CN111909162A - 抗白血病硒代那可丁衍生物的制备方法及其应用 - Google Patents
抗白血病硒代那可丁衍生物的制备方法及其应用 Download PDFInfo
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- CN111909162A CN111909162A CN201910387757.3A CN201910387757A CN111909162A CN 111909162 A CN111909162 A CN 111909162A CN 201910387757 A CN201910387757 A CN 201910387757A CN 111909162 A CN111909162 A CN 111909162A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
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Abstract
Description
技术领域
本发明涉及医药领域,具体涉及一种抗白血病硒代那可丁衍生物的制备方法 及其应用。
背景技术
白血病,亦称作血癌,是一种造血干细胞的恶性增生性病变。病人的骨髓造 血系统产生大量不成熟、无法正常工作的白细胞,造成正常的血小板、红细胞、 白细胞减少。这些尚未发育完全的白细胞,被称为白血病细胞。根据白血病细胞 的分化程度、自然病程的长短可分为急、慢性白血病。按照病变细胞系列分类, 主要分为髓系和淋巴系。临床常见发病类型主要有四种,包括急性淋巴细胞白血 病(ALL),急性髓性白血病(AML),慢性淋巴细胞白血病(CLL)和慢性髓性白血病 (CML)。调查表明,在我国,白血病导致的死亡率,男性居第六位,女性居第八 位,由此可见白血病严重威胁着人类的健康。
化疗药物,作为治疗白血病的有效方式,在临床上广泛使用。例如治疗各种 急慢性白血病的长春新碱,用于治疗急性白血病的阿糖胞苷和甲氨喋呤等。然而 该类药物的毒副作用严重影响了白血病患者的生存质量。近年来,靶向药物,毒 副作用小,在治疗白血病种显示出独特的优势,然而日益增加耐药性成为其临床 应用的瓶颈。因此亟需发展高效低毒,治疗指数高的抗白血病药物。
发明内容
本发明公开了一种能够用于白血病治疗药物的硒代那可丁衍生物及其制备 方法和应用。
设计思路如下:
那可丁(Noscapine)是从罂粟中分离得来的苯酞四氢异喹啉类生物碱,其结构 简单,自然界含量丰富,价格低廉,最早在临床上作为非处方止咳药使用,安全 可靠,可口服给药。1998年被发现对各种实体瘤,如肺癌和结肠癌等,表现出 一定的抑制活性。同时,可以透过血脑屏障,用于脑部神经胶质瘤的治疗。初步 研究表明,其作用机制为微管蛋白抑制剂,与微管蛋白相结合,干扰微管动态平 衡,致使细胞停滞于有丝分裂G2/M期而凋亡,产生抗肿瘤作用。然而该类化合 物在白血病治疗中的应用鲜见报道。
硒作为一种人体所必须的微量元素,有着非常重要的生理功能。适当的摄取 微量硒元素能够有效提高机体的抗氧化能力和抗癌能力、增强免疫功能。近年来, 诸多研究表明,将硒元素引入到抗肿瘤化合物中,可起到协同增效的作用,有效 提高先导化合物的抗肿瘤活性。
鉴于此,本研究通过半合成的方法,合成了一系列9位硒代的那可丁衍生物。 这些衍生物对各种白血病细胞显示出优异的抑制活性,有望开发高效低毒的白血 病治疗药物。
具体的,本发明的技术方案如下:
本发明第一个方面公开了一种硒代那可丁衍生物,所述硒代那可丁衍生物 的结构通式如通式i或通式ii所示:
所述R1或R2基团为烷基、环烷基、芳基、杂芳基、氧烷基、酯烷基、烯丙 基、炔丙基或氰基。
