CN110066281B - 多靶点抗肿瘤活性的吴茱萸碱衍生物及其制备方法与应用 - Google Patents
多靶点抗肿瘤活性的吴茱萸碱衍生物及其制备方法与应用 Download PDFInfo
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- CN110066281B CN110066281B CN201910490799.XA CN201910490799A CN110066281B CN 110066281 B CN110066281 B CN 110066281B CN 201910490799 A CN201910490799 A CN 201910490799A CN 110066281 B CN110066281 B CN 110066281B
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Abstract
本发明属于医药技术领域,提供了一种基于拓扑异构酶1(Top1),拓扑异构酶2(Top2)和组蛋白去乙酰化酶(HDAC)多靶点的小分子抗癌药物及其制备方法,该化合物的结构通式如式(I)和(II)所示。药理实验表明,本发明所述的化合物,对拓扑异构酶1,拓扑异构酶2和组蛋白去乙酰化酶均具有很强的抑制活性,而且具有较强的体外抗肿瘤活性和优秀的体内抑瘤效果。本发明还提供了上述衍生物的制备方法,以及在制备拓扑异构酶抑制剂、组蛋白去乙酰化酶抑制剂和抗肿瘤药物中的应用。
Description
技术领域
本发明涉及医药技术领域,具体地说,是一种多靶点抗肿瘤活性的吴茱萸碱衍生物及其制备方法与应用。
背景技术
当前,癌症已经成为一种严重威胁人类健康和生命的疾病。目前临床上治疗恶性肿瘤主要采用联合用药的方法,但是这种方法存在很多缺陷,比如需要确证药物配伍合理性、可能发生的药物-药物相互作用和复杂的药代动力学性质等。多靶点药物作用于肿瘤疾病网络中的多个关键环节或位点,发挥协同抗肿瘤的效果,其对肿瘤的治疗效果优于单一药物的疗效。此外,多靶点药物拥有相对简单的吸收、分布,代谢和排泄过程,减少药物-药物相互作用的发生,具有更低的副作用和更好的安全性,并使治疗方案大大简化,极大提高病人的依从性。多靶点药物研究已经成为现今抗肿瘤药物研发的一个热点领域。
多靶点药物可以同时调节肿瘤疾病网络系统中的多个环节,不易产生抗药性,对各靶点作用的总效应大于单个效应之和,达到最佳的治疗效果。此外,单个分子拥有相对简单的吸收、分布、代谢和排泄过程,大大减少药物-药物相互作用(Peters,JU.,Polypharmacology–Foe or Friend?,J Med Chem,2013,56(22):8955-8971)。FDA先后批准了多个多靶点酪氨酸激酶抑制剂上市,包括索拉非尼(sorafenib)、达沙替尼(dasatinib)和拉帕替尼(lapatinib)等,标志着多靶点药物已经成为肿瘤治疗和药物研发的新方向。
组蛋白去乙酰化酶(histone deacetylases,HDACs)是当前抗肿瘤药物研究的热门靶点之一。组蛋白的乙酰化/去乙酰化是染色体结构改变和基因表达的重要调节方式,在细胞凋亡、能量代谢、转录和翻译等生命过程中发挥重要作用。HDACs水解组蛋白中赖氨酸侧链上N-端乙酰基,使得核小体变得更加紧密,从而抑制基因的转录。它能调控细胞的多种功能和过程,例如基因表达,染色体改造,细胞增殖、分化、凋亡等。
典型的HDAC抑制剂包含一个帽子结构(Cap group,cap),一个锌离子结合区(Zincbinding group,ZBR),和一个合适的连接基团(Linker)。研究表明,HDAC与p53、热休克蛋白(Hsp90)、拓扑异构酶(Topisomerase,Top)和微管蛋白(Tubulin)等多个抗肿瘤靶点表现出抗肿瘤的协同效应,针对HDAC和协同靶点的多靶点药物研究已经成为克服肿瘤耐药性,增强抗肿瘤疗效的有效手段,目前已有数个HDAC多靶点抑制剂进入临床或临床前研究。
在前期研究中,本发明人所在的课题组发现新型Top1抑制剂吴茱萸碱(Evodiamine),我们对吴茱萸碱进行了系统的结构优化和构效关系研究,使其抗肿瘤活性显著提高,我们合成了一批吴茱萸碱类的衍生物,已经申请的专利如下:中国专利CN201010117531.0,发明名称为“取代吴茱萸碱类抗肿瘤和抗真菌化合物及其制备方法”,授权公布号为:CN101787025B;中国专利CN201110188588.4,发明名称为“吴茱萸碱类化合物及其制备方法与应用”,授权公布号为CN102311434B;中国专利申请CN201410209588.1,发明名称为“氧杂或硫杂吴茱萸碱类抗肿瘤衍生物及其制备方法”,公开号为CN103992336A等。进一步地,本发明人通过深入的抗肿瘤作用机制研究发现,吴茱萸碱衍生物是Top1和Top2双重抑制剂,能够有效诱导肿瘤细胞凋亡,阻滞肿瘤细胞周期于G2/M期。其中,代表化合物3-氟-10-羟基吴茱萸碱等表现出优秀的体外和体内抗肿瘤活性。在前期研究的基础上,本发明人继续开展新型Top1/Top2/HDAC三靶点抑制剂的设计、合成和抗肿瘤活性研究。
发明内容
本发明的第一目的是提供一类多靶点抗肿瘤活性的吴茱萸碱衍生物。
本发明的第二目的是提供如上所述吴茱萸碱衍生物的制备方法。
本发明的第三目的是提供如上所述吴茱萸碱衍生物的应用。
本发明的第一方面,提供一类新的吴茱萸碱衍生物,该类吴茱萸碱衍生物具备多靶点抗肿瘤活性,多靶点为Top1、Top2和HDAC三个靶点。
本发明公开的化合物也即一类具有高活性的Top1/Top2/HDAC三靶点抑制剂。
本发明所述的一类吴茱萸碱衍生物及其药用盐,该化合物的结构通式如式(I)和(II)所示:
其中:
R1、R2为苯环上的取代基,取代基可位于苯环的邻、间、对位,可以是单取代,也可以是多取代,包括:
氢、卤素、氨基、硝基、羟基、氰基、1-4个碳原子的烷基、1-4个碳原子的烷氧基、1-4个碳原子的烷基氨基、1-4个碳原子的氨基烷基、2-4个碳原子的酰基、2-4个碳原子的酰胺基、1-4个碳原子的硫代烷基、三氟甲基、1-4个碳原子的羧基、1-4个碳原子的烷氧基羰基、苯基或杂环;
X为苯基、杂环、1-6个碳原子的烷基、1-6个碳原子的烷基与苯基连接的基团、1-6个碳原子的烷基与杂环连接的基团,1-6个碳原子的饱和或不饱和直链烃基、1-6个碳原子的烷基与酰胺键连接的基团、苯基与含酰胺键烷烃链连接的基团、苯基;
A为羟基或2-氨基苯基。
作为本发明的一个优选实施方案,通式中,X为正丙基、正丁基、苯基、苯乙烯基。
作为本发明的一个优选实施方案,通式中,所述的卤素为氟或氯。
作为本发明的一个优选实施方案,通式中,所述的1-4个碳原子的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基,或叔丁基。
作为本发明的一个优选实施方案,药用盐是有机酸盐或无机酸盐,所述的无机酸盐为盐酸、硫酸、磷酸、二磷酸、氢溴酸或硝酸;所述的有机酸为乙酸、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。
