CN116947744A - 新型戊二酰亚胺衍生物制备方法及其在抗肿瘤药物中的应用 - Google Patents
新型戊二酰亚胺衍生物制备方法及其在抗肿瘤药物中的应用 Download PDFInfo
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- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
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Abstract
本发明公开了一类新型戊二酰亚胺衍生物、它们的制备方法及其在抗肿瘤药物中的应用，属于抗肿瘤药物化学领域。本发明简单高效，绿色环保的合成了戊二酰亚胺类化合物。其具有如下结构通式：该类化合物体外抗肿瘤活性试验表明对多种肿瘤细胞生长具有一定的抑制作用。化合物S4对乳腺癌细胞MCF7、前列腺癌细胞PC3、胃癌细胞MGC803和肝癌细胞HepG2的活性优于抗肿瘤药物5‑氟尿嘧啶，可应用于制备抗肿瘤药物。
Description
技术领域
本发明涉及抗肿瘤药物化学领域，具体涉及一类戊二酰亚胺衍生物、它们的制备方法及其作为一类新的抗肿瘤药物先导化合物的应用。
背景技术
恶性肿瘤的发病率和死亡率居高不下，已成为医学科研和临床实践的重要热点。研发新型有效的抗肿瘤药物，对于探索肿瘤发展机制和临床治疗肿瘤具有重要意义。戊二酰亚胺衍生物具有抗菌、抗病毒、抗原虫、抗肿瘤和免疫抑制等药理活性，在药物设计领域倍受青睐。近年来，含有戊二酰亚胺片段的抗肿瘤小分子被广泛报道，大量文献证明戊二酰亚胺是潜在的抗肿瘤优势结构。
发明内容
本发明目的在于提供一类具有抗肿瘤活性的新型戊二酰亚胺衍生物。
本发明的另一个目的在于提供一种简单高效、绿色环保的合成新型戊二酰亚胺的方法。
本发明的另一个目的在于设计并发现优于抗肿瘤药物5-氟尿嘧啶的强效抗肿瘤药物。
本发明所述一类新型戊二酰亚胺衍生物具有如下通式：
所述新型戊二酰亚胺衍生物选用式(S1～S16)所示化合物：
本发明所述新型戊二酰亚胺衍生物主要通过下列步骤制得：
(1)化合物(H)的制备方法：
溶剂中，将商业化的苯胺E和苄溴F在碱性条件下加热反应得到化合物G，不经分离纯化加入氯丙酰氯室温反应，制备化合物H。所用的碱是氢氧化钾、碳酸钠、氢氧化钠、十二水磷酸钠、碳酸钾、碳酸氢钾、磷酸钠、碳酸氢钠、磷酸钾、三乙胺、吡啶和一水合氨中的一种；所用的溶剂为二甲基亚砜、乙酸乙酯、甲醇、二氧六环、乙醇、四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、异丙醇和乙腈中之一或其中任意两种的混合物；加热反应在25-120℃之间进行。
(2)通式(S1-S16)的制备方法：
溶剂中，化合物H和戊二酰亚胺在碱性条件下加热反应得到化合物S1-S16，所用的碱是氢氧化钾、碳酸钠、氢氧化钠、十二水磷酸钠、碳酸钾、碳酸氢钾、磷酸钠、碳酸氢钠、磷酸钾、三乙胺、吡啶和一水合氨中；所用的溶剂为二甲基亚砜、乙酸乙酯、甲醇、二氧六环、乙醇、四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、异丙醇和乙腈中之一或其中任意两种的混合物；反应在25-120℃之间进行。
本发明优点：本发明简单高效、绿色环保地合成了新型戊二酰亚胺类化合物，总收率达76％以上。该类化合物体外抗肿瘤活性试验表明：其对多种肿瘤细胞生长具有一定的抑制作用。化合物S4对乳腺癌细胞MCF7、前列腺癌细胞PC3、胃癌细胞MGC803和肝癌细胞HepG2的活性优于抗肿瘤药物5-氟尿嘧啶，可作为进一步开发的候选或者先导化合物，应用于制备抗肿瘤药物。
