CN110642869B - 二氢青蒿素的硫醚、亚砜与砜衍生物及其应用 - Google Patents

二氢青蒿素的硫醚、亚砜与砜衍生物及其应用 Download PDF

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CN110642869B
CN110642869B CN201910919541.7A CN201910919541A CN110642869B CN 110642869 B CN110642869 B CN 110642869B CN 201910919541 A CN201910919541 A CN 201910919541A CN 110642869 B CN110642869 B CN 110642869B
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thioether
sulfoxide
dihydroartemisinin
sulfone derivatives
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CN110642869A (zh
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杨大成
张书虹
范莉
刘建
唐雪梅
孟然然
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    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
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Abstract

本发明公开了式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物，式中，n为1或2，m为0时，Y为
Figure DDA0002217120010000011
或
Figure DDA0002217120010000012
n＝2，m＝0时，Y为
Figure DDA0002217120010000013
n为1或2，m为1或2时，Y为
Figure DDA0002217120010000014
或
Figure DDA0002217120010000015
R1、R2和R3各自独立地为H、卤素、C1‑C6烷基、C1‑C6烷氧基、羟基、氨基、C1‑C6烷胺基或C1‑C6烷酰胺基；还公开了所述二氢青蒿素的硫醚、亚砜与砜衍生物在制备抗疟药物、抗利什曼原虫药物、抗血管生成药物、抗肿瘤药物、降血脂药物或/和Wnt信号通路激动剂中的应用。

Description

二氢青蒿素的硫醚、亚砜与砜衍生物及其应用
技术领域
本发明属于药物合成技术领域，涉及一类二氢青蒿素的硫醚、亚砜与砜衍生物及其制药用途。
背景技术
二氢青蒿素(DHA)是青蒿素衍生物，具有高效、低毒的抗疟活性。近年来研究表明，双氢青蒿素及其衍生物还具有抗肿瘤、抗炎、抗组织纤维化等多种生物活性。
研究发现，有机含硫化合物是维持微生物、动物、植物正常生命活动不可或缺的一部分；蛋氨酸和维生素H是含有硫醚结构的天然产物；具有抗菌、杀虫、抗癌活性的大蒜素，具有抗真菌活性的Cyclobrassinine，具有显著抗HIV活性的Epicoccin等，都是从自然界中分离得到的含硫醚结构的有机含硫化合物；青霉素、头孢类药物都含有硫醚结构单元；2011年统计的全美Top200零售药物和处方药物中，含硫药物比例均高达25％左右。
在农用生物活性化合物中，亚砜/砜类衍生物以其良好杀虫、杀菌、除草、植物生长调节等各种生物活性，在农业上显示很大的应用价值。同时，亚砜/砜类化合物也是用于治疗许多疾病的重要药物。通过结构修饰，亚砜/砜类化合物能产生抗肿瘤、抗病毒、抗HIV-1、抗酸、抗溃疡、抗结核等生物活性。
发明内容
本发明的目的在于将一些具有杂环结构的硫醚、亚砜、砜类分子引入到二氢青蒿素结构中，设计合成一类结构新颖的二氢青蒿素的硫醚、亚砜与砜衍生物，并进行生物活性研究，希望获取具有某种生物活性的先导分子，为青蒿素类化合物的广泛研究和应用开发奠定基础。
经研究，本发明提供如下技术方案：
1.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐：
Figure BDA0002217118000000011
式I中，n为1或2，m为0时，Y为
Figure BDA0002217118000000012
n＝2，m＝0时，Y为
Figure BDA0002217118000000013
n为1或2，m为1或2时，Y为
Figure BDA0002217118000000021
R1、R2和R3各自独立地为H、卤素、C1-C6烷基、C1-C6烷氧基、羟基、氨基、C1-C6烷胺基或C1-C6烷酰胺基。
进一步，R1、R2和R3各自独立地为H、C1-C3烷基、C1-C3烷氧基、羟基、氨基、C1-C3烷胺基或C1-C3烷酰胺基。
进一步，R1、R2和R3独立地为H、甲氧基、氨基或乙酰氨基。
进一步，n为1或2，m为0时，Y为
Figure BDA0002217118000000022
n为2，m为0时，Y为
Figure BDA0002217118000000023
n为1或2，m为1或2时，Y为
Figure BDA0002217118000000024
Figure BDA0002217118000000025
2.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备抗疟药物中的应用。
进一步，所述抗疟药物为抗恶性疟原虫或/和伯氏疟原虫红外期的药物。
3.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备抗利什曼原虫的药物中的应用。
进一步，所述抗利什曼原虫的药物为抗杜氏利什曼原虫(Leishmania donovani)的药物。
4.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备抗血管生成的药物中的应用。
5.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备抗肿瘤药物中的应用。
进一步，所述抗肿瘤药物为具有K-ras/Wnt合成致死活性的药物。
进一步，所述肿瘤为结直肠癌。
6.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备降血脂药物中的应用。
进一步，所述降血脂药物为前蛋白转化酶枯草杆菌蛋白酶9(PCSK9)抑制剂。
7.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备Wnt信号通路激动剂中的应用。
进一步，所述Wnt信号通路激动剂为Wnt/β-连环蛋白信号通路激动剂。
除另有说明外，本发明中的术语“消旋体”是指由等量对映体构成的光学不活性的有机物。“立体异构体”是指原子组成及键接相同而原子在三维空间排列上不同的分子。“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。“氮氧化物”是指三级氮连接氧原子形成+N-O-结构单元的有机物。“药学上可接受的盐”可以是酸性盐，也可以是碱性盐，例如无机酸盐、有机酸盐、无机碱盐或有机碱盐。
本发明的有益效果在于：本发明将一些具有杂环结构的硫醚、亚砜、砜类分子引入到二氢青蒿素结构中，设计合成了一类结构新颖的二氢青蒿素的硫醚、亚砜与砜衍生物，生物活性测试结果显示，所述二氢青蒿素的硫醚、亚砜与砜衍生物具有多种生物活性，具有进一步开发为抗疟药物、抗利什曼原虫药物、抗血管生成药物、抗肿瘤药物、降血脂药物或/和Wnt信号通路激动剂的潜力。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚，下面将对本发明的优选实施例进行详细的描述。
