CN105232500B - 萘茜衍生物在制备结核分枝杆菌丝氨酸/苏氨酸蛋白激酶抑制剂中的应用 - Google Patents
萘茜衍生物在制备结核分枝杆菌丝氨酸/苏氨酸蛋白激酶抑制剂中的应用 Download PDFInfo
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Abstract
本发明涉及药物化学领域，具体公开了萘茜衍生物在制备结核分枝杆菌丝氨酸苏氨酸蛋白激酶抑制剂中的应用。所述的萘茜衍生物具有通式(Ⅰ)所示的结构，(Ⅰ)其中，R1选自H、O、C1～C5烷基或无基团；R2选自H、O、C1～C5烷基或无基团；R3选自羟基、C1～C5烷氧基、C1～C5烷基、SCN基或卤素，R4选自羟基、C1～C5烷氧基、C1～C5烷基、SCN基或卤素。本发明所述的化合物具有显著的PKnG抑制活性，可开发为以PKnG为作用靶点的新型抗结核药物，具有良好的潜在应用价值。
Description
技术领域
本发明涉及药物化学领域，具体地说，涉及萘茜衍生物在制备结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G抑制剂中的应用。
背景技术
结核病仍然是世界上最致命的传染性疾病之一。在2013年，估计有900万人染上结核病，并有150万人死亡。每年新发病例高达800万，另一方面，在近40年来都没有新的抗结核病药物上市，严重影响结核病的治疗，所以抗结核药物的研发就变得愈发重要。
全球结核病控制当今面临着重大挑战。尤其是出现的结核分枝杆菌和艾滋病毒的合并感染(结核/艾滋病毒)以及在所有区域出现的耐多药和广泛耐药结核病，使疾病控制活动更趋复杂、更为艰巨。
结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G(PKnG)是结核分枝杆菌在感染宿主细胞后，分泌到宿主细胞内的毒力蛋白，能够干扰吞噬体的成熟以及与溶酶体的转运融合，防止MTB被溶酶体降解[Science,2004,304,1800(2004)]。因此，PknG对于MTB在宿主细胞内的“持留”状态发挥着重要的作用。以PKnG为靶点进行抗结核药物的筛选，对于研制出能控制多重耐药性结核杆菌和根除休眠菌的强力低毒抗结核药物非常关键。
发明内容
本发明的目的是提供萘茜衍生物在制备结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G抑制剂中的应用。
本发明上述目的通过以下技术方案予以实现：
本发明经过大量实验，发现萘茜衍生物能用于制备结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G抑制剂。
上述萘茜衍生物是指申请号为201410359129.1，公开号为CN104744226的中国发明专利所记载的。
所述萘茜衍生物的通式如(Ⅰ)，
其中，
R1选自H、O、C1～C5烷基或无基团；
R2选自H、O、C1～C5烷基或无基团；
R3选自羟基、C1～C5烷氧基、C1～C5烷基、SCN基或卤素；
R4选自羟基、C1～C5烷氧基、C1～C5烷基、SCN基或卤素；
当R1选自O时或R2选自O时，R1和R2为同一基团，在连接R3的碳原子与连接R4的碳原子之间形成环氧基；
当R1选自无基团时或R2选自无基团时，R1和R2同时为无基团，在连接R3的碳原子与连接R4的碳原子之间形成双键。
具体实施方式
以下结合实施实施例进一步解释本发明，但实施例并不对本发明做任何形式的限定。
本发明实施例中标号对应的萘茜衍生物的结构如下所示：
实施例1：萘茜衍生物的制备
化合物4a的合成：在25mL圆底烧瓶中加入200mg(1.05mmol,1equiv)萘茜，异戊二烯(5.25mmol，5equiv)，8mL冰醋酸，80℃油浴下回流反应20h，冷却，减压蒸馏除去溶剂，粗产品溶解在5mlNaOH(2M)溶液中，室温搅拌20min，冰水浴下调节pH至6-7，立即抽虑得滤饼。粗产物进行硅胶柱色谱分离，用乙酸乙酯：石油醚1：80(v/v)洗脱剂洗脱，得到4a。产率:84.5％；红色固体；mp:104.2-105.6℃；IR(KBr):νmax＝3385,1610cm-1.1H NMR(400MHz,cdcl3)δ12.52(s,2H),7.23(d,J＝27.5Hz,2H),5.55(s,1H),3.23(s,2H),3.12(d,J＝7.4Hz,2H),1.81(s,3H).ESI-MS m/z 255.64[M-H]-
化合物4b的合成：制备方法同实施例1，所不同的是用2,3-二甲基-1,3-丁二烯代替异戊二烯，得到化合物4b。产率:80.3％；红色固体；mp:173.2-174.5；IR(KBr):νmax＝3390，1605cm-1.1H NMR(400MHz,cdcl3)δ12.54(s,2H),7.20(s,2H),3.15(s,4H),1.77(s,6H)；ESIMS m/z 269.47[M-H]-.
