CN112724104B - 一种含硒美法仑衍生物及其制备方法和应用 - Google Patents
一种含硒美法仑衍生物及其制备方法和应用 Download PDFInfo
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- 229910052711 selenium Inorganic materials 0.000 title claims abstract description 25
- 239000011669 selenium Substances 0.000 title claims abstract description 25
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 title claims abstract description 24
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D293/12—Selenazoles; Hydrogenated selenazoles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
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Abstract
本发明属于生物制药技术领域，具体涉及一种硒美法仑衍生物及其制备方法和应用。本发明在美法仑结构中引入了硒元素，合成了结构新颖的含硒美法仑衍生物，该类化合物具有抗肿瘤活性，能用于抗癌药物。
Description
技术领域
本发明涉及含硒美法仑衍生物，及其在制药中的应用，属于医药技术领域。
背景技术
美法仑对多种恶性肿瘤均有疗效，但作为氮芥类中的经典药物，存在毒副作用大、选择性差等缺点。硒元素是人体的必需微量元素，被誉为“抗癌之王”和“长寿元素”。硒元素在人体内主要以含硒蛋白质的形式存在，目前已证明有25种硒蛋白发挥作用。硒蛋白对于激活起免疫作用的T细胞有重要的贡献，能够促使CD4+T细胞更倾向分化成Th1细胞，从而产生抗病毒的免疫作用及增强抗肿瘤的反应，同时，硒对于心血管疾病也起到很重要的作用。每天补充硒能增强人体的免疫力。鉴于硒良好的生物、药理活性，特别是对癌症有良好的防治效果，近几十年来，有关于含硒抗肿瘤药物的合成和临床试验也是科学研究的热点。有机硒化合物作为其中一类，受到了广泛的关注和研究。
本发明将硒引入美法仑结构中，以期获得抗肿瘤活性高、毒性低的药物。
发明内容
本发明的目的在于提供一种含硒美法仑衍生物，其具有抗癌作用。
本发明的另一目的在于提供上述含硒美法仑衍生物的制备方法。
本发明的再一目的在于提供上述含硒美法仑衍生物的用途。
以下对本发明进行详细描述。
本发明提供的含硒美法仑衍生物，结构如下所示：
式中，R1各自独立为H,甲基、苄基；R2各自独立为H,4-F、4-OCH3、4-CH3、2-CH3、3-CH3、4-Cl、2-Cl、3-Cl、4-CF3、4-OAc、4-CN和4-NO2。
权利要求1所述的含硒美法仑衍生物，其特征在于，所述化合物的具体实例包括：
本发明还提供了上述化合物的制备方法：
式中，R1各自独立为H,甲基、苄基；R2各自独立为H,4-F、4-OCH3、4-CH3、2-CH3、3-CH3、4-Cl、2-Cl、3-Cl、4-CF3、4-OAc、4-CN和4-NO2。
本发明的一种含硒美法仑衍生物，具有抗肿瘤作用。
通过以下实施例进一步举例说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
具体实施方式
实施例1
美法仑甲酯的制备
取美法仑305mg(1mmol)，溶于10mL无水甲醇中，加入0.15mLSOCl2，-8℃以下反应1h，回流反应2h，减压蒸干，得到美法仑甲酯盐酸盐。美法仑甲酯盐酸盐与二氯甲烷混合，加入207mg(1.5mmol)无水K2CO3粉末，室温搅拌24h，过滤，滤液蒸干，制得美法仑甲酯，收率86.8％。
美法仑苄酯的制备
取美法仑305mg(1mmol)，加入到10mL1，2-二氯乙烷中，加入162mg(1mmol)FeCl3，搅拌，室温下通入HCl气体0.5h，然后加入118.8mg(1.1mmol)苄醇，继续通入HCl气体，回流带水3h，趁热过滤，减压蒸干，重结晶，得到美法仑苄酯盐酸盐。美法仑苄酯盐酸盐与二氯甲烷混合，加入207mg(1.5mmol)无水K2CO3粉末，室温搅拌24h，过滤，滤液蒸干，制得美法仑苄酯，收率87.8％。
实施例2
分别将异硒氰酸酯(1.1mmol)、10mLTHF、122mg(0.8mmol)1，8-二氮杂二环十一碳-7-烯与319mg(1mmol)美法仑甲酯或395mg(1mmol)美法仑苄酯混合，搅拌，加入0.01g活性炭负载的纳米铜，室温搅拌4h，过滤，减压浓缩，残渣加入10mL饱和碳酸钠溶液，搅拌，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析纯化，分别制得化合物如下：
化合物(1)：收率72.2％；ESI-MS(m/z):499[M]+；1H NMR(300MHz，DMSO-d6)δ2.03(s,1H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.60-3.73(m,8H),3.67(s,3H),3.84(m,1H),6.63(d,J＝8.5Hz,2H),6.95(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),7.18-7.38(m,2H),7.57(dd,J＝30.6,7.9Hz,1H).