优选实施例中使用的主要试剂及规格：二氢青蒿素(重庆华立武陵山制药有限公司,AR)；2-溴乙醇、3-溴-1-丙醇(上海达瑞精细化工有限公司,AR)；46.5％三氟化硼乙醚(BF3·Et2O)(上海晶纯试剂有限公司,AR)；5-甲氧基-2-巯基-1H-苯并咪唑(上海达瑞精细化学品有限公司,98％)；间氯过氧苯甲酸(成都爱斯特医药技术有限公司,AR)；15％过氧乙酸(双组份)(成都市科龙化工试剂厂,AR)；2-巯基苯并咪唑、2-巯基苯并噁唑、2-氨基-5-巯基-1,3,4-噻二唑和2-乙酰氨基-5-巯基-1,3,4-噻二唑均为自制；其余试剂均为市售化学纯或分析纯产品，未经纯化直接使用。
优选实施例中使用的主要仪器及型号：精密显微熔点测定仪(X-6,北京福凯仪器有限公司)；数字式自动旋光仪(WZZ-2S,上海精密科学仪器有限公司)；超导核磁共振波谱仪(AV-300,Bruker,瑞士)；高分辨质谱仪(HR ESI MS)(Varian7.0T,Varian,USA)。
实施例1.DHA的硫醚、亚砜与砜衍生物的合成
1.中间体M1的合成
Figure BDA0002217118000000041
中间体M1按照中国专利104418864B(双氢青蒿素与喹诺酮类化合物的偶联物及其制备方法和应用)中所述中间体IM1和IM2的制备方法进行制备。
2.DHA的硫醚衍生物8a的合成
Figure BDA0002217118000000042
在100mL圆底烧瓶中依次加入HS-Y、N,N-二甲基甲酰胺(DMF)和K2CO3，搅拌15min后，加入M1，控温搅拌反应，薄层色谱法(TLC)监测反应进程。反应完成后，加入乙酸乙酯(EtOAc)15mL和饱和NaCl水溶液20mL，静置分层，水层用EtOAc(2×10mL)萃取，合并有机相，饱和NaCl水溶液20mL洗涤,无水Na2SO4干燥，减压旋蒸除去EtOAc，柱层析纯化，干燥，即得目标化合物8a。具体合成条件及结果见表1。
表1目标化合物8a的合成条件及结果
Figure BDA0002217118000000043
Figure BDA0002217118000000051
目标化合物8a表征数据如下：
Figure BDA0002217118000000052
8a-1:黄色油状物；
Figure BDA0002217118000000053
1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝9.3Hz),0.94(3H,d,J＝6.3Hz),1.44(3H,s),1.23-2.05(10H,m),2.31-2.42(1H,m),2.59-2.69(1H,m),3.60(2H,t,J＝5.4Hz),3.79-3.86(1H,m),4.18-4.26(1H,m),4.86(1H,s),5.45(1H,s),7.22-7.32(2H,m),7.44(1H,d,J＝7.5Hz),7.60(1H,d,J＝7.8Hz)；13C NMR(75MHz,CDCl3)δ:164.7,151.9,141.9,124.3,123.9,118.3,109.8,104.1,102.2,88.0,81.0,66.6,52.5,44.3,37.4,36.3,34.5,32.7,30.8,26.1,24.6,24.3,20.3,12.9；HRMS:C24H31NO6S(M+Na)+计算值484.1764,测得值484.1763.
8a-2:m.p.:90.9-922℃；
Figure BDA0002217118000000054
1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.5Hz),0.94(3H,d,J＝5.7Hz),1.48(3H,s),1.23-2.10(10H,m),2.34-2.45(1H,m),2.60-2.69(1H,m),3.39-3.48(1H,m),3.55-3.63(1H,m),3.79-3.86(1H,m),3.97-4.04(H,m),4.82(1H,d,J＝3.3Hz,5.71(1H,s),7.21-7.24(2H,m),7.52-7.54(2H,m)；13C NMR(75MHz,CDCl3)δ:149.6,122.4,104.4,102.3,88.2,81.1,67.4,52.4,44.3,37.4,36.4,34.5,33.4,30.7,26.1,24.6,24.4,20.3,12.9；HRMS:C24H32N2O5S(M+Na)+计算值483.1924,测得值483.1921.
8a-3:m.p.:93.5-94.8℃；
Figure BDA0002217118000000055
1H NMR(300MHz,CDCl3)δ:0.92(3H,d,J＝7.2Hz),0.95(3H,d,J＝5.4Hz),1.48(3H,s),1.27-2.08(10H,m),2.35-2.46(H,m),2.61-2.70(H,m),3.34-3.43(1H,m),3.52-4.60(1H,m),3.86(3H,s),3.94-4.00(2H,m),4.82(1H,s),5.75(1H,s),6.87(1H,d,J＝9.0Hz),7.01(1H,s),7.42(1H,d,J＝8.4Hz)；13C NMR(75MHz,CDCl3)δ:156.2,148.8,137.5,126.9,111.5,107.0,104.3,102.3,97.3,88.1,81.1,67.4,55.8,52.4,44.3,37.4,36.4,34.5,33.6,30.8,26.1,24.6,24.3,20.3,12.9；HRMS:C25H34N2O6S[M+H]+计算值491.2210,测得值491.2212.
Figure BDA0002217118000000061
8a-4:m.p.:120.1-121.7℃；
Figure BDA0002217118000000062
1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.2Hz),0.96(3H,d,J＝6.0Hz),1.43(3H,s),1.22-2.06(10H,m),2.32-2.42(1H,m),2.56-2.67(1H,m),3.41(2H,t,J＝5.7Hz),3.70-3.77(1H,m),4.06-4.14(1H,m),4.82(1H,s),5.44(1H,s)；13C NMR(75MHz,DMSO and CDCl3)δ:103.3,101.3,87.2),80.4,66.1,52.0,43.8,36.7),35.9,34.6,34.1,30.3,25.6,24.1,23.8,20.0,12.6；HRMS:C19H29N3O5S2(M+Na)+计算值466.1441,测得值466.1440.
8a-5:m.p.:108.7-110.1℃；
Figure BDA0002217118000000063
1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.2Hz),0.94(3H,d,J＝6.0Hz),1.42(3H,s),1.22-2.05(10H,m),2.32-2.42(1H,m),2.49(3H,s),2.58-2.64(1H,m),3.44-3.57(2H,m7),3.75-3.81(1H,m),4.13-4.20(1H,m),4.84(1H,s2),5.42(1H,s),13.08(1H,s)；13C NMR(75MHz,CDCl3)δ:168.5,104.1,102.2,88.0,81.0,66.5,52.5,44.3,37.4,36.3,34.6,34.1,30.8,26.1,24.6,24.4,23.0 20.3,12.9；HRMS:C21H31N3O6S2(M+Na)+计算值508.1546,测得值508.1540.
