iyer,N.G.,Ozdag,H.&Caldas,C.p300/CBP and cancer.Oncogene 23,4225–4231.
[12].E.M.Bowers,P.A.Cole,et al.“Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase:Identification of a Selective Small MoleculeInhibitor”Chem Biol 2010,17,471–482.
[13].Balasubramanyam,K.;Swaminathan,V.;Ranganathan,A.;Kundu,T.K.J.Biol.Chem.2003,278,19134.
[14].Balasubramanyam,K.;Varier,R.A.;Altaf,M.;Swaminathan,V.;Siddappa,N.B.;Ranga,U.;Kundu,T.K.J.Biol.Chem.2004,279,51163.
[15].Balasubramanyam,K.;Altaf,M.;Varier,R.A.;Swaminathan,V.;Ravindran,A.;Sadhale,P.P.;Kundu,T.K.J.Biol.Chem.2004,279,33716.
[16].Ravindra,K.C.;Selvi,B.R.;Arif,M.;Reddy,B.A.;Thanuja,G.R.;Agrawal,S.;Pradhan,S.K.;Nagashayana,N.;Dasgupta,D.;Kundu,T.K.J.Biol.Chem.2009,284,24453.
[17].Jonathan H.Shrimp,Alexander W.Sorum,Julie M.Garlick,LauraGuasch,Marc C.Nicklaus,Jordan L.Meier,“Characterizing the Covalent Targets ofa Small Molecule Inhibitor of the Lysine Acetyltransferase P300”ACSMed.Chem.Lett.2016,7,151-155。
发明内容
本发明的目的是基于现有技术的现状以及为克服现有技术存在的缺陷,提供组蛋白乙酰转移酶P300小分子抑制剂及其药用组合物及其应用;尤其提供了具有通式(Ⅰ)结构的化合物或其药学上可接受的盐作为p300小分子抑制剂。这些化合物可以显著降低细胞内组蛋白乙酰化水平、抑制相关肿瘤细胞的生长且具有较好的类药性。
本发明的目的通过以下技术方案得以实现:
本发明提供了一种具有式(Ⅰ)结构类型的化合物或者其药学上可接受的盐作为p300小分子抑制剂,能够抑制组蛋白乙酰转移酶p300的活性,显著降低细胞内组蛋白乙酰化水平且效果强于原p300代表性小分子抑制剂C646,对相关肿瘤细胞具有显著的抑制作用,抑制强度较原化合物C646有所提升;且本发明所公开的化合物能克服原p300小分子抑制剂C646存在的含有潜在毒性基团、溶解性差等缺陷,提高化合物的类药性。
通式(Ⅰ)中,A环代表五元或六元的芳环,以及含氮、氧、硫原子的芳杂环,以及带有1~4个碳原子的酰胺键;
R1代表氢原子、卤素;
R2代表羟基、羧基、带1~4个碳原子的磺烷基、硼酸基团、含氮五元杂环;
R3代表三氟甲基、三氟甲氧基、膦酰基、硝基、二氟甲基、或与邻位碳原子环合为环戊酮;
R4代表氢原子、甲基;
R5代表氢原子、1到4个碳原子长度的直链烷烃或环烷烃;
X代表-C(O)-、-N=;Y代表碳原子、硫原子、或-NH-;当X为-N=时,Y代表碳原子,X、Y间为双键;当X为-C(O)-时,Y代表硫原子或-NH-基团,X、Y间为单键,此时无R5基团。
优选地,本发明所述的一类具有组蛋白乙酰转移酶p300抑制活性的化合物及其药学上可接受的盐,其包括下列化合物:
本发明提供了合成上述化合物的方法。
本发明进一步目的是提供一种治疗肿瘤的药用组合物,其药学活性成分为上述的具有通式(Ⅰ)所示结构的化合物或其药学上可接受的盐。
本发明的进一步目的是提供上述的具有通式(Ⅰ)所示结构的化合物或其药学上可接受的盐作为组蛋白乙酰转移酶p300抑制剂在用于制备治疗与组蛋白乙酰转移酶p300活性异常有关的癌症药物中的应用;
所述的癌症包括前列腺癌、恶性血液肿瘤、乳腺癌、宫颈癌、卵巢癌、非小细胞肺癌、肾细胞癌、黑色素瘤、胃癌、膀胱癌、子宫内膜癌。
本发明的具有通式(Ⅰ)所示结构的化合物作为组蛋白乙酰转移酶p300的抑制剂能克服原p300代表性小分子抑制剂C646含有潜在毒性基团的缺陷;本发明中对上述具有通式(Ⅰ)所示结构的化合物进行了生物学实验,结果显示,制备的上述具有通式(Ⅰ)所示结构的化合物在分子水平能够在较低剂量抑制组蛋白乙酰转移酶p300的活性,在细胞实验中,制备的上述具有通式(Ⅰ)所示结构的化合物能够显著降低细胞内组蛋白乙酰化水平且效果强于原p300代表性小分子抑制剂C646,细胞增殖实验表明制备的上述具有通式(Ⅰ)所示结构的化合物对乳腺肿瘤细胞、前列腺肿瘤细胞等恶性肿瘤细胞具有明显的抑制作用,抑制作用较C646更为显著;溶解性实验表明具有通式(Ⅰ)所示结构的化合物克服了C646只溶于DMSO的缺陷,提高了化合物的类药性。
附图说明
图1是部分化合物在10μM浓度下对血液肿瘤细胞U2932细胞H3K27位乙酰化水平影响的蛋白印迹图。
具体实施方式
以下实施例对本发明做进一步的描述,仅表达了本发明的几种实施方式,其描述的较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以作出若干变形和改进,这些都属于本发明的保护范围。