作为本发明的一个优选实施方案,药用盐不含结晶水,或含一个或一个以上结晶水。
作为本发明的一个优选实施方案,所述的吴茱萸碱衍生物优选为:
B13a:4-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基丁酰胺,
B13b:5-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基戊酰胺,
B13c:6-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基己酰胺,
B13d:7-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基庚酰胺,
B13e:8-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基辛酰胺,
B17a:4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)-N-羟基苯甲酰胺,
B17b:3-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)-N-羟基苯甲酰胺,
B17c:2-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)-N-羟基苯甲酰胺,
B17d:2-(4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯基)-N-羟基乙酰胺,
B17e:(E)-3-(4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯基)-N-羟基丙烯酰胺,
C6:N-(2-氨基苯基)-4-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)丁酰胺,
C11a:N-(2-氨基苯基)-5-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)戊酰胺,
C11b:N-(2-氨基苯基)-6-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)己酰胺,
C11c:N-(2-氨基苯基)-7-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)庚酰胺,
C11e:N-(2-氨基苯基)-4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯甲酰胺,
C11g:N-(2-氨基苯基)-3-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯甲酰胺,
C11f:N-(2-氨基苯基)-2-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯甲酰胺,
C11h:(E)-N-(2-氨基苯基)-3-(4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3:3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯基)丙烯酰胺,
C8a:(E)-N-羟基-3-(4-((5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)丙烯酰胺,
C8b:N-羟基-6-(5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14(5H)-基)己酰胺,
C13a:N-羟基-5-(4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)基)戊酰胺,
C13b:(E)-N-羟基-3-(4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉14-(5H)-基)甲基)苯基)丙烯酰胺,
C13c:N-羟基-2-(4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)乙酰胺,
C13d:N-(2-(羟基氨基)-2-氧代乙基)-4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯甲酰胺,
C13e:N-(3-(羟氨基)-3-氧代丙基)-4-((4-甲氧基-5-氧代7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,11-b]喹唑啉14-(5H)-基)甲基)苯甲酰胺,
C13f:N-(4-(羟基氨基)-4-氧代丁基)-4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉14-(5H)-基)甲基)苯甲酰胺,
C13g:(E)-N-(2-(羟基氨基)-2-氧代乙基)-3-(4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚[2',3':3,4]吡啶并[2,1-b]喹唑-14-(5H)-基)甲基)苯基)丙烯酰胺,
C13h:N-羟基-1-(4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯甲酰基)吡咯烷-2-甲酰胺,
C19a:4-((4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)-N-羟基苯甲酰胺,
C19b:(E)-3-(4-((4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)-N-羟基丙烯酰胺,
C19c:4-(4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)-N-羟基苯甲酰胺,
C19d:8-(4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)-N-羟基丁酰胺,
C19e:6-(4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)-N-羟基己酰胺。
表1.本发明优选化合物的结构式和核磁质谱数据
本发明的第二方面,提供上述吴茱萸碱衍生物及其药用盐的制备方法。
反应流程通法一:化合物B13a-e的合成
Reagents and conditions:(a)(Boc)2O,DMAP,NaOH,THF,K2CO3,reflux,rt,4h,69%;(b)NaH,DMF,0℃,4h,81%-93%;(c)TFA,DCM,rt,3h,62%-93%;(d)NH2OH,CH3OH,45℃,1h,50%-94%.