8a-6:白色浆状物；
Figure BDA0002217118000000064
1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝9.3Hz),0.94(3H,d,J＝6.3Hz),1.44(3H,s),1.23-2.05(12H,m),2.31-2.42(H,m),2.59-2.69(H,m),3.60(2H,t,J＝5.4Hz),3.79-3.86(1H,m),4.18-4.26(1H,m),4.86(1H,s),5.45(1H,s),7.22-7.32(2H,m),7.44(1H,d,J＝7.5Hz),7.60(1H,d,J＝7.8Hz)；13CNMR(75MHz,CDCl3)δ:164.7,151.9,141.9,124.3,123.9,118.3,109.8,104.1,102.2,88.0,81.0,66.6,52.5,44.3,37.4,36.3,34.5,32.7,30.8,28.9,26.1,24.6,24.3,20.3,12.9；HRMS:C25H33NO6S(M+Na)+计算值498.1921,测得值498.1920.
Figure BDA0002217118000000065
8a-7:m.p.:128.9-130.2℃；
Figure BDA0002217118000000066
1H NMR(300MHz,CDCl3)δ:0.87-0.93(6H,m),1.43(3H,s),1.23-2.10(12H,m),2.32-2.41(1H,m),2.58-2.66(1H,m),3.41(2H,t,J＝6.9Hz,3.46-3.53(1H,m),3.94-4.02(1H,m),4.80(1H,d,J＝3.3Hz),5.43(1H,s),7.19-7.22(2H,m),7.51-7.54(2H,m)；13C NMR(75MHz,CDCl3)δ:160.2,148.1,128.4 114.8,104.4,102.3,88.2,81.1,67.4,52.4,44.3,37.4,36.4,34.5,33.430.7,29.3,26.1,24.6,24.4,20.3,12.9；HRMS:C25H34N2O5S(M+Na)+计算值497.2081,测得值497.2076.
8a-8:m.p.:85.2-87.3℃；
Figure BDA0002217118000000073
1H NMR(300MHz,CDCl3)δ:0.87-0.95(6H,m),1.48(3H,s),1.26-2.06(12H,m),2.32-2.41(1H,m),2.61-2.64(1H,m),3.32-3.43(2H,m),3.48-3.52(1H,m),3.83(3H,s,CH3),3.95-3.98(H,m),4.80(1H,s),5.42(1H,s),6.85(1H,d,J＝8.7Hz),7.03(1H,s),7.41(1H,d,J＝8.1Hz)；13C NMR(75MHz,CDCl3)δ:156.1,149.2,111.2,107.0,104.3,102.0,97.3,88.0,81.1,66.1,55.8,52.5,44.3,37.4,36.4,34.5,30.9,29.6,29.3 26.1,24.6,24.5,20.3,12.9；HRMS:C26H36N2O6S(M+Na)+计算值527.2186,测得值527.2186.
8a-9:m.p.:106.5-108.1℃；
Figure BDA0002217118000000074
1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.3Hz),0.96(3H,d,J＝5.7Hz),1.45(3H,s),1.13-2.17(12H,m),2.38(1H,td,J＝13.9,3.6Hz),2.57-2.71(1H,m),3.24(2H,t,J＝7.0Hz,CH 2),3.41-3.57(1H,m),3.90-4.08(1H,m),4.80(1H,d,J＝3.1Hz),5.40(3H,s)；13C NMR(75MHz,CDCl3)δ:164.02,162.55,104.06,101.93,87.84,81.02,66.10,52.44,44.26,37.35,36.50,34.49,31.41,30.82,29.62,26.10,24.56,24.46,20.29,12.99；HRMS:C26H36N2O6S(M+Na)+计算值492.1603,测得值492.1601.
Figure BDA0002217118000000071
8a-10:m.p.:87.3-88.4℃；
Figure BDA0002217118000000075
1H NMR(300MHz,CDCl3)δ:0.93(3H,d,J＝7.6Hz),0.95(3H,d,J＝7.2Hz),1.46(3H,s),1.13-2.12(12H,m),2.32-2.44(1H,m),2.47(3H,s,CH 3),2.60-2.68(1H,m),3.32(2H,t,J＝7.0Hz,CH 2),3.47-3.58(1H,m),3.96-4.05(1H,m),4.82(1H,d,J＝3.1Hz),5.41(1H,s),13.08(s,1H,NH)；13CNMR(75MHz,CDCl3)δ:168.75,164.03,163.15,104.06,101.95,87.80,80.94,66.04,52.40,44.22,37.38,36.28,34.47,31.32,30.76,29.16,26.07,24.55,24.45,20.25,12.95；HRMS:C22H33N3O6S2(M-H)-计算值498.1738,测得值498.1734.
3.DHA的亚砜与砜衍生物8b和8c的合成
Figure BDA0002217118000000072
方法一：在100mL圆底烧瓶中依次加入8a 1mmol、间氯过氧苯甲酸(mCPBA)、适量CH2Cl2至原料溶解，控温搅拌反应，TLC监测反应进程。反应完成后，加入5％Na2CO3水溶液15mL和EtOAc 15mL,静置分层，水层调节pH近中性后再用EtOAc萃取，合并有机相，无水Na2SO4干燥，减压旋蒸除去溶剂，柱层析纯化，干燥，即得目标化合物8b-1～8b-5和8c-1～8c-5。具体合成条件及结果见表2。
表2目标化合物8b-1～8b-5和8c-1～8c-5的合成条件及结果
Figure BDA0002217118000000081
方法二：在100mL圆底烧瓶中依次加入8a 1mmol、过氧乙酸(CH3CO3H)、适量CH2Cl2至原料溶解，控温搅拌反应，TLC监测反应进程。反应完成后，加入饱和NaCl水溶液15mL和EtOAc 15mL,静置分层，水层用EtOAc 10mL萃取，合并有机相，饱和NaCl水溶液10mL洗涤，无水Na2SO4干燥，减压旋蒸除去溶剂，柱层析纯化，干燥，即得目标化合物8b-6～8b-10和8c-6～8c-10。具体合成条件及结果见表3。
表3目标化合物8b-6～8b-10和8c-6～8c-10的合成条件及结果
Figure BDA0002217118000000082
Figure BDA0002217118000000091
目标化合物8b和8c表征数据如下：
Figure BDA0002217118000000092
8b-1:m.p.:89.4-91.6℃；
Figure BDA0002217118000000093
1H NMR(300MHz,CDCl3)δ:0.86-1.11(6H,m),1.46(3H,s),1.30-2.12(10H,m),2.31-2.44(1H,m),2.58(1H,m),3.49-3.67(2H,m),3.79-4.01(m,1H),4.37-4.52(m,1H),5.02(1H,d,J＝3.0Hz),5.32(1H,s),7.26(2H,dd,J＝5.8,2.9Hz),7.81(2H,m)；13C NMR(75MHz,CDCl3)δ:169.97,161.74,153.49,143.78,135.64,127.01,120.52,104.09,101.90,88.04,88.01,80.81,63.56,54.71,53.24,46.45,36.1935.21,33.54,30.08,25.30,23.51,23.20,22.12,12.32；HRMS:C24H32NO7S(M+H)+计算值478.1899,测得值478.1900.