实施例1:合成化合物1:2-(4-(1H-四唑-5-基)苯基)-4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-5-甲基-2,4-二氢-3H-吡唑-3-酮
步骤1,1-(4-氰基苯基)-3-甲基-5-吡唑酮的合成,反应式如下:
将对氰基苯肼盐酸盐(848.1mg,5mmol)溶于醋酸(5ml)中,加入乙酰乙酸乙酯(780.8mg,6mmol),加热回流16h,冷却至室温,减压除去部分溶剂,过滤,二氯甲烷洗涤,将滤得的固体用柱色谱纯化(MeOH:DCM=1:20)得褐色固体(892.5mg,89.6%)。1H NMR(400MHz,DMSO-d6)7.91(d,J=7.8Hz,2H),7.65(d,J=7.8Hz,2H),4.22(s,1H),2.47(s,3H);
步骤2:1-[4-(1H-四唑)-苯基]-3-甲基-5-吡唑酮
向圆底烧瓶中加入1-(4-氰基苯基)-3-甲基-5-吡唑酮(398.4mg,2mmol),NaN3(143.2mg,2.2mmol),ZnBr2(450.3mg,2mmol)和水(4ml)。将反应混合物在剧烈搅拌中加热回流24h,加入盐酸和乙酸乙酯,继续剧烈搅拌直至固体完全消失且水层pH为1。分离有机层,水层用EA(10ml X 2)萃取。将合并的有机层旋蒸除去溶剂后加入0.25M的NaOH溶液20ml,室温搅拌30min至原始沉淀溶解,形成Zn(OH)2悬浮液,过滤悬浮液,固体用1M的NaOH溶液(2ml)洗涤。在剧烈的搅拌下向滤液中加入3M的HCl溶液4ml,使四氮唑沉淀,过滤,将滤出的固体柱色谱纯化(MeOH:DCM=1:8)得淡褐色固体(185.6mg,38.4%)。1H NMR(400MHz,DMSO-d6)8.27(d,J=7.8Hz,2H),7.60(d,J=7.8Hz,2H),6.03(s,1H),4.21(s,1H),2.45(s,3H).;
步骤3:1-溴-4,5-二甲基-2-硝基苯
将4,5-二甲基-2-硝基苯胺(300.0mg,1.8mmol)溶于蒸馏水(11.4ml)与HBr溶液(48%,32ml)的混合溶液中,70℃下搅拌30min,冷却至-5℃后加入NaNO2(780.0mg,11.3mmol)水溶液(4ml)中。保持体系温度-5℃下搅拌15min,加入新制备的冷却的CuBr(3.27g,24.3mmol)的HBr溶液(48%,6ml),70℃加热15min。将反应混合物用二氯甲烷萃取三次(20ml X 3)。将合并的有机相用NaOH(10%,20ml)洗涤,无水NaSO4干燥,过滤,并在减压下蒸去溶剂。柱色谱(PE/EA=9:1)纯化得黄色固体(370.2mg,89.4%)。1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.50(s,1H),2.31(s,3H),2.29(s,3H).;
步骤4:5-(4,5-二甲基-2-硝基苯基)-2-呋喃甲醛
将1-溴-4,5-二甲基-2-硝基苯(230.0mg,1mmol),5-甲酰基-2-呋喃硼酸(183.2mg,1.31mmol)和(Ph3P)2PdCl2(35.1mg,50μmol)溶于DME(3ml)、乙醇(2ml)、2M Na2CO3(3ml)的混合溶剂中,50℃加热1h,冷却至室温。乙酸乙酯萃取(10ml X 3)。合并的有机层用饱和食盐水洗涤,无水NaSO4干燥,过滤,减压浓缩,柱色谱纯化(PE/EA=7:1)得黄绿色絮状固体(130.3mg,53.2%)。1H NMR(400MHz,CDCl3)δ9.67(s,1H),7.66(s,1H),7.58(s,1H),7.32(d,J=3.7Hz,1H),6.74(d,J=3.7Hz,1H),2.39(s,3H),2.38(s,3H).;
步骤5:4-(4,5-二氢-3-甲基-4-((5-(4,5-二甲基-2-硝基苯基)呋喃)-2-亚甲基)-5-氧杂吡唑)-1-(1H-四唑)-苯
将5-(4,5-二甲基-2-硝基苯基)-2-呋喃甲醛(73.6mg,0.3mmol)与1-[4-(1H-四唑)-苯基]-3-甲基-5-吡唑酮(72.7mg,0.3mmol)溶于无水乙醇中,加入二乙胺(21.9mg,0.3mmol)后50℃加热3h。冷却后产物沉淀,过滤收集,柱色谱纯化(MeOH:DCM=1:17)得红褐色固体(80.3mg,57.4%)。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),8.06(d,J=8.8Hz,2H),8.00(d,J=8.7Hz,2H),7.89(s,1H),7.85(s,1H),7.81(s,1H),7.28(d,J=3.7Hz,1H),6.03(s,1H),2.38(s,3H),2.37(s,3H),2.27(s,3H).ES/MS(M+H)+=470.2.。
实施例2:合成化合物2:(4-(4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯基)硼酸
步骤1,2-(4-溴-苯基)-2,4-二氢-5-甲基-3H-吡唑-3-酮的合成,反应式如下:
合成方法同实施例1中步骤1类似,得粉色固体(792.0mg,70.1%)。1H NMR(400MHz,CDCl3):7.87(d,2H,J=8.8Hz),7.49(d,2H,J=8.8Hz),3.39(s,2H),2.16(s,3H).;
步骤2,(4-(3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯基)硼酸