以3-氟-10-羟基吴茱萸碱(B8)为起始原料,先后加入DMAP和Boc酸酐,常温条件下反应,反应完全后加入碳酸钾继续反应,得到关键中间体B9;在过量氢化钠作用下,B9与各种碳链长度的溴代甲酯B10a-e反应,得到3-氟-10-羟基吴茱萸碱的醚类衍生物B11a-e;中间体B11a-e在TFA的二氯甲烷溶液中脱去叔丁氧羰基,得到中间体B12a-e,最后再与新鲜制备的羟胺甲醇溶液(无水硫酸镁充分干燥)反应,减压蒸馏,残留物后加水溶解,调节pH至弱酸性(5-6),得到目标产物B13a-e。
反应流程通法二:化合物B17a-e的合成
Reagents and conditions:(a)K2CO3,DMF,12h,66%-88%;(b)TFA,DCM,rt,6h,64%-69%;(c)NH2OH,CH3OH,45℃,1h,52%-81%.
以N-Boc保护的3-氟-10-羟基吴茱萸碱(B9)为起始原料,在过量K2CO3的作用下,以DMF为溶剂与各种芳香溴代甲酯B14a-e反应得到3-氟十羟基吴茱萸碱的醚类衍生物B15a-e;以TFA为有机酸,将中间体B15a-e脱去叔丁氧羰基保护得到中间体B16a-e;最后再以新鲜制备且充分干燥的羟胺甲醇溶液(NH2OH/NH2OK)为溶剂和原料充分反应约1h,减压蒸干后加水溶解,调节PH至弱酸性(5-6),过滤后得到目标产物B17a-e。
反应流程通法三:化合物C11a-h的合成
Reagents and conditions:(a)NaHor K2CO3,DMF,0℃,4h,66%-94%;(b)TFA,DCM,rt,3h,62%-93%.(c)LiOH,CH3OH/THF/H2O,rt,1h,81%-94%.(c)HATU,TEA,DMF,45℃,1h,65%-95%.
以3-氟-10-羟基吴茱萸碱类衍生物(化合物B9)为起始原料,以过量氢化钠或碳酸钾为碱,以DMF为溶剂在冰水浴下与不同的溴代甲酯类化合物(化合物C7a-h)反应约4h,制备3-氟-10-羟基吴茱萸碱的醚类衍生物(化合物C8a-h);再以TFA为有机酸,于二氯甲烷中反应约3h脱去叔丁氧羰基保护基得到中间体C9a-h;最后,将化合物C9a-h缓慢加入配置的混合溶液中(甲醇:四氢呋喃:水=3:2:1),在氢氧化锂的作用下得到含羧基的中间体C10a-h;以HATU作为缩合剂,三乙胺作为缚酸剂,在DMF溶液中化合物C10a-h与邻苯二胺(化合物C4)发生成酰胺反应,得到目标产物C11a-h。
反应流程通法四:化合物C8a-b、C13a-h和C19a-e的合成
Scheme C1:(a)Ethyl formate,reflux,12h,80%;(b)POCl3,DCM,0℃,6h,53%;(c)triphosgene,THF,reflux,12h,75%;(d)K2CO3,DMF,2.5h,59-67%;(e)DCM,rt,12h,46-54%;(f)NH2OH·HCl,KOH,MeOH,1h,41-49%.
Scheme C2:(a)Ethyl formate,reflux,12 h,90%;(b)POCl3,DCM,0℃,6 h,68%;(c)triphosgene,THF,reflux,12 h,75%;(d)K2CO3,DMF,2.5 h,59-68%;(e)DCM,rt,12 h,39-56%;(f)NH2OH·HCl,KOH,MeOH,1 h,39-48%.
Scheme C3:(a)Ethyl formate,reflux,12h,89%;(b)POCl3,DCM,0℃,6h,61%;(c)triphosgene,THF,reflux,12h,81%;(d)K2CO3,DMF,2.5h,67-79%;(e)DCM,rt,12h,41-62%;(f)NH2OH·HCl,KOH,MeOH,1h,36-49%.