8b-2:m.p.:89.3-91.7℃；
Figure BDA0002217118000000094
1H NMR(300MHz,CDCl3)δ:0.88-1.01(6H,m),1.45(3H,s),1.28-2.12(10H,m),2.34-2.43(1H,m),2.69(1H,m),3.53-3.65(2H,m),3.84-4.03(m,1H),4.30-4.54(m,1H),4.92(1H,d,J＝3.0Hz),5.52(1H,s),7.37(2H,dd,J＝5.8,2.9Hz),7.72(2H,m)；13C NMR(75MHz,CDCl3)δ:170.98,162.84,152.53,143.71,134.54,124.03,119.74,103.99,101.89,87.94,87.91,80.81,60.86,55.77,52.34,44.12,37.0936.22,34.40,30.72,25.92,24.50,24.20 20.16,12.73；HRMS:C24H32N2O6S(M+H)+计算值499.1873,测得值499.1874.
8b-3:m.p.:89.3-91.7℃；
Figure BDA0002217118000000101
1H NMR(300MHz,CDCl3)δ:0.85-0.99(6H,m),1.44(3H,s),1.20-2.12(10H,m),2.29-2.46(1H,m),2.62-2.74(1H,m),3.50-3.66(2H,m),3.89(3H,s),3.80-4.00(1H,m),4.29-4.49(1H,m,4.88(1H,s),5.52(1H,s),7.02(1H,d,J＝8.9Hz),7.13(1H,s),7.61(1H,d,J＝8.9Hz)；13C NMR(75MHz,CDCl3)δ:157.38 151.07,131.02,128.69,114.19,104.03,102.66,101.97,87.96,80.85,60.96,55.68,54.98,52.40,44.17,37.29,37.16,36.27,34.45,30.63,25.91,24.54,24.24,20.17,12.76；HRMS:C26H36N2O7S(M-H)-计算值519.2170,测得值519.2173.
Figure BDA0002217118000000102
8b-4:黄色浆状物；
Figure BDA0002217118000000103
1H NMR(300MHz,CDCl3)δ:0.88(3H,d,J＝7.3Hz),0.97(3H,d,J＝7.3Hz),1.45(3H,s),1.22-2.06(10H,m),2.31-2.47(1H,m),2.65-2.71(1H,m),3.40-3.47(2H,m),3.80-3.92(1H,m),4.24-4.32(1H,m),4.87(1H,d,J＝3.3Hz),5.48(1H,s),6.16(2H,s)；13C NMR(75MHz,CDCl3)δ:171.5,165.5,104.17,101.99,88.06,80.94,61.06,57.42,52.44,44.19,37.26,36.29,34.49,30.75,25.99,24.55,24.39,20.23,12.82；HRMS:C19H29N3O6S2(M-H)-计算值458.1425,测得值458.1425.
8b-5:m.p.117.4-120.3℃；
Figure BDA0002217118000000104
1H NMR(300MHz,CDCl3)δ:0.93-0.99(6H,m),1.45(3H,s),1.22-2.16(10H,m),2.32-2.45(1H,m),2.51(3H,s),2.65-2.76(1H,m),3.48-3.54(2H,m),3.88-3.97(1H,m),4.29-4.49(1H,m),4.89(1H,s),5.47(1H,s),12.76(1H,s,N-H)；13C NMR(75MHz,CDCl3)δ:168.75,104.13,102.83,101.99,87.91,80.87,61.03,57.06,52.41,44.11,37.36,37.24,36.24,34.46,30.70,26.00,24.35,22.99,20.27,12.78；HRMS:C21H31N3O7S2(M-H)-计算值500.1531,测得值500.1530.
8b-6:1H NMR(300MHz,CDCl3)δ:0.92(3H,d,J＝7.4Hz,H-14),0.95(3H,d,J＝5.4Hz),1.44(3H,s),1.13-2.13(12H,m),2.38(1H,td,J＝14.1,3.6Hz),2.58-2.75(1H,m),3.36-3.61(3H,m),4.02-4.07(1H,m),4.80(1H,s),5.38(1H,s),7.36-7.59(2H,m),7.67(1H,d,J＝7.1Hz),7.84(1H,d,J＝6.7Hz).
Figure BDA0002217118000000105
8b-7:m.p.:87.5-90.6℃；1H NMR(300MHz,CDCl3)δ:0.86-0.95(6H,m),1.42(3H,s),1.19-2.07(12H,m),2.30-2.43(m,1H),2.57-2.68(1H,m),3.33-3.55(3H,m),3.94-4.03(1H,m),4.77(1H,d,J＝3.4Hz),5.36(1H,s),7.37(2H,dd,J＝6.1,3.1Hz),7.71(2H,dd,J＝5.4,3.1Hz)；13C NMR(75MHz,CDCl3)δ:152.31,123.71,104.05,102.00,87.82,80.91,66.35,66.25,52.39,52.02,44.17,37.26,36.27,34.43,30.70,26.03,24.51,24.41,22.16,20.26,12.94；HRMS:C25H34N2O6S(M+Na)+计算值513.2030,测得值513.2033.