优选地,所述芳基为苯基、取代苯基、联苯基、萘基或取代萘基;所述杂芳 基为吡啶基、取代吡啶基、噻吩基、取代噻吩、呋喃基、取代呋喃基、吡咯基、 取代吡咯基、喹啉基、取代喹啉基、异喹啉基、取代异喹啉基、苯并噻唑基、取 代苯并噻唑基、吲哚基、取代吲哚基、苯并咪唑基、取代咪唑基、苯并恶唑基、 取代苯并恶唑基、咪唑基、取代咪唑基、恶唑基、取代恶唑基、噻唑基或取代噻 唑基;
所述烷基为C1-C6烷基或氘代烷基;
所述环烷基为C1-C8环烷基或氘代环烷基;
更优选的,所述芳基为取代苯基。
进一步优选,所述硒代那可丁衍生物为以下化合物:
本发明第二个方面公开了一种制备上述的硒代那可丁衍生物的方法,所述硒 代那可丁衍生物的结构通式如通式i所示,包括以下步骤:
以结构式如式I所示的化合物为底物,依次进行羟甲基化反应、氯代反应、 硒氰化钾参与的亲核取代反应、硒醇原位还原生成和亲核取代反应,得到结构通 式如通式i所示的硒代那可丁衍生物;
以结构式如式I所示的化合物为底物,依次进行溴代反应、氨基化反应、重 氮化反应、硒氰化钾参与的亲核取代反应、硒醇原位还原生成和亲核取代反应, 即得到结构通式如通式ii所示的硒代那可丁衍生物,或
以结构式如式I所示的化合物为底物,直接与二硒化物进行自由基加成反应, 即得到结构通式如通式ii所示的硒代那可丁衍生物;
本发明的一优选实施例中,公开了一种制备硒代那可丁衍生物的方法,包括 以下步骤:
本发明的一优选实施例中,公开了一种制备硒代那可丁衍生物的方法,包括 以下步骤:
具体的,步骤如下:
1)化合物Ⅰ在浓盐酸的作用下,发生羟甲基化反应,得到化合物Ⅱ,收率98%。
2)化合物Ⅱ在室温下,与二氯亚砜反应,得氯代产物Ⅲ,收率100%。
3)化合物Ⅲ与硒氰化钾发生亲核取代反应,得到化合物Ⅳ(也就是化合物S1), 收率99%。
4)化合物Ⅳ(也就是化合物S1)经硼氢化钠还原后,继续与卤代烷烃发生亲核 取代反应得到化合物Ⅴ(也就是化合物S3-S22),收率40-72%,
5)化合物Ⅲ在48%氢溴酸和溴水作用下,得到9-溴那可丁Ⅵ,收率95%。
6)化合物Ⅵ经氨基化反应得到目标产物VII,收率80%。
7)化合物Ⅶ经重氮化反应,硒氰化钾参与的亲核取代反应得目标产物VIII,收 率50%。
8)化合物ⅥII经硼氢化钠还原后,继续与碘甲烷发生亲核取代反应,得到化合 物S24,收率68%。
9)化合物ⅥII经硼氢化钠还原后,继续与三氟甲基三甲基硅烷发生亲核取代反应,得到化合物S25,收率71%。
10)化合物Ⅰ在过硫酸钾作用下,与二苯基二硒醚发生自由基加成反应,得到化合物S26,收率95%。
本发明第三个方面公开了上述的硒代那可丁衍生物在白血病领域中的应用。
本发明第四个方面公开了一种治疗白血病的药物,其特征在于,所述药物的 活性成分为权利要求1所述的硒代那可丁衍生物。
在符合本领域常识的基础上,上述各优选条件,可任意组合,而不超出本发 明的构思与保护范围。
本发明相对于现有技术具有如下的显著优点及效果:
本发明通过半合成的方法,合成了一系列9位硒代的那可丁衍生物,该合成 路线短,实验操作简单,且收率效果好;该制备方法得到的硒代的那可丁衍生物 对各种白血病细胞显示出优异的抑制活性,可用于制备高效且低毒的白血病治疗 药物。
具体实施方式
下面结合实施例对本发明的技术方案进行详细描述,但并不因此将本发明限 制在所述的实施例范围之中。
下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商 品说明书选择。本发明所用试剂和原料均市售可得。
本发明中的硒代那可丁衍生物为以下化合物:
本发明的一些优选实施例中,公开了一种制备硒代那可丁衍生物的方法,设 计路线包括以下步骤:
本发明的一些优选实施例中,公开了一种制备硒代那可丁衍生物的方法,设 计路线包括以下步骤:
详细描述如下:
实施例1
1)化合物Ⅱ的合成:
称取1.8g那可丁盐酸盐溶于50mL浓盐酸中,室温分批加入4g多聚甲醛, 加毕,50℃搅拌2小时。反应结束后,冷却,滴加氨水调pH至10,二氯甲烷萃 取(50mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,得1.9g无色油状 液体,产率98%。1H NMR(400MHz,CDCl3)δ6.91(d,J=8.3Hz,1H),6.14(d,J= 8.2Hz,1H),5.88(s,2H),5.45(d,J=4.3Hz,1H),5.23(s,1H),4.56(s,2H),4.31(d, J=4.3Hz,1H),4.01(s,3H),3.92(s,3H),3.79(s,3H),2.70-2.54(m,2H),2.46(s, 3H),2.39-2.27(m,1H),1.90-1.86(m,1H)。
2)化合物Ⅲ的合成:
将1.62g化合物Ⅱ溶于20mL二氯甲烷中,0℃下缓慢滴加0.5mL二氯亚砜, 滴加完毕后,缓慢升至室温,搅拌2小时,滴加氨水调pH至10,二氯甲烷萃取 三次,合并有机相,有机相经无水硫酸钠干燥,过滤,浓缩,得目标产物1.7g, 产率100%。
3)化合物S1的合成:
称取1.38g化合物Ⅲ加入到50mL乙腈中,再加入0.86g KSeCN,80℃下,5 分钟后停止反应,快速冷却至室温,加水稀释,以乙酸乙酯萃取三次,有机相以 饱和食盐水洗,经无水硫酸钠干燥,过滤,浓缩,得目标产物1.6g,产率99%。 1H NMR(400MHz,CDCl3)δ7.01(d,J=8.3Hz,1H),6.20(d,J=8.2Hz,1H),6.05 –5.93(m,2H),5.53(d,J=4.2Hz,1H),4.41(t,J=8.6Hz,2H),4.18(d,J=11.4Hz, 1H),4.09(s,3H),4.04(s,3H),3.86(s,3H),2.82–2.64(m,1H),2.53(d,J=7.0Hz, 3H),2.52–2.37(m,2H),1.90(ddd,J=15.3,8.0,4.6Hz,1H)。
实施例2
化合物S2的合成:
称取0.26g化合物Ⅳ于反应瓶中,0℃下,加入5mL无水四氢呋喃和0.14g TMSCF3,缓慢滴加0.1mL四丁基氟化铵的四氢呋喃溶液(1mol/L),后转移至室 温反应2小时,反应完全后,加水稀释,以乙酸乙酯萃取三次,有机相以饱和食 盐水洗,经无水硫酸钠干燥,过滤,浓缩,所得粗产物经硅胶柱层析纯化,得0.20g 目标产物,产率69%。1H NMR(400MHz,CDCl3)δ6.95(d,J=8.2Hz,1H),6.04(d, J=8.2Hz,1H),5.98(d,J=0.7Hz,2H),5.50(d,J=4.2Hz,1H),4.39(d,J=4.3Hz, 1H),4.27(d,J=11.6Hz,1H),4.12(d,J=11.6Hz,1H),4.09(s,3H),4.02(s,3H), 3.86(s,3H),2.76–2.64(m,1H),2.53(s,3H),2.51–2.32(m,2H),1.88–1.73(m, 1H)。
实施例3
化合物S3的合成:
称取0.11g化合物Ⅳ与0.015g硼氢化钠同时加入到反应瓶中,氮气保护下加入1mL无水乙醇,室温搅拌30分钟后,加入碘甲烷0.035g,室温继续反应2小时, 反应完全后,加水稀释,以乙酸乙酯萃取三次,有机相以饱和食盐水洗,经无水 硫酸钠干燥后,过滤,浓缩,所得粗产物经硅胶柱层析纯化(乙酸乙酯:石油醚 =1:3),得0.071g目标产物,产率68%。1H NMR(400MHz,CDCl3)δ6.89(d,J= 8.3Hz,1H),6.01(d,J=8.2Hz,1H),5.88(dd,J=7.3,1.3Hz,2H),5.46(d,J=4.2 Hz,1H),4.34(d,J=4.2Hz,1H),4.02(s,3H),3.94(s,3H),3.79(s,3H),3.66–3.58 (m,3H),2.65–2.55(m,1H),2.47(s,4H),2.33–2.25(m,1H),1.97(s,3H),1.76 (ddd,J=13.5,6.5,3.1Hz,1H)。