在-78℃条件下,向2-(4-溴-苯基)-2,4-二氢-5-甲基-3H-吡唑-3-酮(379.6mg,1.5mmol)的THF(10ml)溶液中缓慢滴加正丁基锂(2.5M,720μL,1.8mmol),-78℃下搅拌30min,然后一次性加入硼酸三异丙酯(366.8mg,1.9mmol),将反应在-78℃条件下继续搅拌1h,关闭低温装置,使反应体系温度缓慢升至室温,反应完毕后用1M HCl溶液(2ml)淬灭反应,0℃条件下搅拌30min。EA萃取,有机层用无水硫酸镁干燥,过滤,柱色谱纯化(MeOH:DCM=1:15)得白色固体(103.6mg,39.7%)。1H NMR(400MHz,DMSO-d6)8.00(d,J=7.8Hz,2H),7.45(d,J=7.8Hz,2H),3.21(s,1H),1.87(s,3H).;
步骤3:4-(4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯基)硼酸
合成方法同实施例1中步骤5类似,得红褐色固体(20.4mg,56.3%)。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),8.00(d,J=7.8Hz,2H),7.45(d,J=7.8Hz,2H),7.84(s,1H),7.81(s,1H),7.76(s,1H),7.28(d,J=3.7Hz,1H),2.38(s,3H),2.37(s,3H),2.27(s,3H).ES/MS(M+H)+=446.1。
实施例3:合成化合物3:2-(3,5-二氟-4-羟基苯基)-4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-5-甲基-2,4-二氢-3H-吡唑-3-酮
步骤1,4-溴-1,3-二氟-2-(甲氧基甲氧基)苯
在0℃下向4-溴-1,3-二氟苯酚(2.09g,10mmol)的二氯甲烷(20ml)溶液中加入二异丙基乙胺(2.59g,20mmol)和甲氧甲基氯(1.61g,20mmol),将混合物在室温下搅拌2h,反应完毕后用水,5%碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸镁干燥,过滤,旋去溶剂,柱色谱纯化(PE/EA=9:1)得淡黄色油状液体(2.43g,96.7%)。1H NMR(400MHz,CDCl3)δ7.11(s,1H),7.10(s,1H),5.13(s,2H),3.58(s,3H);.
步骤2,3,5-二氟-4-羟基苯基硼酸
在-78℃条件下,向4-溴-1,3-二氟-2-(甲氧基甲氧基)苯(379.6mg,1.5mmol)的THF(10ml)溶液中缓慢滴加正丁基锂(2.5M,720μL,1.8mmol),-78℃下搅拌30min,然后一次性加入硼酸三异丙酯(366.8mg,1.9mmol),将反应在-78℃条件下继续搅拌1h,关闭低温装置,使反应体系温度缓慢升至室温,反应完毕后用1M HCl溶液(2ml)淬灭反应,0℃条件下搅拌30min。EA萃取,有机层用无水硫酸镁干燥,过滤,柱色谱纯化(MeOH:DCM=1:15)得白色固体(103.6mg,39.7%);
步骤3,2-(3,5-二氟-4-羟基苯基)-5-甲基-2,4-二氢-3H-吡唑-3-酮
向100ml烧瓶内加入3,5-二氟-4-羟基苯基硼酸(173.9mg,1mmol)、3-甲基-2-吡唑啉-5-酮(98.1mg,1mmol)和Cu(OAc)2.H2O(199.7mg,1mmol),加入甲醇(36ml)和水(9ml)的混合溶剂,溶质溶解后加入TMEDA(348.6mg,1mmol),敞口在室温下剧烈搅拌1h,反应完毕后旋干溶剂,柱色谱纯化(MeOH:DCM=1:20)得淡黄色色固体(149.1mg,65.9%)。1H NMR(400MHz,dmso)δ6.14(d,J=8.6Hz,2H),4.69(s,1H),1.35(s,3H);
步骤4,2-(3,5-二氟-4-羟基苯基)-4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-5-甲基-2,4-二氢-3H-吡唑-3-酮
合成方法同实施例1中步骤5类似,得红褐色固体。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),7.89(s,1H),7.85(d,J=8.6Hz,2H),7.81(s,1H),7.28(d,J=3.7Hz,1H),6.14(s,1H),2.38(s,3H),2.37(s,3H),2.35(s,3H).ES/MS(M+H)+=454.1。
实施例4:合成化合物4:4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-5-甲基-2-(4-(甲基磺酰基)苯基)-2,4-二氢-3H吡唑-3-酮
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.32(d,J=3.7Hz,1H),7.92(d,J=8.8Hz,2H),7.89(s,1H),7.85(s,1H),7.81(s,1H),7.28(d,J=3.7Hz,1H),7.14(d,J=8.7Hz,2H),2.38(s,3H),2.37(s,3H),2.28(s,3H).ES/MS(M+H)+=480.1。
实施例5:合成化合物5:4-(4-((5-(4,5-二甲基-2-(三氟甲基)苯基)呋喃-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢1H-吡唑-1-基)苯甲酸
步骤1,1-碘-4,5-二甲基-2-硝基苯