8b-8:m.p.:72.0-75.2℃；
Figure BDA0002217118000000111
1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.4),0.93(3H,d,J＝5.8Hz),1.42(3H,s),1.19-2.27(12H,m),2.36(1H,td,J＝14.0,3.3Hz),2.56-2.69(1H,m),3.28-3.57(3H,m),3.88(3H,s,OCH 3),3.95-4.05(1H,m),4.77(1H,d,J＝3.4Hz),5.35(1H,s),7.00(1H,d,J＝8.9Hz),7.11(1H,s),7.59(1H,d,J＝8.9Hz)；13C NMR(75MHz,CDCl3)δ:157.32,150.96,113.98,104.05,101.97,87.81,80.90,66.23,55.68,52.38,51.92,44.16,37.26,36.26,34.40,30.69,26.01,24.49,24.42,22.18,20.25,12.90；HRMS:C26H36N2O7S(M-H)-计算值519.2170,测得值519.2173.
8b-9:m.p.:77.7-80.1℃；
Figure BDA0002217118000000112
1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.3Hz),0.97(3H,d,J＝6.1Hz),1.44(3H,s),1.26-2.12(12H,m),2.38(1H,td,J＝14.0,3.8Hz),2.59-2.70(1H,m),3.26(2H,t,J＝7.5Hz),3.44-3.58(1H,m),3.94-4.06(1H,m),4.80(1H,s),5.38(1H,s),6.16(2H,s,NH 2)；13C NMR(75MHz,CDCl3)δ:171.63,164.61,104.16,102.00,87.88,80.97,66.22,53.34,52.35,44.13,37.30,36.25,34.39,30.73,26.00,24.52,24.44,22.11,20.24,12.95；HRMS:C20H31N3O6S2(M-H)-计算值472.1582,测得值472.1580.
Figure BDA0002217118000000113
8b-10:m.p.:108.3-111.4℃；
Figure BDA0002217118000000114
1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.3Hz),0.96(3H,d,J＝5.1Hz),1.44(3H,s),1.12-2.29(12H,m),2.38(1H,td,J＝13.9,3.8Hz),2.49(3H,s,CH 3),2.59-2.73(1H,m),3.32(2H,t,J＝7.3Hz),3.47-3.58(1H,m),3.97-4.09(1H,m),4.80(1H,d,J＝3.8Hz),5.38(1H,s),12.90(1H,s,NH)；13C NMR(75MHz,CDCl3)δ:171.13,168.71,163.15,104.08,101.93,87.83,80.85,66.11,53.83,52.34,44.11,37.36,36.24,34.40,30.68,26.03,24.53,24.44,22.97,20.23,12.95；HRMS:C22H33N3O7S2(M-H)-计算值514.1687,测得值514.1685.
8c-1:m.p.:91.5-93.7℃；
Figure BDA0002217118000000115
1H NMR(300MHz,CDCl3)δ:0.81(3H,d,J＝7.3Hz),1.02(3H,d,J＝5.7Hz),1.37(3H,s),1.26-2.09(10H,m),2.40(1H,m),2.52-2.68(1H,m),3.81-3.87(1H,m)4.01(2H,m),4.25-4.29(H,m),4.64(1H,d,J＝3.3Hz),5.53(1H,s),7.36(2H,dd,J＝6.2,3.1Hz),7.82(2H,dd,J＝5.5,3.2Hz)；13CNMR(75MHz,CDCl3)δ:151.48,127.31,103.43,101.51,84.92,78.81,64.29,54.73,51.23,42.91,37.21,36.26,32.54,31.09,23.99,24.45,22.85,21.01,12.31；HRMS:C24H31NO8S(M-H)-计算值492.1692,测得值492.1691.
8c-2:m.p.:93.3-95.7℃；
Figure BDA0002217118000000116
1H NMR(300MHz,CDCl3)δ:0.74(3H,d,J＝7.3Hz),0.92(3H,d,J＝5.7Hz),1.45(3H,s),1.16-2.04(10H,m),2.37(1H,m),2.51-2.66(1H,m),3.78-3.84(1H,m)3.91(2H,m),4.21-4.26(H,m),4.74(1H,d,J＝3.3Hz),5.49(1H,s),7.46(2H,dd,J＝6.2,3.1Hz),7.76(2H,dd,J＝5.5,3.2Hz)；13CNMR(75MHz,CDCl3)δ:147.48,125.23,104.24 102.31 87.99,80.93,61.39,55.21,52.25,43.97,37.02,36.23,34.27,30.50,25.96,24.45,23.83,20.21,12.51；HRMS:C24H32N2O7S(M-H)-计算值491.1858,测得值491.1857.
Figure BDA0002217118000000121
8c-3:m.p.:90.4-92.6℃；
Figure BDA0002217118000000122
1H NMR(300MHz,CDCl3)δ:0.75(3H,d,J＝7.3Hz),0.92(3H,d,J＝5.5Hz),1.45(3H,s),1.14-2.04(10H,m),2.37(H,m),2.52-2.65(H,m),3.73-3.97(3H,m),3.88(3H,s),4.22(1H,m),4.74(1H,d,J＝3.3Hz),5.49(1H,s),7.08(1H,d,J＝9.0Hz),7.10(1H,s),7.67(1H,d,J＝9.0Hz)；13C NMR(75MHz,CDCl3)δ:171.36,158.43,146.42,116.15,104.19,102.32,97.3,87.96,80.92,61.44,55.65,55.30,52.24,43.98,36.99,36.23,34.28,30.52,25.92,24.41,23.83,20.19,12.53；HRMS:C25H34N2O8S(M+Na)+计算值545.1928,测得值545.1922.
8c-4:m.p.:103.0-104.8℃；
Figure BDA0002217118000000123
1H NMR(300MHz,CDCl3)δ:0.88(3H,d,J＝7.2Hz),0.97(3H,d,J＝6.1Hz),1.44(3H,s),1.20-2.13(10H,m),2.38(1H,m),2.58-2.68(1H,m),3.76-3.98(3H,m),4.29-4.41(1H,m),4.82(1H,s),5.45(1H,s),6.38(2H,s,NH)；13C NMR(75MHz,CDCl3)δ:104.24,102.39,88.03,81.01,61.19,55.68,52.36,44.08,37.13,36.26,34.43,30.60,25.97,24.52,24.00,20.28,12.75；HRMS:C19H29N3O7S2(M-H)-计算值474.1374,测得值474.1370.