以不同取代的色胺(化合物C1和C14)和邻氨基苯甲酸(化合物C4和C9)为原料,通过酯化、缩合、环合等得到不同取代的咔啉及靛红酸酐类衍生物,然后再经过环合反应得到14位不同取代的吴茱萸碱中间体,最后与新鲜制备的羟胺溶液发生氨解反应得到目标化合物。
本发明的第三方面,是提供上述的吴茱萸碱衍生物及其药用盐的医药用途。
本发明提供了上述的吴茱萸碱衍生物及其药用盐在制备治疗基因表达异常而引起疾病的药物中的应用。
所述疾病包括肿瘤、内分泌紊乱、免疫系统疾病、遗传病或神经系统疾病等。
本发明提供了上述的吴茱萸碱衍生物及其药用盐在制备抗肿瘤药物中的应用。
本发明提供了上述的吴茱萸碱衍生物及其药用盐在制备Top1、Top2和HDAC三靶点抑制剂中的应用,所述的应用,具体是作为多靶点抗肿瘤药物。
作为本发明的一个优选实施方案,所述的肿瘤,为肠癌、肺癌、乳腺癌、白血病等。
本发明的吴茱萸碱衍生物及其药用盐作为Top1/Top2/HDAC三靶点抑制剂在制备治疗恶性肿瘤或与分化增值相关疾病药物方面的应用。
本发明优点在于:
1、本发明的化合物经抗肿瘤活性实验,证明大部分化合物具有较好体外抗肿瘤活性,优选化合物具有优秀的体内肿瘤生长抑制活性。
2、本发明为深入研究和开发新结构类型抗肿瘤药物开辟了新的途径,提供了新的策略。
附图说明
附图1是目标化合物在浓度为100μM时的Top1抑制实验结果。条带1,超螺旋质粒pBR322 DNA;条带2,Top1+DNA;条带3,Top+DNA+CPT;条带4-13,Top1+DNA+目标化合物(B13a、B13c、B13b、B17a、B17c、B17b、B13e、B13d、B17d、B17e)。
附图2是目标化合物在100μM浓度下对Top1的抑制活性结果。条带1:pBR322DNA;条带2:Top1+DNA;条带3:Top1+CPT+DNA;条带4-18:Top1+DNA+目标化合物(C19a、C19b、C19c、C19d、C19e、C13a、C13b、C13c、C13d、C13e、C13f、C13g、C13h、C8a、C8b)。
附图3是目标化合物在浓度为100μM时的Top2抑制试验结果。条带1,超螺旋质粒pBR322 DNA;条带2,Top2+DNA;条带3,Top2+DNA+依托泊苷;条带4,Top2+DNA+目标化合物(B13a、B13c、B13b、B17a、B17c、B17b、B17e、B13d、B17d、B13e)。
附图4是目标化合物在浓度为50μM时的Top2酶活性抑制试验结果。条带1,超螺旋质粒pBR322 DNA;条带2,Top2+DNA;条带3,Top2+DNA+依托泊苷;条带4,Top2+DNA+目标化合物(B13a、B13c、B13b、B17a、B17c、B17b、B17e、B13d、B17d、B13e)。
附图5是目标化合物在100μM浓度下对Top2的抑制活性结果。条带1:pBR322DNA;条带2:Top2+DNA;条带3:Top2+DNA+Eto;条带4-18:Top2+DNA+目标化合物(C19a、C19b、C19c、C19d、C19e、C13a、C13b、C13c、C13d、C13e、C13f、C13g、C13h、C8a、C8b)。
附图6是目标化合物在50μM浓度下对Top2的抑制活性结果。条带1:pBR322DNA;条带2:Top2+DNA;条带3:Top2+DNA+Eto;条带4-18:Top2+DNA+目标化合物(C19a、C19b、C19c、C19d、C19e、C13a、C13b、C13c、C13d、C13e、C13f、C13g、C13h、C8a、C8b)。
附图7是化合物C8a、C19b、SAHA对HCT116裸鼠移植瘤模型的抑制作用结果。(A)小鼠肿瘤体积变化图;(B)小鼠重量变化图。
具体实施方式
下面结合具体实施方式,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1:
制备4-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基丁酰胺(B13a)
(一)制备中间体B9:叔丁基-3-氟-10-羟基-14-甲基-5-氧代-7,8,13b,14-四氢吲哚[2',3':3,4]吡啶并[2,1-b]喹唑啉-13(5H)羧酸叔丁酯
将3-氟-10-羟基吴茱萸碱(化合物B8)500mg(1.48mmol)与BOC酸酐0.97g(4.45mmol)置于50mL烧瓶中,加入20mL干燥的四氢呋喃充分溶解,在搅拌下加入4-二甲氨基吡啶(DMAP)18mg(0.148mmol),室温下搅拌反应1小时,使用硅胶薄层色谱对反应进行监测。反应完毕后进行减压蒸干,加入20mL甲醇并充分混匀,取碳酸钾1.1g加入至混悬液中,室温下搅拌反应3小时,反应结束后再次减压蒸干,加入冰水30mL溶解,缓慢滴加醋酸溶液调节pH至弱酸性(5-6),静置后析出大量黄色固体,减压过滤得到目标产物B9,黄色固体0.45g,产率69%。1H-NMR(DMSO-d6,600MHz)δ:9.36(s,1H),7.98(d,J=8.9Hz,1H),7.59(dd,J=3.1,8.7Hz,1H),7.44-7.40(m,1H),7.28-7.26(m,1H),6.94(d,J=2.6Hz,1H),6.87(dd,J=2.4,9.0Hz,1H),6.16(s,1H),4.62-4.59(m,1H),3.15-3.12(m,1H),2.92-2.90(m,1H),2.73-2.67(m,1H),2.36(s,3H),1.45(s,9H)。