化合物4c的合成：制备方法同实施例1，所不同用丁二烯代替异戊二烯，反应瓶换成25ml密封耐压瓶，得到化合物4c。产率:84.6％；红色固体；mp:179.2-180.0℃；IR(KBr):νmax＝3410，1606cm-1.1H NMR(400MHz,cdcl3)δ12.48(s,2H),7.17(d,J＝0.8Hz,2H),5.85(s,2H),3.20(s,4H)；ESI-MS m/z 241.47[M-H]-.
化合物5a,5b的合成：在10mL圆底烧瓶中加入0.2mmol化合物4，间氯过氧苯甲酸(0.32mmol，1.6equiv)，2mL氯仿，室温下反应0.5-1h，减压蒸馏除去溶剂，粗产物进行硅胶柱色谱分离，得到5a、5b。
5a产率:92.3％；棕红色固体；mp:153.4-154.1℃；IR(KBr):νmax＝3396,1603cm-1；1H NMR(400MHz,cdcl3)δ12.52(s,2H),7.21(s,2H),3.93(s,1H),3.15(d,J＝18.4Hz,1H),2.95(d,J＝18.2Hz,1H),2.67-2.51(m,2H),1.35(s,3H)；ESI-MS m/z 271.73[M-H]-.
5b产率:69.9％；棕红色固体；mp:158.0-158.8℃；IR(KBr):νmax＝3385，1610cm-1；1H NMR(400MHz,cdcl3)δ12.38(s,2H),7.12(s,2H),3.33(s,1H),3.28(s,1H),2.67(s,1H),2.62(s,1H),1.49(s,6H)；13C NMR(101MHz,cdcl3)δ185.73,158.57,141.39,129.57,111.39,60.51,30.03,19.24；HRMS(ESI-ion trap)m/z[M–H]-calcd forC16H13O5285.0769,found 285.0767
化合物6a,6b的合成：向25ml烧瓶中加入0.2mmol化合物5，NaHSO4(1mmol,5equiv),3mlCH2Cl2,常温搅拌6h，加蒸馏水1ml，继续反应0.5h。用二氯甲烷萃取，干燥，减压蒸馏除去溶剂，粗产物进行硅胶柱色谱分离，得到6a-6b。
6a 1,4,6,7-四羟基-6-甲基-5,6,7,8-四氢蒽-9,10-二酮。产率:76.03％；红色固体；mp:169.5-170.0℃；IR(KBr):νmax＝3401,1610cm-1；1H NMR(400MHz,cdcl3)δ12.61(s,2H),7.22(s,2H),4.22(t,J＝5.8Hz,2H),3.16(d,J＝16.9Hz,1H),2.95(d,J＝18.9Hz,1H),2.67(t,J＝17.3Hz,2H),1.60(s,3H)；ESIMS m/z 289.35[M-H]-.
6b 1,4,6,7-四羟基-6,7-二甲基-5,6,7,8-四氢蒽-9,10-二酮。产率:57.5％；红色固体；mp:182.6-183.5℃；IR(KBr):νmax＝3414.1601cm-1；1H NMR(400MHz,dmso)δ12.42(s,2H),7.33(s,2H),4.64(s,2H),2.50(s,4H),1.23(s,6H)；13C NMR(101MHz,dmso)δ186.54,157.28,143.79,129.42,111.31,70.32,35.23,22.81；HRMS(ESI-ion trap)m/z[M–H]-calcd for C16H15O6303.0874,found 303.0872.
化合物10a的合成：在10ml圆底烧瓶中加入化合物4a，2.5ml氯仿，剧烈搅拌下逐滴加入139μl三氟甲磺酸，5min后，加入3ml水，用氯仿萃取，干燥，减压蒸馏除去溶剂，粗产物进行硅胶柱色谱分离，得到化合物10a。产率：85.5％；红色固体；mp:86.5-87.1℃；IR(KBr):νmax＝3424.6,1605.8cm-1；1H NMR(300MHz,CDCl3)δ12.79(d,J＝0.5Hz,1H),12.60(d,J＝1.3Hz,1H),7.19(s,2H),6.60(s,1H),2.83(t,J＝9.9Hz,2H),2.36(t,J＝9.8Hz,2H),2.05(s,3H)；ESI-MS m/z 255.64[M-H]-.
化合物8ab的合成：向10ml烧瓶中加入0.2mmol化合物(5)，CeCl3·7H2O(0.1mmol,0.5equiv)，2ml CH3CN，常温搅拌12h，水洗，用氯仿萃取，干燥，过滤，减压蒸馏除去溶剂，粗产物进行硅胶柱色谱分离，得到目标物8ab。产率38.5％；红色固体；mp:173.9-174.6℃；IR(KBr):νmax＝3529.7,1610.5cm-1；1H NMR(400MHz,CDCl3)δ12.50(s,1H),12.48(s,1H),7.21(s,2H),4.17(t,J＝5.0Hz,1H),3.35(ddt,J＝19.9,4.8,2.3Hz,1H),3.16–3.08(m,1H),3.05–2.97(m,1H),2.79(d,J＝19.7Hz,1H),1.25(s,3H)；13C NMR(101MHz,CDCl3)δ185.31,185.13,159.40,142.61,141.28,135.42,130.01,120.75,111.59,70.78,61.10,34.10,30.93,29.85,25.49；HRMS(EI)m/z(M+H)+calcd for C14H10O5Cl 308.0446,found308.0444.