向4,5-二甲基-2-硝基苯胺(498.5mg,3mmol)中加入对甲苯磺酸一水合物(1.72g,9mmol)的乙腈溶液(12ml)。将得到的铵盐悬浮液冷却至10-15℃后非常缓慢的向体系内滴加NaNO2(414.0mg,6mmol)和KI(1.25g,7.5mmol)的混合水溶液(1.8ml)。反应在室温下搅拌3h,TLC监测反应。反应完成后将反应混合物倒入50ml的水中,用饱和碳酸氢钠溶液调节pH至9-10。混合物用Na2S2O3(2M,6ml)处理。将沉淀的2-硝基碘苯过滤,柱色谱纯化(PE:EA=10:1)得淡黄色固体(405.0mg,48.7%)。1H NMR(400MHz,cdcl3)δ7.80(s,1H),7.72(s,1H),2.29(s,6H);
步骤2,1,2-二甲基-4-硝基-5-三氟甲基苯
将1-碘-4,5-二甲基-2-硝基苯(637.2mg,2.3mmol)溶于DMF(15ml)中,加入CuI(1.1g,5.8mmol)、FSO2CF2COOMe(4.4g,23.0mmol)和HMPA(4.1g,23.0mmol),混合物在80℃下加热搅拌2h,冷却至室温,加水(60ml)稀释,乙酸乙酯萃取(60mlX3)。合并有机相,干燥,浓缩,柱色谱纯化(PE/EA=7:1)得黄色固体(323.4mg,64.1%)。1H NMR(400MHz,cdcl3)δ7.70(s,1H),7.56(s,1H),2.40(s,6H).19F NMR(376MHz,cdcl3)δ-59.40(s);
步骤3,4,5-二甲基-2-(三氟甲基)苯胺
将1,2-二甲基-4-硝基-5-三氟甲基苯(3.29g,15.0mmol),活性炭(450.0mg),氯化铁六水合物(40.0mg,0.15mmol)和10mL甲醇的混合物加热回流15分钟。然后15分钟内逐滴加入一水合肼(1.82mL,37.5mmol)。搅拌混合物并加热回流过夜。将混合物冷却至室温后,过滤除去炭黑。在旋转蒸发器上除去溶剂后,将残余物用柱色谱纯化(流动相为纯石油醚)得到无色液体(2.64g,93.0%)。1H NMR(400MHz,CDCl3)7.14(s,1H),6.53(s,1H),3.69(s,2H,NH2),2.17(s,3H);
步骤4,1-溴-4,5-二甲基-2-(三氟甲基)苯
将2-硝基苯胺(2.46g,13mmol)溶于蒸馏水(76ml)与HBr溶液(48%,20ml)的混合溶液中,70℃下搅拌30min,冷却至-5℃后加入NaNO2(5.65g,81.9mmol)的水溶液(25ml)中。保持体系-5℃下搅拌15min,加入新制备的冷却的CuBr(25.17g,175.5mmol)的HBr溶液(48%,25ml),70℃加热15min,将混合物用二氯甲烷萃取三次(20ml X 3)。将合并的有机相萃取物用NaOH(10%,20ml)洗涤,用无水NaSO4干燥,过滤,并在减压下蒸去溶剂。柱色谱(PE/EA=9:1)纯化得黄色固体(2.21g,67.2%)。1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.43(s,1H),2.28(s,1H),2.26(s,1H);
其他步骤合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),8.06(d,J=8.8Hz,2H),8.00(d,J=8.7Hz,2H),7.89(s,1H),7.66(s,1H),7.52(s,1H),7.28(d,J=3.7Hz,1H),2.38(s,3H),2.37(s,3H),1.01(d,J=6.5Hz,5H).ES/MS(M+H)+=469.1。
实施例6:合成化合物6:4-(3-甲基-5-氧代-4-((5-(2-(三氟甲氧基)苯基)呋喃-2-基)亚甲基)-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。δ8.52(d,J=3.6Hz,1H),8.11(d,J=8.8Hz,2H),8.02(d,J=8.7Hz,2H),7.82~7.70(m,4H),7.28(d,J=3.7Hz,1H),6.14(s,1H),2.38(s,3H).,ES/MS(M+H)+=457.1。
实施例7:合成化合物7:4-(4-((5-(2-(二甲基膦酰基)-4,5-二甲基苯基)呋喃-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢-1H--吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.32(d,J=3.7Hz,1H),7.92(d,J=8.8Hz,2H),7.89(s,1H),7.85(s,1H),7.81(s,1H),7.28(d,J=3.7Hz,1H),7.14(d,J=8.7Hz,2H),2.38(s,3H),2.37(s,3H),2.28(s,3H).ES/MS(M+H)+=477.2。
实施例8:合成化合物8:4-(3-甲基-5-氧代-4-((5-(3-氧代-2,3-二氢-1H-茚-4-基)呋喃-2-基)亚甲基)-4-,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.24(d,J=8.7Hz,2H),7.71(d,J=8.8Hz,2H),7.65~7.53(m,3H),7.50(d,J=3.7Hz,1H),7.33(d,J=3.6Hz,1H),6.19(s,1H),3.06~2.63(m,4H),2.46(s,3H),.ES/MS(M+H)+=427.1。
实施例9:合成化合物9:4-(4-((5-(2-(二氟甲基)苯基)呋喃-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.27(d,J=8.7Hz,2H),7.70(d,J=8.8Hz,2H),7.67~7.49(m,4H),7.47(d,J=3.7Hz,1H),7.13(d,J=3.7Hz,1H),6.44(t,J=12.8Hz,1H),6.21(s,1H)2.46(s,3H),.ES/MS(M+H)+=423.1。