(二)制备中间体B11a:叔丁基-3-氟-10-(4-甲氧基-4-氧代丁氧基)-14-甲基-5-氧代-7,8,13b,14-四氢吲哚[2',3':3,4]吡啶并[2,1-b]喹唑啉13(5H)-羧酸叔丁酯
将化合物B9约150mg(0.34mmol)置于25mL烧瓶中,加入5mL干燥的DMF作为溶剂充分溶解,在冰水浴下缓慢加入氢化钠9.8mg(0.41mmol),0℃下搅拌反应1小时,溶液变为深棕色后,加入溴代丁酸甲酯74mg,室温下搅拌反应3小时。反应结束后,加入45mL水,并用50mL乙酸乙酯萃取三次,保留有机相,饱和食盐水反洗后加入适量无水硫酸钠进行充分干燥,减压蒸干后得到粗产物,利用硅胶柱层析进行纯化,洗脱剂体系为二氯甲烷:甲醇(100:2),得黄色固体0.15g,产率为84%。1H-NMR(DMSO-d6,600MHz)δ:8.06(d,J=8.9Hz,1H),7.59(dd,J=3.1,8.7Hz,1H),7.44-7.41(m,1H),7.28-7.26(m,1H),7.20(d,J=2.6Hz,1H),7.01(dd,J=2.4,9.0Hz,1H),6.18(s,1H),4.62(dd,J=4.8,12Hz,1H),4.07-4.05(m,2H),3.61(s,3H),3.17-3.12(m,1H),3.02(d,J=15Hz,1H),2.75-2.70(m,1H),2.36(s,3H),2.03-1.99(m,2H),1.46(s,9H),1.23(s,1H),0.84-0.83(m,1H)。
(三)制备中间体B12a:4-((3-氟-14-甲基-5-氧代-5,7,8,13,13b,14-六氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)丁酸甲酯
称取化合物B11a 0.1g置于25mL烧瓶中,加4mL干燥的二氯甲烷溶解,搅拌下缓慢滴加2mL三氟乙酸,室温下反应3小时,反应完毕后,滴加饱和碳酸氢钠溶液,调节溶液PH至弱碱性(7-8),加入乙酸乙酯30mL,萃取三次,饱和食盐水反洗两次后加入适量无水硫酸钠进行充分干燥,减压蒸干后得到粗产物,利用硅胶柱层析进行纯化,洗脱剂体系为二氯甲烷:甲醇(100:2),得黄色固体70mg,产率为86%。1H-NMR(DMSO-d6,600MHz)δ:10.99(s,1H),7.53(dd,J=3.1,8.9Hz,1H),7.39-7.36(m,1H),7.24(d,J=8.9Hz,1H),7.19-7.17(m,1H),6.98(dd,J=2.3,6.7Hz,1H),6.75(dd,J=2.4,9.0Hz,1H),6.08(s,1H),4.63-4.60(m,1H),3.98(t,J=6.3Hz,2H),3.61(s,3H),3.17-3.15(m,1H),2.83-2.79(m,2H),2.68(s,3H),2.48-2.46(m,2H),2.00-1.96(m,2H)。
(四)制备目标产物B13a
取盐酸羟胺4.67g(67mmol)溶于35mL甲醇中,冰水浴下缓慢加入氢氧化钾5.61g(100mmol),待完全溶解后在室温下反应1小时,反应结束后进行过滤,得滤液为新鲜制备的羟胺甲醇溶液。称取化合物B12a 60mg置于25mL烧瓶中,加入新鲜制备的羟胺甲醇溶液8mL,室温下搅拌反应2小时,反应结束后,充分减压蒸干,加入20mL水溶解,缓慢滴加醋酸溶液调节体系pH至7,静置后白色固体析出,减压过滤,将滤饼烘干后得白色固体43mg,产率为73%。1H-NMR(DMSO-d6,600MHz)δ:10.99(s,1H),10.42(s,1H),8.70(s,1H),7.53(dd,J=3.2,8.8Hz,1H),7.40-7.36(m,1H)7.24(d,J=8.4Hz,1H),7.18(q,J=4.8Hz,1H),6.98(d,J=1.8Hz,1H),6.76(dd,J=2.5,8.8Hz,1H),6.06(s,1H),4.68-4.60(m,1H),3.95(t,J=6.5Hz,2H),3.22-3.17(m,1H),2.82(t,J=5.5Hz,2H),2.68(s,3H),2.14(t,J=7.54Hz,2H),1.91-1.96(m,2H).13C-NMR(150MHz,DMSO-d6,TMS)δ:169.18,125.12,159.96,155.97,153.01,146.44,132.21,132.21,130.69,126.58,122.47,122.37,122.10,121.99,121.17,120.87,113.99,113.69,113.04,112.76,111.85,101.79,69.75,67.81,40.77,40.50,39.38,39.11,37.04,29.35,25.53,20.07.MS(ESI negative):m/z[M-H]-:437.16。
化合物B13a-e、B17a-e制备方法参照实施例1。
实施例2:
制备N-(2-氨基苯基)-5-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)戊酰胺(C11a)
(一)制备中间体C10a:5-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉10-基)氧基)戊酸
