CN114149392B - 莪术烯含氮衍生物及其制备和应用 - Google Patents
莪术烯含氮衍生物及其制备和应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
本发明属于医药技术领域，涉及一系列莪术烯含氮衍生物及其制备和应用，具有如式Ⅰ结构，其中，NR1R2如权利要求和说明书所述。本发明还包括莪术烯含氮衍生物药学上可接受的盐和溶剂化物，以及含有所述莪术烯含氮衍生物或其药学上可接受的盐作为活性成分的药物组合物。本发明所述的莪术烯含氮衍生物及其药用盐类具有较好的抗癌活性，其制备方法简单可行，易操作。本发明还涉及合成莪术烯含氮衍生物中间体的制备方法。
Description
技术领域：
本发明涉及一系列新的莪术烯含氮衍生物及其制备和应用，还涉及该衍生物的盐类和以该衍生物或其盐类为活性成分的药物组合物，及其在制备治疗癌症药物中的应用，属于医药技术领域。
背景技术：
莪术油是传统中药温莪术的根茎挥发油，其制剂在临床上长期用于抗肿瘤、抗病毒等。莪术烯是莪术油的重要成分(周冲,刘慧俊,崔友,等.莪术油中莪术烯的分离及结构鉴定[J].烟台大学学报,2010,23(4):294-296.Costa J S,Barroso A S,Mourao R H V,etal.Seasonal and antioxidant evaluation of essential oil from eugenia unifloraL.,curzerene-rich,thermally produced in situ[J].Biomolecules,2020,10,328；doi:10.3390/biom10020328)。作为一种倍半萜类天然产物，莪术烯具有显著的抗肿瘤活性，对肺腺癌细胞SPC-A有增殖抑制作用，且呈时间依赖性和剂量依赖性。莪术烯能够诱导G2/M期阻滞及细胞凋亡，也可以通过下调GSTA1的表达，抑制SPC-A细胞的体内增殖能力。明显抑制SPC-A荷瘤裸鼠的肿瘤生长的同时，莪术烯对荷瘤裸鼠的体重和器官未见明显影响，具有较低的毒副作用，有望成为周期特异性治疗肺癌的一种天然单体化合物(Wang Y,Li J,GuoJ.et al.Cytotoxic and antitumor effects of curzerene from curcuma longa[J].Planta Medica.2017,83:23-29)。
目前对莪术烯的研究主要集中于提取分离技术和药理活性研究，对其进行结构改造方面的文献未见报道。
莪术烯水溶性差，限制了其临床应用。针对这一问题，本发明首次明确提出保持莪术烯的含双键的倍半萜骨架，在烯丙位甲基上引入亲水性的含氮基团，从而改善水溶性，提高抗肿瘤活性，合成了本发明所述莪术烯含氮衍生物，并经药理试验研究了其抗肿瘤活性。
发明内容：
本发明以莪术烯为先导化合物，为提高化合物的极性或亲水性、增强其抗癌活性，在烯丙位甲基碳原子上引入含氮结构，合成了莪术烯衍生物，并经药理试验证明可抑制多种肿瘤细胞增殖，它们的主要作用为抗肿瘤。
本发明提供莪术烯含氮衍生物结构如下式I：
其中，NR1R2为取代或未取代的5-6元杂环基、C1-C4烷基氨基、C3-C7环烷基氨基，所述取代基选自：C1-C12烷基、苯基、C1-C6烷氧基苯基、C2-C6烯基、C2-C6炔基、含有羟基的C1-C6烷基、含有苯基的C1-C6烷基；所述杂环基含有1-3个N、O或S的杂原子。
优选地，NR1R2为取代或未取代的哌嗪基、
C1-C4烷基氨基，所述取代基选自：C1-C6烷基、苯基、C1-C4烷氧基苯基、C2-C6烯基、C2-C6炔基、含有羟基的C1-C4烷基、含有苯基的C1-C4烷基。
更为优选地，NR1R2为取代或未取代的哌嗪基、
C1-C4烷基氨基，所述取代基选自：甲基、乙基、丙基、异丙基、甲氧基苯基、乙氧基苯基、苯基甲基、苯基乙基。
本发明优选自如下化合物：
本发明提供莪术烯含氮衍生物及其药用盐类的制备方法，其合成路线如下：
其中，NR1R2如权利要求所述。
优选：
本发明上述莪术烯含氮衍生物及其药用盐类的制备过程中所用溶剂为常用的反应溶剂，无特殊要求。
本发明提供了含上述莪术烯含氮衍生物及其药用盐类，所述的药用盐为与合适的非毒性有机酸或无机酸成的盐。如盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、乙酸、酒石酸、水杨酸、甲磺酸、丁二酸、柠檬酸、苹果酸、乳酸、富马酸、马来酸等。
本发明提供了一种药物组合物，所述组合物由上述的莪术烯含氮衍生物及其药用盐类和药学上可被接受的赋形剂组成。本发明还提供了莪术烯含氮衍生物及其药用盐类及其组合物在制备抗肿瘤药物中的用途，所述的肿瘤为宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、淋巴癌、慢性髓原白血病、原髓细胞白血病。
本发明所描述的莪术烯含氮衍生物，是为改善莪术烯的水溶性和提高抗癌活性，而在其分子中引入含氮基团所合成的化合物，这些衍生物可能具有更强的生理活性和较大极性，其氨基便于和酸成盐来达到改善水溶性的目的。