实施例10:合成化合物10:4-(4-((5-(4,5-二甲基-2-硝基苯基)噻吩-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.71(d,J=3.7Hz,1H),8.31(d,J=8.8Hz,2H),8.11(d,J=8.7Hz,2H),7.93(s,1H),7.83(s,1H),7.80(s,1H),7.15(d,J=3.7Hz,1H),2.38(s,3H),2.37(s,3H),2.19(s,3H).ES/MS(M+H)+=462.1。
实施例11:合成化合物11:4-(4-((5-(4,5-二甲基-2-硝基苯基)-1H-吡咯-2-基)亚甲基)-3-甲基-5-氧代-4,5-二氢1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.52(d,J=3.6Hz,1H),8.11(d,J=8.8Hz,2H),8.02(d,J=8.7Hz,2H),7.89(s,1H),7.83(s,1H),7.81(s,1H),7.25(d,J=3.7Hz,1H),2.38(s,3H),2.37(s,3H),2.19(s,3H).ES/MS(M+H)+=445.1。
实施例12:合成化合物12:4-(4-((2-(4,5-二甲基-2-硝基苯基)噻唑-5-基)亚甲基)-3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.52(s,1H),8.11(d,J=8.8Hz,2H),8.02(d,J=8.7Hz,2H),7.89(s,1H),7.83(s,1H),7.81(s,1H),2.38(s,3H),2.37(s,3H),2.19(s,3H).ES/MS(M+H)+=463.1。
实施例13:合成化合物13:4-(4-(2-((4,5-二甲基-2-硝基苯基)氨基)-2-氧代乙基)-3-甲基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得红色固体。1H NMR(400MHz,DMSO-d6):δ10.36(s,1H),8.24(d,J=8.8Hz,2H),8.14(s,1H),7.92(s,1H),7.73(d,J=8.7Hz,2H),2.97~2.73(m,3H),2.00(s,3H).ES/MS(M+H)+=425.2。
实施例14:合成化合物14:4-(5-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-2,4-二氧代噻唑烷-3-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):8.30(s,1H),δ8.05(d,J=7.9Hz,2H),7.99(d,J=3.7Hz,1H),7.97(s,1H),7.38(d,J=7.9Hz,2H),7.36(d,J=3.7Hz,1H),7.25(s,1H),2.29(s,3H),2.26(s,3H).ES/MS(M+H)+=465.1。
实施例15:合成化合物15:4-(4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-2,5-二氧代咪唑烷-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):8.37(s,1H),δ8.14(d,J=7.9Hz,2H),8.04(d,J=3.7Hz,1H),7.38(d,J=7.9Hz,2H),7.36(d,J=3.7Hz,1H),7.25(s,1H),6.52(s,1H),5.50(s,1H),2.29(s,3H),2.26(s,3H).ES/MS(M+H)+=448.1。
实施例16:合成化合物16:4-(4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-3-乙基-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
步骤1,4-(4,5-二氢-3-乙基-5-氧代吡唑)-1-苯甲酸
将4—羧基苯肼盐酸盐(1.55g,8.2mmol)溶于醋酸(7.5ml)中,加入丙酰乙酸乙酯(1.42g,9.8mmol),加热回流16h,冷却至室温,减压除去部分溶剂,过滤,二氯甲烷洗涤,将滤得的固体用柱色谱纯化(MeOH:DCM=1:20)得褐色固体(1.85g,97.1%)。1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),7.99(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),5.42(s,1H),2.47(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H);.
其他步骤合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.64(d,J=3.7Hz,1H),8.11(d,J=8.8Hz,2H),8.02(d,J=8.7Hz,2H),7.89(s,1H),7.83(s,1H),7.81(s,1H),7.25(d,J=3.7Hz,1H),2.38(s,3H),2.37(s,3H),2.19(q,J=6.5Hz,2H),1.01(t,J=6.5Hz,3H).ES/MS(M+H)+=460.2。.