8c-5:m.p.:166.1-168.5℃；
Figure BDA0002217118000000124
1H NMR(300MHz,CDCl3)δ:0.86(3H,d,J＝7.3Hz),0.94(3H,d,J＝6.1Hz),1.43(3H,s),1.18-2.12(10H,m),2.37(1H,m),2.54(3H,s),2.58-2.68(1H,m),3.79-3.89(1H,m),3.93-4.01(1H,m),4.38(1H,m),4.80(1H,d,J＝3.3Hz),5.41(1H,s),12.88(1H,s)；13C NMR(75MHz,CDCl3)δ:168.75,164.03,163.13,104.10,102.53,87.96,80.78,61.18,55.95,52.38,44.03,37.18,36.25,34.44,30.51,29.58,25.95,24.51,24.00,20.22,12.64；HRMS:C21H31N3O8S2(M-H)-计算值516.1480,测得值516.1481.
Figure BDA0002217118000000125
8c-6:1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.4Hz),0.94(3H,d,J＝5.4Hz),1.44(3H,s),1.15-2.10(12H,m),2.34(1H,td,J＝14.1,3.6Hz),2.43-2.69(1H,m),3.31-3.43(3H,m),4.12-4.08(1H,m),4.78(1H,s),5.38(1H,s),7.32-7.49(2H,m),7.72(1H,d,J＝7.1Hz),7.90(1H,d,J＝6.7Hz).13C NMR(75MHz,CDCl3)δ:163.4,150.7,145.7,130.2,125.3,116.3,106.3,103.2,101.5,87.5,80.2,65.7,53.4,43.3,36.7,35.7,34.1,31.9,30.2,28.5,25.7,24.8,23.1,21.9,11.9；HRMS:C25H33NO8S(M+Na)+计算值530.1819,测得值530.1818.
8c-7:m.p.:87.5-90.6℃；
Figure BDA0002217118000000131
1H NMR(300MHz,CDCl3)δ:0.88(3H,d,J＝6.9Hz),0.94(3H,d,J＝6.0Hz),1.44(3H,s),1.19-2.27(12H,m),2.39(1H,td,J＝14.1,3.8Hz),2.60-2.69(1H,m),3.45-3.53(3H,m),3.85-3.92(1H,m),4.81(1H,d,J＝3.3Hz),5.44(1H,s),7.21(2H,s),7.73(2H,s)；HRMS:C25H34N2O7S(M-H)-计算值505.2014,测得值505.2013.
8c-8:m.p.:81.2-85.0℃；
Figure BDA0002217118000000132
1H NMR(300MHz,CDCl3)δ:0.88(3H,d,J＝7.3Hz),0.95(3H,d,J＝5.8Hz),1.41(3H,s),1.25-2.17(12H,m),2.37(1H,td,J＝14.0,3.8Hz),2.56-2.71(1H,m),3.40-3.51(1H,m),3.59(2H,t,J＝7.5Hz),3.89(3H,s,OCH3),3.91-3.99(1H,m),4.75(1H,d,J＝3.3Hz),5.37(1H,s),7.06-7.12(2H,m),7.68(1H,d,J＝8.9Hz)；13C NMR(75MHz,CDCl3)δ:158.46,145.89,116.18,104.14,101.94,87.86,80.94,65.59,60.42,55.69,52.35,44.12,37.26,36.26,34.36,30.70,25.95,24.48,24.40,23.09,20.23,12.88；HRMS:C26H36N2O8S(M-H)-计算值535.2120,测得值535.2125.
Figure BDA0002217118000000133
8c-9:m.p.:82.2-89.5℃；
Figure BDA0002217118000000134
1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.1Hz),0.97(3H,d,J＝5.8Hz),1.44(3H,s),1.13-2.22(12H,m),2.32-2.43(1H,m),2.64-2.70(1H,m),3.34-3.64(3H,m),3.92-4.00(1H,m),4.78(1H,s),5.38(1H,s),6.51(2H,s,NH2)；13C NMR(75MHz,CDCl3)δ:104.20,101.88,87.89,80.99,65.50,52.85,52.35,44.10,37.30,36.25,34.38,30.72,26.01,24.51,24.44,23.14,20.24,12.93；HRMS:C20H31N3O7S2(M-H)-计算值488.1531,测得值488.1537.
8c-10:m.p.:111.9-114.2℃；
Figure BDA0002217118000000135
1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.3Hz),0.97(3H,d,J＝5.9Hz),1.44(3H,s),1.27-2.22(12H,m),2.38(1H,td,J＝14.0,3.8Hz),2.54(3H,s,CH3),2.60-2.68(1H,m),3.42-3.62(3H,m),3.93-4.04(1H,m),4.78(1H,d,J＝3.3Hz),5.36(1H,s),12.80(1H,s,NH)；13C NMR(75MHz,CDCl3)δ:168.89,164.05,162.37,104.11,101.94,87.80,80.81,65.44,53.01,52.33,44.07,37.35,36.23,34.39,30.64,29.61,26.00,24.53,24.43,23.05,20.22,12.92；HRMS:C22H33N3O8S2(M-H)-计算值530.1636,测得值530.1639.