本发明的莪术烯含氮衍生物及其药用盐类具有较好的抗癌活性，其制备方法简单可行，易操作。
具体实施方式：
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围。
实施例1
的合成
加入13.00mmol莪术烯和20.00mmol冰醋酸加到15mL二氯甲烷中，冰浴下缓慢滴加40.00mmol次氯酸钠水溶液(含有效氯8％)。加毕继续反应20min。加10mLNa2SO3水溶液，分出有机层，水层用二氯甲烷萃取，合并有机相，用水和饱和氯化钠洗涤，无水硫酸钠干燥。过滤除去干燥剂，滤液浓缩得淡黄色油状物，收率76.3％。
实施例2
的合成通法
将1.80mmol实施例1产物和2.50mmol碳酸钾加到10mL丙酮中。搅拌下滴加2.00mmol胺类化合物，加热回流反应2-3h。减压蒸除丙酮，加入10mL饱和氯化钠，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥。过滤除去干燥剂，滤液浓缩得化合物1-10。
按此合成方法得到：
化合物1：黄色油状物。ESI-MS m/z:301.2[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.17(1H,s),5.87(1H，dd，J＝10.6，17.7Hz),5.05-4.68(4H,m),3.12-2.11(15H,m),1.86(3H,s),1.01(3H,s)。
化合物2：黄色油状物。ESI-MS m/z:315.2[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.16(1H,s),5.87(1H,dd,J＝10.8,17.8Hz),5.01-4.71(4H,m),3.10-2.15(18H,m),1.87(3H,s),1.02(3H,s)。
化合物3：黄色油状物。ESI-MS m/z:343.3[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.18(1H,s),5.86(1H,dd,J＝10.8,17.7Hz),5.04-4.67(4H，m),3.10-2.13(16H,m),1.87(3H,s),1.63-0.55(9H,m).
化合物4：黄色油状物。ESI-MS m/z:377.3[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.10-6.52(6H,m),5.87(1H,dd,J＝10.5,17.7Hz),5.02-4.71(4H,m),3.08-2.15(15H,m),1.87(3H,s),1.00(3H,s).
化合物5：黄色油状物。ESI-MS m/z:407.3[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.15(1H,s),6.74-6.43(4H,m),5.86(1H,dd,J＝10.8,17.8Hz),5.02-4.70(4H,m)，3.74(3H,s),3.09-2.08(15H,m),1.86(3H,s),1.00(3H,s).
化合物6：黄色油状物。ESI-MS m/z:286.2[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.16(1H,s),5.87(1H,dd,J＝10.8,17.7Hz),5.03-4.72(4H,m)，3.07-2.10(11H,m),1.87(3H,s),1.73-1.49(4H,m),1.01(3H,s)。
化合物7：黄色油状物。ESI-MS m/z:300.2[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.16(1H,s),5.85(1H,dd,J＝10.6,17.7Hz),5.05-4.72(4H,m)，3.11-2.12(11H,m),1.86(3H,s),1.66-1.41(6H,m),1.02(3H,s)。
化合物8：黄色油状物。ESI-MS m/z:260.2[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.17(1H,s),5.86(1H,dd,J＝10.8,17.6Hz),5.02-4.72(4H,m)，3.09-2.10(13H,m),1.87(3H,s),1.01(3H,s)。
化合物9：黄色油状物。ESI-MS m/z:302.2[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.18(1H,s),5.87(1H,dd,J＝10.5,17.8Hz),5.02-4.70(4H,m),3.75-3.55(4H,m),3.10-2.12(11H,m),1.86(3H,s),1.00(3H,s).