化合物(2)。收率70.6％；ESI-MS(m/z):575[M]+；1H NMR(300MHz，DMSO-d6)δ2.03(s,1H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.73(m,8H),3.84(m,1H),5.27(s,2H),6.63(d,J＝8.5Hz,2H),6.95(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),7.18-7.38(m,7H),7.57(dd,J＝30.6,7.9Hz,1H).
化合物(4)：收率73.8％；ESI-MS(m/z):593[M]+；1H NMR(300MHz，DMSO-d6)δ2.01(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.73(m,8H),3.84(m,1H),5.34(s,2H),6.54(d,J＝8.5Hz,2H),6.96(dd,J＝10.8,4.3Hz,1H),7.02(d,J＝8.4Hz,2H),7.19-7.22(m,6H),7.59(s,1H).
化合物(5)：收率74.3％；ESI-MS(m/z):605[M]+；1H NMR(300MHz，DMSO-d6)δ2.01(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.73(m,8H),3.74(s,3H),3.84(m,1H),5.34(s,2H),6.54(d,J＝8.5Hz,2H),6.99(dd,J＝10.8,4.3Hz,1H),7.02(d,J＝8.4Hz,2H),7.09-7.19(m,6H),7.41(s,1H).
化合物(6)：收率74.9％；ESI-MS(m/z):589[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),2.35(s,3H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.73(m,8H),3.84(m,1H),5.34(s,2H),6.54(d,J＝8.5Hz,2H),6.98(dd,J＝10.8,4.3Hz,1H),7.07(d,J＝8.4Hz,2H),7.18-7.19(m,6H),7.51(s,1H).
化合物(7)：收率70.5％；ESI-MS(m/z):589[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),2.35(s,3H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.55(d,J＝8.5Hz,2H),7.05(d,J＝8.4Hz,2H),7.18-7.39(m,7H),7.56(dd,J＝30.6,7.9Hz,1H).
化合物(8)：收率73.1％；ESI-MS(m/z):589[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),2.35(s,3H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.54(d,J＝8.5Hz,2H),7.00(s,1H),7.05(d,J＝8.4Hz,2H),7.18-7.38(m,6H),7.56(dd,J＝30.6,7.9Hz,1H).
化合物(9)：收率37.2％；ESI-MS(m/z):620[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.55(d,J＝8.5Hz,2H),7.08(d,J＝8.4Hz,2H),7.40(dd,J＝10.8,4.3Hz,1H),7.19(m,5H),8.19(m,1H),8.61(s,1H).
化合物(10)：收率68.8％；ESI-MS(m/z):611[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.54(d,J＝8.5Hz,2H),7.08(d,J＝8.4Hz,2H),7.12(dd,J＝10.8,4.3Hz,1H),7.18-7.41(m,6H),7.59(dd,J＝30.5,7.9Hz,1H).
化合物(11)：收率63.7％；ESI-MS(m/z):611[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.55(d,J＝8.5Hz,2H),7.06(d,J＝8.4Hz,2H),7.18-7.37(m,7H),7.56(dd,J＝30.5,7.8Hz,1H).
化合物(12)：收率62.9％；ESI-MS(m/z):611[M]+；1H NMR(300MHz，DMSO-d6)δ2.01(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.30(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.54(d,J＝8.5Hz,2H),6.96(d,J＝8.4Hz,2H),7.15(s,1H),7.19-7.40(m,6H),7.56(dd,J＝30.5,7.8Hz,1H).
化合物(13)：收率72.5％；ESI-MS(m/z):643[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.55(d,J＝8.5Hz,2H),7.07(d,J＝8.4Hz,2H),7.06(dd,J＝10.8,4.3Hz,1H),7.19-7.39(m,6H),7.58(dd,J＝30.6,7.9Hz,1H).
化合物(14)：收率74.3％；ESI-MS(m/z):633[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),2.08(s,3H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.56(d,J＝8.5Hz,2H),7.01(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),7.19-7.35(m,6H),7.53(s,1H).
化合物(15)：收率75.5％；ESI-MS(m/z):600[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.04(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.84(m,1H),5.34(s,2H),6.55(d,J＝8.5Hz,2H),7.08(d,J＝8.4Hz,2H),7.37(dd,J＝10.8,4.3Hz,1H),7.19(m,5H),7.59(m,1H),7.62(s,1H).