实施例4-9:化合物S4-S9的合成与S3的合成方法相同。
实施例10
化合物S10的合成:
称取0.11g化合物Ⅳ(也就是化合物S1)与0.015g硼氢化钠同时加入到反应瓶 中,氮气保护下加入5mL无水乙醇,室温搅拌30分钟后,加入溴甲基环丙烷 0.042g,室温继续反应2小时,反应完全后,加水稀释,以乙酸乙酯萃取三次, 有机相以饱和食盐水洗,经无水硫酸钠干燥后,过滤,浓缩,所得粗产物经硅胶 柱层析纯化(乙酸乙酯:石油醚=1:3),得0.078g目标产物,产率72%。1H NMR (400MHz,CDCl3)δ6.92(d,J=8.3Hz,1H),6.02(d,J=7.2Hz,1H),5.89(dd,J= 7.6,1.3Hz,2H),5.47(d,J=3.1Hz,1H),4.35(d,J=4.0Hz,1H),4.02(s,3H),3.93 (s,3H),3.79(s,3H),3.70(q,J=11.7Hz,2H),2.61(m,1H),2.53(d,J=7.2Hz,2H), 2.47(s,3H),2.30(m,1H),1.78(m,2H),1.06–0.96(m,1H),0.59–0.48(m,2H),0.21–0.10(m,2H)。
实施例11
化合物S11的合成:
称取0.11g化合物S1与0.015g硼氢化钠同时加入到反应瓶中,氮气保护下加入5mL无水乙醇,室温搅拌30分钟后,加入溴代环戊烷0.037g,室温继续反应2小 时,反应完全后,加水稀释,用乙酸乙酯萃取三次,有机相以饱和食盐水洗,经 无水硫酸钠干燥后,浓缩,所得粗产物经硅胶柱层析纯化(乙酸乙酯:石油醚 =1:3),得0.078g目标产物,产率70%。1H NMR(400MHz,CDCl3)δ6.97(d,J= 8.3Hz,1H),6.04(d,J=8.1Hz,1H),5.95(dd,J=6.7,1.4Hz,2H),5.52(d,J=3.7 Hz,1H),4.41(d,J=4.1Hz,1H),4.09(s,3H),4.01(s,3H),3.85(s,3H),3.78–3.64 (m,2H),3.36–3.26(m,1H),2.63(s,1H),2.52(d,J=8.0Hz,4H),2.35(t,J=7.7 Hz,1H),2.18–2.00(m,2H),1.89–1.53(m,10H).LRMS(ESI)Calcd.forC28H33NO7Se[(M+H)+]576.1,found 576.1。
实施例12
化合物S12的合成:
称取0.11g化合物S1与0.015g硼氢化钠同时加入到反应瓶中,氮气保护下加入5mL无水乙醇,室温搅拌30min后,加入溴代环庚烷0.044g,室温继续反应2小时, 反应完全后,加水稀释,以乙酸乙酯萃取三次,有机相以饱和食盐水洗,经无水 硫酸钠干燥后,浓缩,所得粗产物经硅胶柱层析纯化(乙酸乙酯:石油醚=1:3), 得0.078g目标产物,产率42%。