化合物10：黄色油状物。ESI-MS m/z:405.3[M+H]+.1H NMR(300MHz,CDCl3)δ(ppm):7.35-6.50(6H,m),5.86(1H,dd,J＝10.8,17.7Hz),5.05-4.72(4H,m),3.14-2.07(19H,m),1.87(3H,s),1.00(3H,s).
实施例3
用MTT法测定了目标化合物对人肝癌细胞HepG2、人结肠癌细胞HCT116、人肺癌细胞A549、人黑色素瘤细胞A375-S2和人纤维肉瘤细胞HT-1080五类肿瘤细胞的增殖抑制作用。
1)贴壁细胞选用对数生长期的贴壁肿瘤细胞，用胰酶消化后，用含10％小牛血清的RPMI l640培养基配成5×104/ml的细胞悬液，接种在96孔培养板中，每孔100μl，37℃，5％CO2培养24h。实验组更换新的含不同浓度被测样品(10～100μmol·L-1)的培养液，对照组则更换含等体积溶剂的培养液，每组设3个平行孔，37℃，5％CO2培养48h。弃去上清液，用PBS小心洗2次，每孔加入100μl新鲜配制的含0.5mg/ml MTT的培养基，37℃继续培养4h。小心弃去上清，并加入150μl DMSO，用微型振荡器混匀10min后，用酶标仪在492nm处测定光密度值(OD)。
2)悬浮细胞选用对数生长期的细胞，用含10％小牛血清的RPMI l640培养基配成1×104/ml的细胞悬液，接种在96孔培养板中，每孔50μl，37℃，5％CO2培养24h。实验组加入含不同浓度被测样品(10～100μmol·L-1)的培养液50μl，对照组则加入含等体积溶剂的培养液，每组设3个平行孔，37℃，5％CO2培养48h，每孔加入10μl新鲜配制的含5mg/ml MTT的培养基，37℃继续培养4h。用三联液(SDS 10g，10M HCl 0.1mL，异丁醇5mL，用蒸馏水稀释至100mL)100μl溶解结晶，37℃孵育12h。用酶标仪在492nm处测定光密度值(OD)。
按以下公式计算药物对肿瘤细胞体外增殖的抑制率(Inhibition Rate，IR％)：
IR％＝(1-ODsample/ODcontrol)×100％
用ICP1.0.0软件计算药物的半数抑制浓度(IC50)。
结果见下表，与莪术烯比较，所有目标化合物抑制五种肿瘤细胞株的IC50值均有所降低，因此在烯丙位甲基碳原子上引入含氮结构片段，可以提高体外抗肿瘤活性。
表1化合物1-10和莪术烯抑制肿瘤细胞增殖的IC50值
Claims (8)
1.一种莪术烯含氮衍生物及其盐，具有式I的结构：
2.如权利要求1所述的莪术烯含氮衍生物及其盐，其特征在于，
NR1R2为取代或未取代的哌嗪基、
、
、
、C1-C4烷基氨基，所述取代基选自：甲基、乙基、丙基、异丙基、甲氧基苯基、乙氧基苯基、苯基甲基、苯基乙基。
3.如下所述的莪术烯含氮衍生物及其盐，其特征在于，选自
4.如权利要求1-3任何一项所述的莪术烯含氮衍生物及其盐，其特征在于，所述的盐指酸加成盐，所述的酸为有机酸或无机酸，选自盐酸，氢溴酸，氢碘酸，硫酸，磷酸，硝酸，乙酸，酒石酸，水杨酸，甲磺酸，丁二酸，柠檬酸，苹果酸，乳酸，富马酸或马来酸。
5.一种药物组合物，其特征在于，包含权利要求1-4任何一项所述的莪术烯含氮衍生物及其盐和药学上可接受的赋形剂。
6.如权利要求1所述的莪术烯含氮衍生物及其盐的制备方法，其特征在于：
合成路线如下：
7.权利要求1-4任何一项所述莪术烯含氮衍生物及其盐或权利要求5所述的药物组合物在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的应用，其特征在于：所述的肿瘤为宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、淋巴癌、原髓细胞白血病。
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