附图说明
图1为化合物(S4)的1H-NMR图；
图2为化合物(S4)的13C-NMR图谱。
具体实施方式
为对本发明进行更好地说明，举实施例如下：
化合物(S4)的制备
将3,4,5-三甲氧基苯胺(10mmol)和碳酸氢钾(12mmol)混合，加入15mL的乙腈，体系中加入4-甲氧基苄溴(12mmol)，升温到85℃反应6小时。不经分离纯化加入氯丙酰氯(12mmol)室温反应3小时。加入戊二酰亚胺(12mmol)和碳酸氢钾(12mmol)，补加10mL的乙腈，升温到85℃反应6小时。TLC监测反应进程，待反应结束后，向体系中加入蒸馏水，淬灭反应，然后用二氯甲烷萃取3次(每次20mL)，再用饱和食盐水萃取3次(每次20mL)，二氯甲烷有机相用无水硫酸镁干燥，滤除残渣，滤液减压蒸馏。所得粗产品用硅胶柱柱层析分离纯化，石油醚/乙酸乙酯＝10:1洗脱，得化合物(S4)。
化合物(S4)的抗肿瘤活性测定：
筛选所用化合物均是由本发明合成、纯化而得；样品储备液：称取1-2mg样品置于1mL EP管中，然后用DMSO配制成溶液，4℃保存放置，实验时根据所需浓度利用培养基稀释。取对数生长期的乳腺癌细胞MCF7、前列腺癌细胞PC3、胃癌细胞MGC803和肝癌细胞HepG2接种至96孔板中，培养24h后，弃去培养基，加入不同浓度的戊二酰亚胺衍生物。药物作用72h后，每孔加入20μL MTT，继续培养3h后，吸去液体，加入120μL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率，计算公式如下：抑制率(％)＝(1-给药组吸光度值/空白组吸光度值)×100％。试验结果采用SPSS软件计算IC50值。抗肿瘤药物5-氟尿嘧啶为对照品。其中，化合物S4对乳腺癌细胞MCF7、前列腺癌细胞PC3、胃癌细胞MGC803和肝癌细胞HepG2的活性优于抗肿瘤药物5-氟尿嘧啶，可应用于制备抗肿瘤药物，实验结果见表1。
表1化合物体外抗肿瘤IC50值
Claims (4)
1.新型戊二酰亚胺衍生物，其特征在于，具有如下通式所示结构：
2.如权利要求1所述的新型戊二酰亚胺衍生物，其特征在于，优选如下化合物之一：
3.如权利要求1所述的新型戊二酰亚胺衍生物在制备药物中的应用，其特征在于，将其做为活性成分用于制备抗肿瘤药物。
4.如权利要求1所述的新型戊二酰亚胺衍生物的制备方法，其特征在于，包括以下步骤：
(1)化合物(H)的制备方法：
溶剂中，将商业化的苯胺E和苄溴F在碱性条件下加热反应得到化合物G，不经分离纯化加入氯丙酰氯室温反应，制备化合物H。所用的碱是氢氧化钾、碳酸钠、氢氧化钠、十二水磷酸钠、碳酸钾、碳酸氢钾、磷酸钠、碳酸氢钠、磷酸钾、三乙胺、吡啶和一水合氨中的一种；所用的溶剂为二甲基亚砜、乙酸乙酯、甲醇、二氧六环、乙醇、四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、异丙醇和乙腈中之一或其中任意两种的混合物。
(2)通式(S1-S16)的制备方法：
溶剂中，化合物H和戊二酰亚胺在碱性条件下加热反应得到化合物S1-S16，所用的碱是氢氧化钾、碳酸钠、氢氧化钠、十二水磷酸钠、碳酸钾、碳酸氢钾、磷酸钠、碳酸氢钠、磷酸钾、三乙胺、吡啶和一水合氨中；所用的溶剂为二甲基亚砜、乙酸乙酯、甲醇、二氧六环、乙醇、四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、异丙醇和乙腈中之一或其中任意两种的混合物。
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