1H NMR(400MHz,CDCl3)δ6.97(d,J=8.3Hz,1H), 6.03(d,J=8.2Hz,1H),5.96(dd,J=7.2,1.4Hz,2H),5.52(d,J=4.1Hz,1H),4.40 (d,J=4.2Hz,1H),4.09(s,3H),4.02(s,3H),3.85(s,3H),3.70(dd,J=22.5,11.6Hz, 2H),3.19–3.09(m,1H),2.68–2.59(m,1H),2.53(s,4H),2.40–2.29(m,1H),2.19 –2.07(m,2H),1.87–1.75(m,1H),1.70(tdd,J=11.7,5.3,2.8Hz,4H),1.55(dd,J =8.3,4.1Hz,3H),1.53–1.39(m,3H);13C NMR(100MHz,CDCl3)δ168.3,152.1, 147.6,146.5,141.1,139.2,133.4,130.8,120.0,118.5,117.9,117.8,112.3,100.8,81.9, 63.3,62.3,60.9,59.5,56.8,49.6,46.3,44.5,41.7,36.1,36.1,28.1,28.0,26.9,23.7, 16.7.LRMS(ESI)Calcd.for C30H39NO7Se[(M+H)+]604.2,found604.2。
实施例13
化合物S13的合成:
称取0.11g化合物Ⅳ与0.015g硼氢化钠同时加入到反应瓶中,氮气保护下加入5mL无水乙醇,室温搅拌30分钟后,加入溴化苄0.043g,室温继续反应2小时, 反应完全后,加水稀释,以乙酸乙酯萃取三次,有机相以饱和食盐水洗,经无水 硫酸钠干燥后,浓缩,所得粗产物经硅胶柱层析纯化(乙酸乙酯:石油醚=1:3), 得0.089g目标产物,产率75%。1HNMR(400MHz,d6-DMSO)δ7.34–7.26(m,4H), 7.23–7.18(m,1H),6.89(d,J=8.3Hz,1H),6.03(d,J=8.2Hz,1H),5.95(dd,J= 10.6,1.4Hz,2H),5.51(d,J=4.1Hz,1H),4.39(d,J=4.2Hz,1H),4.08(s,3H),4.02 (s,3H),3.88(dd,J=23.2Hz,11.7Hz,2H),3.79(s,3H),3.70(dd,J=29.3,11.7Hz, 2H),2.65–2.54(m,1H),2.52(s,3H),2.47–2.23(m,2H),1.71(ddd,J=15.5,8.7, 4.5Hz,1H).LRMS(ESI)Calcd.for C30H32NO7Se[(M+H)+]598.1,found 598.1。
实施例14-22:化合物S14-S22的合成方法与S13的合成方法相同。
实施例23
化合物S23的合成:
称取0.28g化合物IV加入到10mL乙腈中,再加入0.12g KSCN,80℃下, 反应过夜,冷却至室温,加水稀释,以乙酸乙酯萃取三次(10mL×3),有机相 以饱和食盐水洗,经无水硫酸钠干燥,过滤,浓缩旋干,经柱层析分离得得0.21 g目标产物,分离收率71%。1H NMR(400MHz,CDCl3)δ7.01(d,J=8.3Hz,1H), 6.20(d,J=8.2Hz,1H),6.05–5.93(m,2H),5.53(d,J=4.2Hz,1H),4.41(t,J=8.6 Hz,2H),4.18(d,J=11.4Hz,1H),4.09(s,3H),4.04(s,3H),3.86(s,3H),2.82–2.64 (m,1H),2.53(d,J=7.0Hz,3H),2.52–2.37(m,2H),1.93–1.87(m,1H)。
实施例24
1)化合物Ⅵ的合成