称取化合物C8a 0.1g置于25mL烧瓶中,加10mL配置好的四氢呋喃:甲醇:水=3:2:1混合溶液充分溶解,搅拌下缓慢加入20mg水合氢氧化锂,室温下反应3小时,反应完毕后,减压蒸干除去有机相,缓慢滴加稀盐酸溶液,调节溶液PH至弱酸性,有黄色固体析出,减压过滤后将滤饼烘干,得黄色固体90mg,产率为93%。1H-NMR(DMSO-d6,600MHz)δ:12.05(s,1H),10.98(s,1H),7.53(dd,J=3.1,8.9Hz,1H),7.40-7.36(m,1H)7.24(d,J=8.7Hz,1H),7.18(q,J=4.8Hz,1H),6.99(d,J=2.0Hz,1H),6.76(dd,J=2.3,8.6Hz,1H),6.06(s,1H),4.62-4.59(m,1H),3.96-3.94(m,2H),3.21-3.16(m,1H),2.82-2.81(m,2H),2.68(s,3H),2.28(t,J=7.1Hz,2H),1.75-1.70(m,2H),1.68-1.65(m,2H)。
(二)制备目标产物C11a
称取化合物C10a 90mg(0.19mmol)、HATU 0.15g(0.38mmol)与邻苯二胺42mg(0.22mmol)置于25mL烧瓶中,加入10mL干燥的二氯甲烷充分溶解,搅拌下缓慢滴加0.5mL三乙胺溶液,室温下反应2小时,反应完毕后加水溶解,后加入乙酸乙酯30mL,萃取三次,饱和食盐水反洗两次后加入适量无水硫酸钠进行充分干燥,减压蒸干后得到粗产物,利用硅胶柱层析进行纯化,洗脱剂体系为二氯甲烷:甲醇(100:3),得黄色固体90mg,产率为84%。1H-NMR(DMSO-d6,600MHz)δ:10.98(s,1H),9.12(s,1H),7.53(dd,J=2.8,8.9Hz,1H),7.40-7.35(m,1H),7.24(d,J=8.8Hz,1H),7.20-7.14(m,2H),7.00(s,1H),6.88(t,J=7.3Hz,1H),6.79(dd,J=2.2,8.9Hz,1H),6.71(d,J=7.7Hz,1H),6.53(t,J=7.6Hz,1H),6.06(s,1H),4.82(s,2H),4.63-4.59(m,1H),4.00(s,2H),3.22-3.15(m,1H),2.82-2.79(m,2H),2.67(s,3H),2.39(t,J=6.7Hz,2H),1.79-1.76(m,4H).13C-NMR(150MHz,DMSO-d6,TMS)δ:171.50,163.49,159.14,155.98,153.14,146.45,142.37,132.18,130.63,129.12,126.61,126.17,125.76,124.02,122.51,122.42,122.11,122.01,121.16,120.85,116.64,116.37,114.01,113.70,113.06,112.75,111.86,101.69,69.76,68.13,65.49,40.82,37.03,35.91,28.98,22.56,20.10.MS(ESI positive):m/z[M+H]+:528.24
化合物C6、C11a-h制备方法参照实施例2。
实施例3:
制备(E)-N-羟基-3-(4-((5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)丙烯酰胺(C8a)
制备目标产物C8a
色胺(8.0g,50mmol)、甲酸乙酯(23g)加入干燥的反应瓶中,80℃加热回流12小时,待反应完全后,减压蒸干溶剂,然后加入50mL二氯甲烷,在冰浴条件下缓慢滴加三氯氧磷(12mL)反应2小时,然后升温至室温继续反应4小时,反应完全后减压蒸干二氯甲烷及未反应的三氯氧磷,残留物用CH3COOH(200mL,50%)溶解,然后用NH3H2O调节pH至9-10,析出黄色固体,减压过滤,滤饼水洗(2×30mL),干燥后得粗产品C3。取化合物N-甲基啶红酸酐(1.0g,6.1mmol)、K2CO3(1.0g,7.36mmol)化合物加入反应瓶中,搅拌下反应0.5小时,随后加入4-溴甲基肉桂酸甲酯(1.9g,7.36mmol)室温下反应2小时,待反应完全后,将反应液倒入200mL冰水中,析出白色固体,减压过滤,滤饼水洗(2×30mL),干燥后得粗产品C6a。化合物C3与化合物C6a在二氯甲烷中发生环合反应可得关键中间体C7a,然后加入新鲜制备的盐酸羟胺溶液,室温下搅拌1小时,用CH3COOH调节pH至7,有白色固体析出,减压过滤,干燥即可得白色固体C8a(0.15g,收率41%)。
1H-NMR(DMSO-d6,600MHz)δ:11.15(s,1H),7.76(d,J=7.79Hz,1H),7.46(t,J=8.25Hz,3H),7.28-7.37(m,5H),7.09(t,J=7.10Hz,1H),6.99(t,J=7.56Hz,1H),6.86(t,J=7.56Hz,2H),6.41(d,J=15.81Hz,1H),6.33(s,1H),4.57-4.63(m,3H),3.19-3.29(m,1H),2.88-2.96(m,1H),2.70-2.75(m,1H).13C-NMR(DMSO-d6,600MHz)δ:165.13,163.16,147.24,140.21,138.38,136.73,134.24,133.65,131.75,128.58,128.01,126.65,122.31,120.51,119.67,119.38,119.28,118.64,117.84,112.11,111.95,70.64,53.04,46.25,42.12,19.72.HR-MS(ESI)m/z:calcd for C28H25N4O3[M+H]+465.1921,Found 465.1935.