实施例17:合成化合物17:4-(3-环丙基-4-((5-(4,5-二甲基-2-硝基苯基)呋喃-2-基)亚甲基)-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体(101.3mg,72%)。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),8.06(d,J=8.8Hz,2H),8.00(d,J=8.7Hz,2H),7.89(s,1H),7.85(s,1H),7.81(s,1H),7.28(d,J=3.7Hz,1H),2.38(s,3H),2.37(s,3H),1.01(d,J=6.5Hz,5H).ES/MS(M+H)+=472.1。
实施例18:合成化合物18:2-(3,5-二氟-4-羟基苯基)-4-((5-(4,5-二甲基-2-(三氟甲基)苯基)呋喃-2-基)亚甲基)-5-甲基-2,4-二氢-3H-吡唑-3-酮
合成方法如实施例1,得淡黄色固体。1H NMR(400MHz,DMSO-d6):δ8.89(d,J=3.7Hz,1H),7.96(d,J=8.6Hz,2H),7.85(s,1H),7.81(s,1H),7.28(d,J=3.7Hz,1H),6.14(s,1H),2.46(s,3H),2.39(s,3H),2.25(s,3H).ES/MS(M+H)+=477.1。
实施例19:合成化合物19:4-(3-甲基-4-((5-(2-硝基苯基)呋喃-2-基)亚甲基)-5-氧代-4,5-二氢-1H-吡唑-1-基)苯甲酸
合成方法如实施例1,得深红色固体。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),8.06(d,J=8.8Hz,2H),8.00(d,J=8.7Hz,2H),7.89~7.85(m,4H),7.81(s,1H),7.28(d,J=3.7Hz,1H),2.26(s,3H).ES/MS(M+H)+=418.1。
实施例20:合成化合物20:2-(3,5-二氟-4-羟基苯基)-5-甲基-4-((5-(2-(三氟甲氧基)苯基)呋喃-2-基)亚甲基)-2,4-二氢-3H吡唑-3-酮
合成方法如实施例1,得灰黄色固体。1H NMR(400MHz,DMSO-d6):δ8.73(d,J=3.7Hz,1H),7.89(s,1H),7.82~7.70(m,4H),7.28(d,J=3.7Hz,1H),6.14(d,J=8.6Hz,2H),2.38(s,3H),2.37(s,3H),2.35(s,3H).ES/MS(M+H)+=465.1。
实施例21:合成化合物21:2-(3,5-二氟-4-羟基苯基)-5-甲基-4-((5-(3-氧代-2,3-二氢-1H-茚-4-基)呋喃-2-基)亚甲基)-2,4-二氢-3H-吡唑-3-酮
合成方法如实施例1,得粉红色固体。1H NMR(400MHz,DMSO-d6):δ8.81(d,J=3.7Hz,1H),7.91(d,J=8.6Hz,2H),7.82~7.70(m,4H),7.28(d,J=3.7Hz,1H),6.14(s,1H),2.47~2.39(s,4H),2.35(s,3H).ES/MS(M+H)+=435.1。
实施例22:合成化合物22:2-(3,5-二氟-4-羟基苯基)-4-((5-(2-(二氟甲基)苯基)呋喃-2-基)亚甲基)-5-甲基-2,4-二氢-3H吡唑-3-酮
合成方法如实施例1,得深红色固体。得粉红色固体。1H NMR(400MHz,DMSO-d6):δ8.76(d,J=3.7Hz,1H),7.90(d,J=8.6Hz,2H),7.84~7.73(m,4H),7.17(d,J=3.7Hz,1H),6.44(t,J=12.8Hz,1H),6.32(s,1H),2.31(s,3H).ES/MS(M+H)+=431.1。
实施例23:化合物对组蛋白乙酰转移酶p300抑制活性测试
采用AlphaLISA技术检测所述化合物抑制组蛋白乙酰转移酶p300活性的IC50值;在本实验中,组蛋白乙酰转移酶p300将乙酰辅酶A上的乙酰基转移到组蛋白H3K9位,使其发生乙酰化,化合物对p300的抑制可通过检测H3K9位点的乙酰化程度来实现;H3生物素化底物与供体微珠结合;特异性抗H3K9乙酰化抗体偶联的受体微珠也与乙酰化的位点结合,供体微珠与受体微珠可以相互作用,从而产生615nm的光信号;光信号的强度与H3K9位点乙酰化程度正相关,结果反映化合物对p300酶活性的抑制效果;
实验方法
1.用Assay buffer稀释p300enzyme,acetyl CoA,inhibitors and Histone H3(1-21)peptide.
2.将以下试剂依次加入384微孔板白板:
---5μL of inhibitor(2X)or Assay Buffer
---2.5μL of enzyme(4X)
---Incubate for 10min at 37
---2.5μL of Histone H3(1-21)peptide/acetyl CoA mix(4X)
3.用Topseal封住微孔板,室温孵育90min.