实施例2.DHA的硫醚、亚砜与砜衍生物的抗疟活性测试
疟疾是经按蚊叮咬或输入带疟原虫者的血液而感染疟原虫所引起的虫媒传染病。
DHA的硫醚、亚砜与砜衍生物的抗疟活性委托美国礼来公司Open InnovationDrug Discovery(OIDD)program进行测试，包括目标化合物对恶性疟原虫(Plasmodiumfalciparum)DD2株的抑制率、对人肝癌细胞HepG2中伯氏疟原虫(P.berghei)红外期(EEF)的抑制率以及对人肝癌细胞HepG2的毒性；首先进行单浓度初筛(Primary SP)，然后进行多浓度测试(Primary CRC)。结果见表4。
表4 DHA的硫醚、亚砜与砜衍生物的抗疟活性测试结果
Figure BDA0002217118000000141
Figure BDA0002217118000000151
Figure BDA0002217118000000161
由表4可以看出，测试化合物除8a-4外对恶性疟原虫均有极强的抑制活性(抑制率87％-117％)，其中化合物8a-3,8a-8,8b-4,8b-7,8b-9,8c-3,8c-8,8c-9在12.5μM测试浓度下的抑制率接近或超过100％；对伯氏疟原虫红外期的抑制活性相对低一些(30％-86％)，其中化合物8a-1,8a-2,8a-5,8a-7,8b-10,8c-4,8c-7,8c-8,8c-10的抑制率在60％-86％；且大部分化合物的细胞毒性低(抑制率小于30％)甚至没有毒性，具有进一步开发为抗疟药物特别是抗恶性疟原虫或/和伯氏疟原虫红外期药物的潜力。
实施例3.DHA的硫醚、亚砜与砜衍生物的抗利什曼原虫活性测试
利什曼原虫(Leishmania spp.)泛指利什曼虫属的锥体虫科原虫，是一种会引起利什曼病的寄生虫。利什曼原虫的主要宿主为脊椎动物，常见的感染对象包括蹄兔目、啮齿目、犬科和人类。利什曼病有三种主要形式：内脏性(最严重)、皮肤性(最常见)和粘膜皮肤性。其中内脏利什曼病也被称为黑热病，由杜氏利什曼原虫(Leishmania donovani)引起，其特征是发热、体重减轻、脾和肝肿大及贫血的无规律发作，在印度次大陆和东非是高发性地方病，如果不进行治疗，在超过95％的病例中是致死性的。皮肤利什曼病是内脏利什曼病的后遗症，通常在已明显治愈黑热病之后6个月至1年或多年出现，也可能会更早地发生，通常在身体的暴露部位引起皮肤病变，主要是溃疡，留下终身的疤痕和严重的残疾，主要发生在东非和印度次大陆，患有皮肤利什曼病的人被认为是潜在的黑热病感染源。目前利什曼病的治疗存在安全性/毒性(包括心脏毒性)、治愈率不完全、施用困难、治疗持续时间长、缺乏依从性且产生抗药性等问题。
DHA的硫醚、亚砜与砜衍生物的抗利什曼原虫活性委托美国礼来公司OpenInnovation Drug Discovery(OIDD)program进行测试。结果见表5。
表5 DHA的硫醚、亚砜与砜衍生物的抗利什曼原虫活性测试结果
Figure BDA0002217118000000171
Figure BDA0002217118000000181
从表5可知，测试化合物都能够抑制杜氏利什曼原虫(L.donovani)的生长，在5μM测试浓度下，有24个化合物的抑制率大于30％，14个化合物(8a-1,8a-2,8a-3,8a-8,8a-9,8a-10,8b-4,8b-7,8b-8,8c-1,8c-2,8c-8,8c-9,8c-10)的抑制率不低于50％，可作为抗利什曼原虫特别是抗杜氏利什曼原虫的药物进一步开发。
实施例4.DHA的硫醚、亚砜与砜衍生物的抗血管生成活性测试
在多种疾病的发病机制中均涉及到血管生成，包括实体瘤、眼内新生血管综合征如增殖性视网膜病变和年龄相关性黄斑变性等。与正常的组织细胞相比，在实体肿瘤中，新血管的生成能够使肿瘤细胞获得生长优势和自主增殖能力。同时，研究发现肿瘤切片中微血管密度与患者生存率之间存在一定联系。血管内皮生长因子(VEGF)在正常的血管生成以及肿瘤和眼科疾病相关的异常血管生成中均起着重要的调节作用。对VEGF信号通路的抑制可限制多种肿瘤的进展以及其他以血管异常增生为特点的并发症的发生与发展。
DHA的硫醚、亚砜与砜衍生物的抗血管生成活性委托美国礼来公司OpenInnovation Drug Discovery(OIDD)program进行测试。结果见表6。
表6 DHA的硫醚、亚砜与砜衍生物的抗血管生成活性测试结果
Figure BDA0002217118000000191
Figure BDA0002217118000000201
从表6可以看出，测试化合物大部分具有抗血管生成活性，其中4个化合物(8a-1,8a-7,8a-8,8c-7)在10μM测试浓度下的抑制活性大于50％，化合物8a-7的抑制活性最高达到106.7％；在2μM测试浓度下，化合物8a-7的抑制率同样超过100％；特别地，从抗血管生成IC50值看，化合物8a-1和8a-7均在1.5μM以下，可作为抗血管生成药物进一步开发。
实施例5.DHA的硫醚、亚砜与砜衍生物的K-ras/Wnt合成致死活性测试
合成致死(Synthetic lethality)是指2个非致死性基因同时突变引发死亡的一种基因互作现象。肿瘤细胞区别于正常细胞的一个重要特征是存在肿瘤相关基因的突变，寻找与肿瘤相关基因存在合成致死关系的基因并以此为靶标研发药物，干扰其活性，理论上能够高选择性地杀灭肿瘤细胞，为肿瘤治疗提供新的突破口。K-ras是一种原癌基因，长约35kb，位于12号染色体，是RAS基因家族成员之一，编码K-ras蛋白。K-ras蛋白具有分子开关作用，在很多信号通路中发挥重要作用。研究表明，体细胞K-ras基因突变与多种人类恶性肿瘤如肺癌、白血病、黏蛋白腺癌、胰腺癌、结直肠癌等有关，而生殖细胞K-ras基因突变与努南综合征和心脏-面部-皮肤(cardio-facio-cutaneous)综合征相关。Wnt信号通路激活是K-ras突变细胞的存活所必需的。
DHA的硫醚、亚砜与砜衍生物的K-ras/Wnt合成致死活性委托美国礼来公司OpenInnovation Drug Discovery(OIDD)program进行测试。结果见表7-1和7-2。
表7-1 DHA的硫醚、亚砜与砜衍生物的K-ras/Wnt合成致死活性测试结果
Figure BDA0002217118000000211
表7-2 DHA的硫醚、亚砜与砜衍生物的K-ras/Wnt合成致死活性测试结果
Figure BDA0002217118000000221
从表7-1和7-2可以看出，测试化合物对人结直肠癌细胞(DLD-1、HCT116、SW480)具有一定的K-ras/Wnt合成致死活性；对于癌细胞DLD-1，在20μM测试浓度下，有10个化合物的K-ras/Wnt合成致死抑制活性超过50％，其中化合物8a-1,8a-8,8a-10的抑制活性超过90％；对于癌细胞HCT116，在20μM测试浓度下的抑制活性低一些，但化合物8a-1～8a-3,8a-6,8a-9,8a-10的K-ras/Wnt合成致死抑制活性仍超过50％；对于癌细胞SW480，有9个化合物的抑制活性超过50％，其中化合物8a-1,8a-9,8a-10的K-ras/Wnt合成致死抑制活性超过80％；此外，化合物8a-1,8a-10对三种测试癌细胞均具有很强的K-ras/Wnt合成致死抑制活性，表现出结构优势。本发明是首次发现DHA的硫醚、亚砜与砜衍生物具有K-ras/Wnt合成致死抑制活性，可作为抗肿瘤药物进一步开发。