称取4.0g那可丁盐酸盐溶于15mL HBr(48%)水溶液中,剧烈搅拌,室温 下,将50mL新制溴水缓慢滴加到反应体系中,直到有黄色固体析出。滴加完毕 后,反应1小时。反应结束后,用25%氨水调节pH至10,二氯甲烷萃取(50mL×3), 饱和食盐水洗,合并有机相,无水硫酸钠干燥,过滤,浓缩,经柱层析分离得到 4.3g白色固体,产率90%。1H NMR(400MHz,CDCl3)δ7.02(d,J=8.3Hz,1H), 6.30(d,J=8.2Hz,1H),6.02(s,2H),5.50(d,J=4.5Hz,1H),4.34(d,J=4.6Hz, 1H),4.10(s,3H),3.98(s,3H),3.88(s,3H),2.67(m,2H),2.54–2.41(m,4H),1.96 (m,1H)。
2)化合物Ⅶ的合成
向3g化合物Ⅱ的20mL无水DMSO的溶液中加入0.99g NaN3,再加入0.87g Cu2O和L-脯氨酸。加毕,将反应瓶置于100℃下反应24小时,TLC监测反应进 程。反应完毕后,饱和氯化铵水溶液淬灭,后用二氯甲烷萃取三次,水洗,合并 有机相,有机相经无水硫酸钠干燥,过滤,浓缩,经柱层析分离得到黄色固体 2.1g,产率80%。1H NMR(400MHz,CDCl3)δ6.97(d,J=8.3Hz,1H),6.16(d,J= 8.2Hz,1H),5.94(dd,J=3.5,1.4Hz,2H),5.61(d,J=4.0Hz,1H),4.38(d,J=4.0 Hz,1H),4.08(s,3H),3.88(s,3H),3.85(s,3H),3.30(s,2H),2.60–2.54(m,2H), 2.51(s,3H),2.48–2.26(m,2H)。
3)化合物Ⅷ的合成
称取1.7g化合物Ⅲ加入到50mL H2O中,0℃下缓慢滴加0.5mL浓盐酸于反 应瓶中,再加入0.28g亚硝酸钠,搅拌30min后,以乙酸钠水溶液调节pH至6, 随后加入0.58g KSeCN,室温搅拌反应3h,反应基本完全后,加入50mL乙酸乙 酯,依次以饱和碳酸钠水溶液和水洗,有机相经无水硫酸钠干燥,过滤,浓缩, 经柱层析分离得到1.0g白色固体,产率50%。
4)化合物S24的合成
称取0.52g化合物Ⅷ与76mg硼氢化钠同时加入到反应瓶中,氮气保护下加 入5mL无水乙醇,室温搅拌30min后,加入碘甲烷0.035g,室温继续反应2小时, 反应完全后,加水稀释,以乙酸乙酯萃取三次,有机相以饱和食盐水洗,经无水 硫酸钠干燥,过滤,浓缩,所得粗产物经硅胶柱层析纯化,得0.36g目标产物, 产率68%。1H NMR(400MHz,CDCl3)δ6.93(d,J=8.2Hz,1H),6.09(d,J=8.0Hz, 1H),6.01(dd,J=5.3,1.2Hz,2H),5.50(d,J=4.2Hz,1H),4.39(d,J=4.2Hz,1H), 4.10(s,3H),4.03(s,3H),3.86(s,3H),2.91-2.81(m,1H),2.78-2.65(m,1H),2.55 (s,3H),2.36(m,J=8.3Hz,1H),2.22–2.13(m,3H),1.88(s,1H)。
实施例25
化合物S25的合成:
称取0.26g化合物Ⅷ于反应瓶中,0℃下,加入5mL无水THF和0.14g TMSCF3, 缓慢滴加0.1mL四丁基氟化铵四氢呋喃溶液(1mol/L),后转移至室温反应2小时, 反应完全后,加水稀释,以乙酸乙酯萃取三次,有机相以饱和食盐水洗,经无水 硫酸钠干燥,过滤,浓缩,所得粗产物经硅胶柱层析纯化,得0.20g目标产物, 产率71%。1H NMR(400MHz,CDCl3)δ6.91(d,J=8.2Hz,1H),6.15–5.97(m, 3H),5.49(d,J=4.2Hz,1H),4.41(d,J=4.2Hz,1H),4.11(s,3H),4.09(s,3H),3.85 (s,3H),2.94–2.77(m,1H),2.75–2.64(m,1H),2.54(s,3H),2.40–2.26(m,1H), 1.99–1.86(m,1H)。
实施例26
化合物S26的合成:
称取0.41g化合物Ⅰ于反应瓶中,加入0.088mL三氟乙酸(TFA)、0.04g二苯基 二硒醚和0.11g K2S2O8,室温反应16小时,反应完全后,加水搅拌30min后,加水 稀释,以乙酸乙酯萃取三次,有机相以饱和食盐水洗,经无水硫酸钠干燥,过滤, 浓缩,得0.54g目标产物,产率95%。1H NMR(400MHz,CDCl3)δ7.32–7.17(m, 7H),6.68(d,J=8.3Hz,1H),6.09(d,J=8.3Hz,1H),6.00(dd,J=14.8,1.2Hz,2H), 5.49(d,J=4.2Hz,1H),4.40(d,J=4.2Hz,1H),4.08(d,J=1.5Hz,6H),3.80(s, 3H),2.95–2.77(m,1H),2.71–2.60(m,1H),2.51(s,3H),2.39–2.20(m,1H),1.85 (m,1H)。
实施例27
本实施例发现合成的硒代那可丁衍生物具有抗白血病活性,通过药理实验进 行验证,具体的,使用CCK-8法开展相应的细胞增殖抑制活性分析。实验步骤 如下:
1.样品配制:用DMSO(购买于Merck公司)溶解上述实施例合成的S1-S26 以及那可丁(梯希爱(上海)化成工业发展有限公司)(作为阴性对照),加入PBS 配成1000mg/mL的溶液或均匀的混悬液,然后用含DMSO的PBS稀释;
2.人白血病细胞株
JURKAT、U937、KAUSMI-1(ATCC和中科院细胞库);
3.培养液
RPMI 1640+10%FBS+双抗;
4.其他材料
全波长多功能酶标仪:Varioskan Flash型号,Thermo scientific生产厂商,进口96孔板等;
5.实验方法:本实验采用的是CCK-8法。向96孔板每个孔加入100mL浓 度为7-8x103个/mL的人白血病细胞株的细胞悬液,置37℃,5%CO2培养箱内。 培养24小时后,依次向每个孔中加入样品液100mL,并设三复孔。37℃,5%CO2作用48小时。然后每个孔加入CCK-8溶液20mL,置培养箱内作用2-4小时。 然后用全波长多功能酶标仪测450nm处OD值。
体外白血病细胞抑制活性结果见表1。
表1不同化合物对体外白血病细胞的活性抑制结果
结果显示,与阴性对照(那可丁)相比,实施例1-26中大部分制备的硒代 那可丁衍生物对白血病细胞株的细胞活性抑制效果更好,其中化合物S12的效果 最好。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施 例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替 代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的硒代那可丁衍生物,其特征在于,所述芳基为苯基、取代苯基、联苯基、萘基或取代萘基;所述杂芳基为吡啶基、取代吡啶基、噻吩基、取代噻吩、呋喃基、取代呋喃基、吡咯基、取代吡咯基、喹啉基、取代喹啉基、异喹啉基、取代异喹啉基、苯并噻唑基、取代苯并噻唑基、吲哚基、取代吲哚基、苯并咪唑基、取代咪唑基、苯并恶唑基、取代苯并恶唑基、咪唑基、取代咪唑基、恶唑基、取代恶唑基、噻唑基或取代噻唑基;
所述烷基为C1-C6烷基或氘代烷基;
所述环烷基为C1-C8环烷基或氘代环烷基。
3.根据权利要求2所述的硒代那可丁衍生物,其特征在于,所述芳基为取代苯基。
9.根据权利要求1-3中任意一项所述的硒代那可丁衍生物在白血病领域中的应用。
10.一种治疗白血病的药物,其特征在于,所述药物的活性成分为权利要求1所述的硒代那可丁衍生物。
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