4.配制1X Epigenetics Buffer 1;
5.用1X Epigenetics Buffer 1配置Anti-acetyl-Histone H3Lysine 9(H3K9Ac)AlphaLISA Acceptor Beads(100ug/mL),终浓度为20ug/mL;
6.加入5uL的5X Anti-acetyl-Histone H3Lysine 9(H3K9Ac)AlphaLISAAcceptor Beads,封口孵育60mins;
7.用1X Epigenetics Buffer 1配置Streptavidin Donor beads(50ug/mL),终浓度为20ug/mL.;
8.加入10uL的Streptavidin Donor beads,封口避光孵育30min;
9.使用EnVision读数;
代表性的化合物的IC50如表1所示:
表1:化合物对p300抑制活性
+++:代表IC50<1μM
++:代表1μM≤IC50<10μM
+:代表IC50≥10μM。
实施例24:Western Blot检测化合物对EP300HAT结构域催化活性的影响
按下述实验步骤:
将处于对数生长期的白血病细胞U2932按每孔200-300万的密度接种到6孔板中;
培养过夜后加入特定浓度的C646和EPZ6438,C646浓度为10μM,EPZ6438浓度为2μM;
化合物作用4天,1000rpm离心,富集细胞,PBS洗两遍以去除残留血清;
加入适量的2%SDS后用枪头反复搅动使细胞充分裂解后转移到EP管中,100℃水浴20分钟得到澄清的全细胞裂解液;
对细胞裂解液进行BCA定量,按定量结果,用4×蛋白上样缓冲液(200mM Tris-HClpH 6.8,100mM DTT,2%SDS,20%甘油,1mM钒酸钠,0.1%溴酚蓝)进行稀释,100℃水浴20分钟。蛋白样品直接使用或存放于-20℃;
蛋白样品上样到合适密度SDS-聚丙烯酰胺凝胶中,在Tris-甘氨酸-SDS电泳缓冲液(25mM Tris,250mM甘氨酸(pH8.3),0.1%SDS)中以80-120V电泳约2小时;
电泳结束后用半干印迹法将蛋白从凝胶转移至硝酸纤维素滤膜,转移缓冲液配方为192mM甘氨酸、25mM Tris、20%甲醇,按所需蛋白分子量大小转移1.5h;
用丽春红(Ponceau S)染色确定转移情况和蛋白条带位置,依据蛋白Marker分子量裁剪相应目的条带;
然后用封闭液(含3%BSA的TBST)室温封闭1-2小时;
加入相应的抗体于4℃孵育过夜。次日,用TBST洗涤液(20mM Tris-HCl(pH 7.2-7.4,室温),150mM NaCl,0.1%(v/v)Tween20)室温洗涤3次,每次10min;
加入用封闭液稀释的辣根过氧化物酶标记的二抗(1:2000),室温孵育1h。然后条带用TBST漂洗三次,每次10min;
用Milipore(Milipore,USA)发色液在Imagequan成像系统进行发色成像。
实施例25:SRB法检测细胞增殖实验
本实验依据原理:磺酰罗丹明B(Sulforhodamine B,SRB)比色法,主要用于检测细胞增殖情况;SRB是一种粉红色阴离子染料,易溶于水,在酸性条件下可特异性地与细胞内组成蛋白质的碱性氨基酸结合;在540nm波长下产生吸收峰,吸光值与细胞量成线性正相关,故可用作细胞数的定量检测;
所述SRB法步骤如下:
将处于对数生长期的实体瘤细胞以800个/孔,血液瘤3000-5000个/孔的密度种于96孔培养板中;
细胞培养过夜后每孔10μL加入梯度稀释的EP300HAT结构域抑制剂C646,各浓度梯度分别为50μM、25μM、12.5μM、6.25μM、3.625μM、1.56μM、0.78μM、0.39μM(DMSO含量不超过1‰),每个浓度设三复孔,并设定相应浓度的DMSO溶液对照及无细胞空白孔对照;
固定:C646作用6天后,弃培液,每孔加入100μL预冷10%三氯乙酸(TCA)于4℃固定1h。然后用蒸馏水洗涤5次,60°烘箱干燥;
染色:每孔加入100μL磺酰罗丹明B(SRB)染液(4mg/ml,溶于1%冰乙酸),室温染色30min后弃去染色液,1%(v/v)冰乙酸洗涤96孔板除去未与细胞蛋白结合SRB,60°烘箱干燥;
检测:每孔加入150μL 10mM Tris溶液,溶解与细胞蛋白结合的SRB,在酶标仪560nm或515nm波长下测定吸光度OD值;
按下述公式计算抑制率:抑制率(%)=(ODvehicle-ODtreated)/ODvehicle×100%。采用软件SoftmaxPro 5.4.1(Molecular Device)中四参数法logit method计算待测化合物的IC50;
实验重复三次以上,数据表示为均值±S.D.。
本申请中代表性的化合物对肿瘤细胞增殖抑制IC50如表2所示:
表2:人乳腺癌细胞MCF-7增殖抑制结果
化合物编号 | IC<sub>50</sub>(μM) |
1 | ++ |
2 | ++ |
3 | +++ |
4 | ++ |
5 | +++ |
6 | +++ |
7 | ++ |
8 | +++ |
9 | ++ |
10 | +++ |
11 | + |
12 | ++ |
13 | ++ |
14 | ++ |
15 | ++ |
16 | ++ |
17 | ++ |
18 | +++ |
19 | ++ |
20 | / |
21 | / |
22 | / |
C646 | ++ |
+++:代表IC50<10μM
++:代表10μM≤IC50<50μM
+:代表IC50≥50μM
/:代表正在测试。
实施例26:siRNA干扰实验验证靶点效应:
乳腺癌MCF-7、T47D细胞株按每孔30-50万的密度接种到6孔板中;待细胞融合度达40%-50%时,弃去培养基,每孔细胞加入800uLI Reduced SerμM Media备用;按照lipofectamineTMRNAiMAX瞬时干扰试剂盒操作说明书准备两份l00μLIReduced SerμM Media,第一份加入5μL LipofectamineTMRNAiMAX Transfection Reagent,第二份加入5μL浓度为20μM的siRNA对照干扰储备液或EP300siRNA干扰储备液,混匀之后室温静止5min,将RNAiMAX稀释液加入siRNA稀释液中,混匀之后室温静止20min,将混合液滴入上述细胞培养基中,混匀,即总体系培液为1ml Opti-MEM,siRNA转染终浓度为100nM将细胞放入培养箱中培养6-8小时后换成原正常培液继续培养48h。siRNA序列由上海吉玛公司合成,相应的正义链碱基序列为:
EP300siRNA-1#5’-GUGAGGGAGAUGAUUAUAUTT-3’;
EP300siRNA-2#5’-CGACCUCUCACAGAAACUA TT-3’;
细胞培养48h后,将每个孔的细胞分别用胰酶消化,1ml正常培养终止消化;细胞计数,取适宜的相同细胞量的siNC和siEP300-1、siEP300-2细胞分别接种到96孔板中,以及6孔板中:用96孔板SRB法检测siRNA干扰EP300对细胞增殖的影响,用6孔板平板克隆实验检测干扰对克隆形成的影响;96孔板设5个复孔,在接种细胞6天后收样,用SRB法测定细胞增值抑制率,并计算干扰EP300后相对对照组的相对细胞增值率,三次以上结果平均值以柱状图表示;6孔板平板克隆实验在接种细胞14天后,培养板上出现肉眼可见的克隆时,终止培养。弃去培养液,每孔加入1ml固定液(含10%乙酸、10%甲醇及80%ddH2O),室温固定30min后弃去固定液,加入1%的结晶紫甲醇溶液(m/v),室温染色30min;最后,用蒸馏水冲洗未结合的结晶紫;室温晾干,用扫描仪记录克隆形成情况。
实施例27:化合物在甲醇中的溶解性实验
将化合物分别取1mg、10mg、100mg,并将其分别溶于1mL甲醇中,充分震荡,静置,通过观察溶液澄清情况和溶液底部沉淀情况初步判断化合物在甲醇中的溶解度范围;结果显示:
代表性的化合物在甲醇中的溶解度如表3所示:
表2:代表性化合物在甲醇中的溶解度
+:代表溶解度<1mg/mL
++:代表1mg/mL≤IC50<10mg/mL
+++:代表10mg/mL≤IC50<100mg/mL
++++:代表溶解度≥100mg/mL。
Claims (8)
1.具有如下通式Ⅰ结构的化合物或其药学上可接受的盐:
式中,A环代表五元或六元的芳环,以及含氮、氧、硫原子的芳杂环,以及带有1~4个碳原子的酰胺键;
R1代表氢原子、卤素;
R2代表羟基、羧基、带1~4个碳原子的磺烷基、硼酸基团、含氮五元杂环;
R3代表三氟甲基、三氟甲氧基、膦酰基、硝基、二氟甲基、或与邻位碳原子环合为环戊酮;
R4代表氢原子、甲基;
R5代表氢原子、1到4个碳原子长度的直链烷烃或环烷烃;
X代表-C(O)-、-N=;Y代表碳原子、硫原子、或-NH-;当X为-N=时,Y代表碳原子,X、Y间为双键;当X为-C(O)-时,Y代表硫原子或-NH-基团,X、Y间为单键,此时无R5基团。
7.根据权利要求1~6任一项所述的化合物或其药学上可接受的盐在用于制备治疗与组蛋白乙酰转移酶p300异常表达有关的癌症药物中的应用。
8.根据权利要求7所述的应用,其中,所述癌症为前列腺癌、恶性血液肿瘤、乳腺癌、宫颈癌、卵巢癌、非小细胞肺癌、肾细胞癌、黑色素瘤、胃癌、膀胱癌或子宫内膜癌。
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---|---|---|---|---|
CN113384578A (zh) * | 2021-05-10 | 2021-09-14 | 澳门科技大学 | 呋喃苯甲酸类化合物作为微粒体前列腺素e2合酶1抑制剂的应用 |
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WO2022138944A1 (ja) * | 2020-12-25 | 2022-06-30 | 国立研究開発法人国立がん研究センター | Swi/snf複合体機能異常がんの合成致死性に基づく治療法 |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130142887A1 (en) * | 2010-01-05 | 2013-06-06 | The Johns Hopkins University | Use of histone acetyltransferase inhibitors as novel anti-cancer therapies |
-
2018
- 2018-08-28 CN CN201810987825.5A patent/CN110862383A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130142887A1 (en) * | 2010-01-05 | 2013-06-06 | The Johns Hopkins University | Use of histone acetyltransferase inhibitors as novel anti-cancer therapies |
Non-Patent Citations (1)
Title |
---|
无: "RN 898740-88-0", 《STN REGISTRY》 * |
Cited By (4)
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---|---|---|---|---|
WO2022138944A1 (ja) * | 2020-12-25 | 2022-06-30 | 国立研究開発法人国立がん研究センター | Swi/snf複合体機能異常がんの合成致死性に基づく治療法 |
CN115124517A (zh) * | 2021-03-26 | 2022-09-30 | 复旦大学 | 芳香族化合物、其制备方法、药物组合物和应用 |
CN113384578A (zh) * | 2021-05-10 | 2021-09-14 | 澳门科技大学 | 呋喃苯甲酸类化合物作为微粒体前列腺素e2合酶1抑制剂的应用 |
CN114591180A (zh) * | 2022-03-18 | 2022-06-07 | 绍兴贝斯美化工股份有限公司 | 一种4,4′,5,5′-四甲基[1,1′-联苯]-2,2′-二胺的制备方法 |
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