化合物C8b、C13a-h、C19a-e制备方法参照实施例3。
实施例4:目标化合物HDAC1酶抑制测试
1)实验材料:
HDAC1酶,缓冲液(137mM氯化钠,2.7mM氯化钾,1mM氯化镁,0.1mg/mLBSA,PH=8的Tris-HCl 25mM),HDAC substrate 3,胰蛋白酶,96孔黑色板。
2)实验方法:
(a)96孔黑色板平衡至室温。
(b)用含有10%的DMSO的缓冲液稀释待测化合物,化合物的浓度依次为100μM,30μM,10μM,3μM,1μM,0.3μM,0.1μM,0.03μM,0.01μM,0.003μM。
(c)将11μL的HDAC1加入到400μL的缓冲液中,摇匀;
(d)向96孔板上第2-11孔加入35μL刚刚配好的含有HDAC1酶的缓冲液,并依次加入5μL稀释好的不同浓度的化合物到对应的反应孔中,对于阴性对照(第一个孔)和空白对照孔(第十一个孔),分别加入40μL和5μL assay buffer。。
(e)向所有反应孔中加入加入100μM的HDAC substrate5μL和0.5mg/mL的胰蛋白酶5μL,37度孵化30分钟后读数。
(f)依据公式计算抑制率:抑制率=(100%活性孔-样品孔)/100%活性孔*100,在GraphPad软件中将酶活性对化合物浓度的曲线进行拟合,求出化合物的IC50值。
实验结果表明这些杂交化合物都表现出良好的HDAC1抑制活性,均在纳摩尔级,其中两个化合物表现出10c(IC50=0.011μM)和25(IC50=0.025μM)优于阳性对照药SAHA(IC50=0.039μM)的HDAC1抑制活性。
表1.目标化合物对HDAC1的抑制活性
NT=not testd.
实施例5:Top1介导的DNA解螺旋实验
1)实验材料:
小牛胸腺DNA拓扑异构酶Ⅰ、负超螺旋DNA质粒pBR322、琼脂糖、DMSO、10x buffer缓冲液、0.1%BSA和EtBr。
2)实验仪器
凝胶电泳采用BioRad公司PowerPac电泳仪和Sub-Cell Model 96电泳槽,凝胶扫描定量采用BioRad公司的Gel Doc EZ全自动凝胶成像系统。
3)实验方法
先将1x TAE溶液配置成浓度为0.8%的琼脂糖凝胶。依次向1.5mL样品管中加入10μL水,2μL buffer,2μL 0.1% BSA,Top1 0.5U,DNA0.5μL,不同的药物0.2μL,定容到20μL。然后将样品管放入37℃水浴中,孵化15分钟。加入2μL 6x loading buffer至样品管中。110V电泳40-50分钟,用0.5μg/mL EtBr染色15分钟,凝胶成像系统观察电泳结果。
实验结果表明(图1、2),除了化合物B17e在100μM的浓度下表现出微弱的Top1抑制活性,其他化合物在该浓度下均没有Top1抑制活性。
实施例6:Top2介导的DNA解螺旋实验
1)实验材料:
小牛胸腺DNA拓扑异构酶Ⅱ、负超螺旋DNA质粒pBR322、琼脂糖、DMSO、10x buffer缓冲液、0.1%BSA和EtBr。
2)实验仪器
凝胶电泳采用BioRad公司PowerPac电泳仪和Sub-Cell Model 96电泳槽,凝胶扫描定量采用BioRad公司的Gel Doc EZ全自动凝胶成像系统。
3)实验方法
先将1x TAE溶液配置成浓度为0.8%的琼脂糖凝胶。依次向1.5mL样品管中加入10μL水,2μL buffer,2μL 0.1% BSA,Top1 0.5U,DNA 0.5μL,不同的药物0.2μL,定容到20μL。然后将样品管放入37℃水浴中,孵化15分钟。加入2μL 6x loading buffer至样品管中。110V电泳40-50分钟,用0.5μg/mL EtBr染色15分钟,凝胶成像系统观察电泳结果。
实验结果表明(图3、4、5和6),我们设计得到目标化合物均具有良好的Top2抑制活性,其中,在50μM浓度下,化合物B17a、B17b、B17d和B17e,仍具有Top2抑制活性。
实施例7:目标化合物体外抗肿瘤活性测试
1)样品配制:用DMSO(Merck)溶解成后,加入PBS(-)配成1000μM的溶液或均匀的混悬液,然后用含DMSO的PBS(-)稀释。样品终浓度100、10、1、0.1、0.01、0.001μM。
2)细胞株
HCT116(人肠癌细胞)、MCF-7(人乳腺癌细胞)、A549(人肺癌细胞),均由本实验室冻存和传代。
3)培养液
DMEM或PRMI1640+10%FBS+双抗
4)试验方法
CCK-8法。96孔板每孔加入浓度为6-10×104个/mL的细胞悬液100μL,置37℃,5%CO2培养箱内。24小时后,加入样品液,10μL/孔,设三复孔,37℃,5% CO2作用48小时。每孔加入10μL CCK-8溶液,然后37℃下避光孵育1-4小时后,用全波长多功能酶标仪测450nm OD值。
我们选取多种较为常见的实体瘤人肿瘤细胞株(肠癌肿瘤细胞(HCT116)、乳腺癌细胞(MCF-7)、肝癌细胞(HepG-2)、人髓性白血病细胞(K562)、红细胞白血病细胞(HEL)和肺癌肿瘤细胞(A549)进行体外抗肿瘤活性测试,设置阳性对照药分别为SAHA、10-羟基吴茱萸碱(10-OH-Evo)、SAHA和10-OH-Evo联用。
表3.目标化合物对实体瘤细胞的体外抗肿瘤活性
aNT=not tested.
大部分化合物对以上四种实体瘤细胞具有较好的体外抗肿瘤活性,当连接子基团的碳链长度分别为4、5、6个碳原子时,化合物的体外抗肿瘤活性最优,作用机制研究发现B13c、B13d、B17a、B17c为Top2/HDAC双靶点抑制剂。
表4.目标化合物对HDAC1的抑制活性和体外抗肿瘤活性
NT=not tested.