化合物14b的合成：向10ml烧瓶中加入0.2mmol化合物5b，20mgAmbertyst-15，2ML不同的醇溶液。然后将烧瓶放到超声清洗器的水浴锅中,反应0.5-1h，温度控制在24-28℃。过滤，减压蒸馏除去溶剂，粗产物进行硅胶柱色谱分离，得到14b。产率60.5％；红色固体mp:103.8-104.2℃；IR(KBr):νmax＝3423.7,1643.4cm-1；1H NMR(400MHz,CDCl3)δ12.52(d,J＝4.8Hz,2H),7.20–7.07(m,2H),3.38(dt,J＝7.7,3.9Hz,1H),3.24(dt,J＝7.9,3.8Hz,1H),2.93(t,J＝20.9Hz,2H),2.64(dd,J＝19.7,9.0Hz,2H),1.40(dd,J＝13.2,6.4Hz,2H),1.35(s,3H),1.29(s,3H),1.28–1.19(m,2H),0.81(td,J＝7.2,1.8Hz,3H)；13C NMR(101MHz,CDCl3)δ186.44,158.53,144.26,143.19,129.46,111.71,75.58,72.36,61.17,35.70,32.45,29.32,23.33,19.48,17.57,13.91；HRMS(ESI-ion trap)m/z[M–H]-calcd forC20H23O6359.1500,found 359.1498.
化合物F5a的合成：称取113.4mg的4a溶解于9ml丙酮与水的混合溶液(丙酮：水＝2：1)中，再加入1.88wt％的OsO4叔丁醇溶液0.2ml，50％的NMO水溶液0.8ml，室温搅拌6h后，TLC监测反应完全，加入Na2S2O3溶液(2ml,2M)搅拌1h后停止反应，减压蒸馏除去大部分丙酮，萃取，硫酸镁干燥，过滤，浓缩，柱层析分离提纯(EA:PE＝1:2)，得到62.3mg，产率48.7％。
MS(ESI,M-H:289.24)1H NMR(500MHz,DMSO)δ12.39(d,J＝2.5Hz,2H),7.36(s,2H),4.83(d,J＝5.1Hz,1H),4.51(s,1H),3.58(s,1H),2.73(s,2H),2.54(s,2H),1.17(s,3H).
实施例2：对实施例1中的化合物对结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G(PKnG)的抑制实验
采用ADP高通量激酶检测试剂盒ADP-GloTMKinase Assay Kit(Promega公司品)进行化合物抑制结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G的抑制实验，在200μlPCR管内加入一定量试剂盒中纯的ATP、激酶反应溶液、纯化的PKnG)，室温孵育20min,同时准备阳性对照、阴性对照和空白对照孔，本实施例所用抑制PKnG活性的阳性对照为AX20017,阴性对照为DMSO、ATP、PKnG蛋白，空白对照只加入DMSO、ATP，实验设计详见表1。10min孵育结束后，取5uL激酶反应溶液至新的已经加入5uLADP-GloTM试剂PCR管中，编号，ADP-GloTM试剂终止激酶反应，并且除去体系中剩余的ATP，反应40min之后加入试剂盒中的激酶检测试剂10uL，激酶检测试剂将反应体系中生成的ADP转化为ATP，使用偶联的萤光素酶/萤光素反应检测新合成的ADP的含量，反应一定时间之后将总体积20uL的PCR管内的溶液转移到384孔白板平底内，通过多功能酶标仪读出每个孔内的荧光读值。根据荧光读值按照一下计算方法算出各种化合物对PKnG酶活的抑制率：抑制率(％)＝1-(实验组-空白组)/(阴性对照组-空白组)。
表1化合物对PKnG的抑制酶活性分析体系表
表2萘茜衍生物的抗结核活性结果(IC50μM)
注：AX20017为阳性对照。
Claims (1)
1.萘茜衍生物在制备结核分枝杆菌丝氨酸/苏氨酸蛋白激酶G抑制剂中的应用；所述萘茜衍生物的通式如(Ⅰ)，
其中，
R1选自H、O、C1～C5烷基或无基团；
R2选自H、O、C1～C5烷基或无基团；
R3选自羟基、C1～C5烷氧基、C1～C5烷基、SCN基或卤素；
R4选自羟基、C1～C5烷氧基、C1～C5烷基、SCN基或卤素；
当R1选自O时或R2选自O时，R1和R2为同一基团，在连接R3的碳原子与连接R4的碳原子之间形成环氧基；
当R1选自无基团时或R2选自无基团时，R1和R2同时为无基团，在连接R3的碳原子与连接R4的碳原子之间形成双键。
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