实施例3
分别将1mmol化合物(2)，(4)，(13)，(14)溶于10mL乙酸乙酯中，加入40mg 10％Pd/C，搅拌下通入氢气，室温反应6h，过滤，滤液浓缩，硅胶柱层析，分别制得化合物如下：
化合物(3)：收率93.9％；ESI-MS(m/z):485[M]+；1H NMR(300MHz，DMSO-d6)δ2.01(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.88(m,1H),6.63(d,J＝8.5Hz,2H),6.95(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),7.18-7.38(m,2H),7.56(dd,J＝30.6,7.9Hz,1H),11.00(brs 1H).
化合物(16)：收率92.7％；ESI-MS(m/z):503[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.88(m,1H),6.56(d,J＝8.5Hz,2H),6.99(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),7.19(m,1H),7.58(dd,J＝30.4,7.9Hz,1H),11.00(brs 1H).
化合物(17)：收率94.6％；ESI-MS(m/z):553[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.88(m,1H),6.54(d,J＝8.5Hz,2H),6.98(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),7.19(m,1H),7.56(dd,J＝30.5,7.9Hz,1H),11.00(brs 1H).
化合物(18)：收率95.4％；ESI-MS(m/z):543[M]+；1H NMR(300MHz，DMSO-d6)δ2.00(s,1H),2.08(s,3H),3.05(dd,J＝13.7,7.8Hz,1H),3.29(dd,J＝13.7,5.1Hz,1H),3.61-3.63(m,8H),3.88(m,1H),6.55(d,J＝8.5Hz,2H),6.97(dd,J＝10.8,4.3Hz,1H),7.08(d,J＝8.4Hz,2H),6.95(m,1H),7.51(dd,J＝30.5,7.9Hz,1H),11.00(brs 1H).
实施例4
化合物体外抗肿瘤活性用IC50值评定：将细胞按一定密度接种于含10体积％小牛血清的RPMI1640培养基(内含适量青霉素、链霉素和谷氨酰胺)的96孔板中，5wt％CO2，37℃条件下培养24小时后，换用不同浓度受试药物(用PBS配制成1μg/mL工作液，使用时按需要用培养基稀释)的新鲜培养基，不同稀释浓度的阳性对照药美法仑药液为阳性对照，每组设6个平行孔，继续培养24小时。取出96孔培养板，每孔加入20μL 5mg/mL的MTT，继续培养4小时。取出培养板，倒出培养基，每孔加入200μL DMSO，平板摇床震摇5分钟，待结晶溶解后，酶联检测仪，于570nm波长下测定各孔的OD值。用Bliss法求出半数抑制浓度IC50。含硒美法仑衍生物对SMMC-7721(人肝癌)、H460(人肺癌)、HepG2(人肝癌)和WCF-7(人乳腺癌)细胞株的抑制活性如表1所示。结果显示，含硒美法仑衍生物具有好的抗癌活性，能用于抗癌药物。
表1 含硒美法仑衍生物抗癌活性
实施例5
取接种肿瘤细胞6～8d的HepA荷瘤小鼠，无菌条件下抽取腹水，3倍生理盐水稀释，配制成肿瘤细胞混悬液，然后将其接种于小鼠的腋窝皮下，0.2mL/只。接种次日，将小鼠随机分为5组，每组10只，雌雄各半，即对照组、美法仑组和化合物(16)组(6μmol/kg)，各组均采用20％PEG400的水溶液配制。对照组均给予相同对应量的20％PEG400的水溶液，其他各组给予相应浓度的药物，药物现用现配。按照0.2mL/20g ip给药。给药7d后，颈椎脱臼处死，剥离瘤体，称量质量，计算肿瘤抑制率(表2)。
肿瘤抑瘤率/％＝1－试验组平均瘤重/对照组平均瘤重。
结果显示，化合物(16)的抑瘤效果优于美法仑。
表2 体内抑瘤活性
Claims (3)
1.一种含硒美法仑衍生物，如下式所示：
2.根据权利要求1所述的一种含硒美法仑衍生物，所述化合物(1)、(2)、(4)、(5)、(6)、(7)、(8)、(9)、(10)、(11)、(12)、(13)、(14)、(15)的制备方法如下：
所述化合物(3)、(16)、(17)、(18)的制备方法如下：
3.根据权利要求1所述的一种含硒美法仑衍生物在制备抗肿瘤药物中的应用。
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| WO2009132310A1 (en) * | 2008-04-25 | 2009-10-29 | Wisconsin Alumni Research Foundation | Inhibitors of udp-galactopyranose mutase thwart mycobacterial growth |
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| WO2009132310A1 (en) * | 2008-04-25 | 2009-10-29 | Wisconsin Alumni Research Foundation | Inhibitors of udp-galactopyranose mutase thwart mycobacterial growth |
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