其中,以苄基为连接子的化合物B17c对K562和HEL细胞株生长抑制作用均较强(IC50分别为291nM和86nM),当增加苄基取代链长度后(化合物B17d),对K562和HEL细胞株仍然具有优秀的体外抗肿瘤活性(IC50值分别为177nM和98nM)。该类化合物同样具有较强的Top2抑制活性,可能是化合物对HDAC1与Top2双靶点的协同作用提升了抗肿瘤活性,作用机制有待深入研究。此外,具有肉桂酸酯结构的第三类化合物B17e对HEL细胞具有较强的生长抑制作用(IC50=29nM)。
表5.目标化合物酶抑制活性和体外活性结果(μM)
表6.目标化合物对血液肿瘤细胞的体外抗活性
NT=not tested.
其中,以对位取代苄基为连接子的化合物C11e对K562和HEL细胞株生长抑制作用均较强(IC50分别为248nM和237nM),而以其他位置取代苄基为连接子的化合物C11f和C11g对K562细胞株的抑制活性虽有所降低,但对HEL细胞株仍保留着中等活性(IC50分别为0.83μM和0.66μM)。由于该类化合物具有较强的Top2抑制活性,可能是由于同时对HDAC1与Top2具有抑制作用从而产生协同作用。此外,具有肉桂酸酯结构的第三类化合物C11h对HEL和K562细胞具有较强的生长抑制作用(IC50值分别为0.13μM和0.24μM)。综上,该类化合物对HEL和K562两种细胞株均具有一定的的生长抑制作用,其中,化合物C11e和C11h具有较强的抗肿瘤活性,具有进一步的研究价值。
表7.目标化合物的体外抗肿瘤活性(IC50,μM)
测试结果显示,化合物C8a、C8b、C13b、C19b、C19d、C19e均表现出较好的HDAC1抑制活性,其中C13b、C19d、C19e的IC50值均小于5nM,优于阳性药SAHA。对其构效关系进行初步总结:当连接链为脂肪链且链长大于6个碳原子时,具有较好的HDAC1抑制活性;当连接链为芳香链时,只有连接链为苄基肉桂酰胺时化合物的HDAC1抑制活性较好,其余相似化合物活性相对较差。而吲哚环上甲氧基的存在对HDAC抑制活性影响较小。结合化合物的体外抗肿瘤活性,我们选择化合物C8a、C8b、C19b、C19e四个化合物进行进一步研究。
实施例8:目标化合物体内抗肿瘤效果
根据以上试验结果,选择人结肠癌HCT116裸鼠移植瘤模型对化合物C8a、C19b的体内抗肿瘤活性进行了测试,给药剂量为20mg/kg,腹腔注射每天给药两次,连续给药14天。结果显示(图7),化合物C8a、C19b均表现出一定的体内抑制活性,化合物C8a的体内抑瘤率为42.4%,与对照药SAHA相比有所提升(26.7%),有进一步的研究价值。
表8.化合物C8a、C19b、SAHA对HCT116裸鼠移植瘤的疗效
本发明的化合物经抗肿瘤活性实验,证明大部分化合物具有较好体外抗肿瘤活性,优选化合物具有优秀的体内肿瘤生长抑制活性。本发明为深入研究和开发新结构类型抗肿瘤药物开辟了新的途径,提供了新的策略。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明原理的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (2)
1.一类吴茱萸碱衍生物及其药用盐,其特征在于,所述的吴茱萸碱衍生物为:
B13a:4-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基丁酰胺,
B13b:5-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基戊酰胺,
B13c:6-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基己酰胺,
B13d:7-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基庚酰胺,
B13e:8-((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑啉-10-基)氧基)-N-羟基辛酰胺,
B17a:4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)-N-羟基苯甲酰胺,
B17b:3-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)-N-羟基苯甲酰胺,
B17c:2-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)-N-羟基苯甲酰胺,
B17d:2-(4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯基)-N-羟基乙酰胺,
B17e:(E)-3-(4-(((3-氟-14-甲基-5-氧代5,7,8,13,13b,14-六氢[2',3':3,4]吡啶并[2,1-b]喹唑-10-基)氧基)甲基)苯基)-N-羟基丙烯酰胺,
C8a:(E)-N-羟基-3-(4-((5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)丙烯酰胺,
C8b:N-羟基-6-(5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14(5H)-基)己酰胺,
C13a:N-羟基-5-(4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)基)戊酰胺,
C13b:(E)-N-羟基-3-(4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉14-(5H)-基)甲基)苯基)丙烯酰胺,
C13c:N-羟基-2-(4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)乙酰胺,
C13d:N-(2-(羟基氨基)-2-氧代乙基)-4-((4-甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯甲酰胺,
C19a:4-((4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)-N-羟基苯甲酰胺,
C19b:(E)-3-(4-((4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)甲基)苯基)-N-羟基丙烯酰胺,
C19d:8-(4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)-N-羟基丁酰胺,
C19e:6-(4,9-二甲氧基-5-氧代-7,8,13,13b-四氢吲哚并[2',3':3,4]吡啶并[2,1-b]喹唑啉-14-(5H)-基)-N-羟基己酰胺。
2.权利要求1所述的吴茱萸碱衍生物及其药用盐在制备抑制剂中的应用,其特征在于,所述抑制剂为Top2抑制剂或HDAC抑制剂。
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