实施例6.DHA的硫醚、亚砜与砜衍生物的PCSK9抑制活性测试
PCSK9是由肝脏合成的蛋白酶，该酶经分子内自身催化切开后分泌入血，与肝细胞表面低密度脂蛋白受体(LDL-R)结合，促进LDL-R降解,致使低密度脂蛋白胆固醇(LDL-C)水平升高。PCSK9抑制剂被认为是继他汀类药物后的新一代降脂药物,其中获益最大的是在强化降脂治疗后LDL-C仍无法达标的高风险冠心病患者和无法耐受大剂量他汀类药物治疗的高胆固醇血症患者。
DHA的硫醚、亚砜与砜衍生物的PCSK9抑制活性委托美国礼来公司OpenInnovation Drug Discovery(OIDD)program进行测试。部分化合物的测试结果见表8-1和8-2。
表8-1 DHA的硫醚、亚砜与砜衍生物的PCSK9抑制活性测试结果(Eff-1)
Figure BDA0002217118000000231
表8-2 DHA的硫醚、亚砜与砜衍生物的PCSK9抑制活性测试结果(Eff-2)
Figure BDA0002217118000000241
表8-1测试了DHA的硫醚、亚砜与砜衍生物对人肝癌细胞HepG2分泌PCSK9的抑制率以及对HepG2细胞的毒性。表8-2采用AlphaLisa方法测试了部分DHA的硫醚、亚砜与砜衍生物对人肝癌细胞HuH7分泌PCSK9的抑制率，采用CellTiter-Glo试剂测试了部分DHA的硫醚、亚砜与砜衍生物对Huh7细胞的毒性。由表8-1和8-2可以看出，测试化合物大多数能抑制人肝癌细胞HepG2分泌PCSK9，其中8a-7、8b-10、8c-10的活性相对更强，且对HepG2细胞毒性较低或基本无毒性，尤其是8a-7，不仅在5μM测试浓度下对HepG2细胞分泌PCSK9的抑制率达到101.9％，还能抑制HuH7细胞分泌PCSK9，作为PCSK9抑制剂具有进一步开发为降血脂药物的潜力。
实施例7.DHA的硫醚、亚砜与砜衍生物的Wnt信号通路激动活性测试
Wnt信号传导途径是由配体蛋白质Wnt和膜蛋白受体结合激发的一组多下游通道的信号转导途径。经此途径，通过细胞表面受体胞内段的活化过程将细胞外的信号传递到细胞内。Wnt信号通路广泛存在于无脊椎动物和脊椎动物中，是一类在物种进化过程中高度保守的信号通路。Wnt/β-连环蛋白(β-catenin)途径是Wnt途径中的一种，该途径会使得β-catenin能够积聚并定位于细胞核，随后通过基因转导以及TCF/LEF(T细胞因子/淋巴增强因子)转录因子诱导Wnt最终作用的目标基因转录，诱导后续的细胞反应的发生。在人类胚胎干细胞、造血干细胞、肠道干细胞、皮肤干细胞内Wnt信号通路具有维持干细胞增殖和抑制分化的功能。另外进一步的研究也发现Wnt信号通路在肿瘤干细胞的增殖和分化中也表现出与正常干细胞相似的功能。因此，对Wnt信号通路的小分子调节剂(激动剂或抑制剂)的研究不仅具有重要的科研意义，还具有极大的潜力开发出以Wnt信号通路为靶向的药物。
DHA的硫醚、亚砜与砜衍生物的Wnt信号通路激动活性委托美国礼来公司OpenInnovation Drug Discovery(OIDD)program进行测试。部分化合物的测试结果见表9。
表9 DHA的硫醚、亚砜与砜衍生物的Wnt信号通路激动活性测试结果
Figure BDA0002217118000000251
Figure BDA0002217118000000261
表9测试了DHA的硫醚、亚砜与砜衍生物促进β-catenin蛋白在小鼠成肌细胞C2C12(Wnt条件培养基培养)的细胞核定位表达的活性。结果显示，测试化合物均能促进β-catenin蛋白在C2C12细胞核定位表达，其中8a-1和8a-7的活性相对更强，显示出较好的Wnt信号通路激动活性，具有进一步开发为Wnt信号通路激动剂的潜力。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离本发明权利要求书所限定的范围。

Claims (10)

1.式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐：
Figure FDA0003379665780000011
式I中，n为1或2，m为0时，Y为
Figure FDA0003379665780000012
n＝2，m＝0时，Y为
Figure FDA0003379665780000013
n为1或2，m为1或2时，Y为
Figure FDA0003379665780000014
R1、R2和R3各自独立地为H、卤素、C1-C6烷基、C1-C6烷氧基、羟基、氨基、C1-C6烷胺基或C1-C6烷酰胺基。
2.如权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐，其特征在于：R1、R2和R3各自独立地为H、C1-C3烷基、C1-C3烷氧基、羟基、氨基、C1-C3烷胺基或C1-C3烷酰胺基。
3.如权利要求2所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐，其特征在于：R1、R2和R3独立地为H、甲氧基、氨基或乙酰氨基。
4.如权利要求3所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐，其特征在于：n为1或2，m为0时，Y为
Figure FDA0003379665780000015
n为2，m为0时，Y为
Figure FDA0003379665780000016
n为1或2，m为1或2时，Y为
Figure FDA0003379665780000017
Figure FDA0003379665780000018
5.权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐在制备抗疟药物中的应用。
6.权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐在制备抗利什曼原虫的药物中的应用。
7.权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐在制备抗血管生成的药物中的应用。
8.权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐在制备抗肿瘤药物中的应用。
9.权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐在制备降血脂药物中的应用。
10.权利要求1所述的二氢青蒿素的硫醚、亚砜与砜衍生物或其互变异构体、药学上可接受的盐在制备Wnt信号通路激动剂中的应用。
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