CN116199704A - 一类大田软海绵酸衍生物及其制备方法和制备hiv潜伏激活药物的应用 - Google Patents
一类大田软海绵酸衍生物及其制备方法和制备hiv潜伏激活药物的应用 Download PDFInfo
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Abstract
本发明公开了一类大田软海绵酸衍生物及其制备方法和制备HIV潜伏激活药物的应用，OA衍生物的结构式为
化合物3不仅细胞毒性降低，而且HIV潜伏激活活性显著提升，EC50达46±13.5nM，机制研究表明3通过促进P‑TEFb从7SK snRNP中解离，以重新激活潜伏的HIV‑1，为OA衍生物的HIV潜伏激活药物开发提供了重要的线索和先导化合物。
Description
技术领域
本发明属于医药领域，具体涉及一类大田软海绵酸(okadaic acid,OA)衍生物的制备方法及其在HIV潜伏激活药物中的应用。
背景技术
HIV是对人类社会威胁巨大的一类疾病。虽然近年HIV的治疗和预防已经取得一定的进步，但仍未找到治愈的有效途径。因此针对该重大疾病的药物研发具有重要的社会意义和经济价值。目前国际上最为常用的HIV治疗方法是高效抗逆转录病毒疗法(HAART)。不过由于转录沉默的HIV-1前病毒会潜伏在静息期的CD4+T细胞中以逃过宿主的免疫反应和药物作用。潜伏HIV难以杀灭是寻求治愈HIV感染所面临的最大的一个障碍。因此，如何激活潜伏HIV病毒已成为HAART法治疗的关键。近来国际上兴起的艾滋病治疗新方法是“shockand kill”策略——即潜伏HIV转录激活与抗病毒药物联用，实施“Shock and Kill”方案最为关键的一点就是要找到一种特异且有效的方法来激活潜伏期的HIV，并且不广泛引起T细胞的激活。目前，世界上一些著名的制药公司(如Merck、Gilead Science等)和众多科研单位都致力于筛选能激活潜伏HIV转录的化合物。现已发现的小分子激活剂主要有组蛋白去乙酰化酶(HDAC)抑制剂、组蛋白甲基转移酶抑制剂、转录延伸因子激活剂和蛋白激酶C(PKC)激动剂等，然而在这些已知的HIV激活剂中，大多存在剂量限制等的安全问题、强细胞毒性或是未证实的临床效应。因此寻找高效、低毒的HIV激活剂在抗HIV新药研究中极具价值。
大田软海绵酸(okadaic acid,OA)为含有38个碳长链脂肪酸形成的聚醚类分子，最开始是从海洋海绵Halichondria okadai中分离得到，而后被鉴定为Dinophysis和Prorocentrum属甲藻产生。大田软海绵酸为腹泻性贝类毒素，不但危害海洋生态平衡，还会通过海洋食物链的富集威胁人类健康，是引起人类食用水生贝壳类发生腹泻性中毒的主要毒素。近年来，学者研究发现OA是多种丝氨酸/苏氨酸蛋白磷酸酶(PP)抑制剂，尤其是PP1和PP2A。因此，它经常被用作工具药来研究蛋白质可逆磷酸化调节的细胞过程，包括糖原代谢的控制、细胞周期和基因表达的协调以及细胞骨架结构的维持等。值得注意的是，有研究报导OA具有激活潜伏HIV病毒的活性。然而，由于它具有严重的毒性，限制了其开发成为HIV潜伏激活药物潜力。因此，对OA进行结构改造，获得新的OA衍生物，有望发现毒性降低、HIV潜伏激活活性显著的化合物，为HIV潜伏激活药物的开发提供基础。
现有技术中公开的专利申请文件及文献中，大田软海绵酸OA及其衍生物的应用集中在药理学研究的工具药，没有将其开发成为抗HIV药物的相关研究。
发明内容
本发明的目的在于克服现有技术的至少一个不足，提供一类低毒性的大田软海绵酸衍生物及其制备方法和制备HIV潜伏激活药物的应用。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
一类大田软海绵酸衍生物，具有38个碳长链脂肪酸形成的聚醚类分子骨架，其结构式如式Ⅰ所示：
或式Ⅰ所示化合物药学上可接受的盐、立体异构体、溶剂化物、配合物、酯化物、酰胺化物。
在一些大田软海绵酸衍生物的实例中，所述药学上可接受的盐选自化合物的酸或碱加成盐。
本发明的第二个方面，提供：
一种HIV潜伏激活组合物，包括载体和活性成分，所述活性成分选自本发明第一个方面所述一类大田软海绵酸衍生物中的至少一种。
在一些HIV潜伏激活组合物的实例中，所述组合物为口服制剂、注射制剂、吸入制剂或透皮制剂。
本发明的第三个方面，提供：
一种治疗HIV潜伏感染的组合物，包括载体、HIV抑制剂和HIV潜伏激活剂，所述HIV潜伏激活剂选自本发明第一个方面所述一类大田软海绵酸衍生物中的至少一种。
在一些组合物的实例中，所述组合物为口服制剂、注射制剂、吸入制剂或透皮制剂。
在一些组合物的实例中，所述HIV抑制剂选自齐多夫定、扎西他滨、依非韦伦、利匹韦林、奈非那韦、安泼那韦等中的至少一种。
本发明的第四个方面，提供：
本发明第一个方面所述一类大田软海绵酸衍生物在制备HIV潜伏激活剂中的应用。
本发明的第五个方面，提供：
本发明第一个方面所述一类大田软海绵酸衍生物，包括使用大田软海绵酸OA为原料，在其C-2,7,24,27位羟基进行酯化反应得到化合物2和3，
本发明的有益效果是：
本发明的一些实例，首次通过对大田软海绵酸OA进行结构修饰，制备得到一批新型的大田软海绵酸OA衍生物。
本发明一些实例的大田软海绵酸OA衍生物，发现化合物3不仅细胞毒性降低，而且HIV潜伏激活活性显著提升，EC50达46±13.5nM，机制研究表明3通过促进正性转录延伸因子b(P-TEFb)从7SK-小核核糖核蛋白复合物(7SK snRNP)中解离，以重新激活潜伏的HIV-1。发明人的研究为OA衍生物的HIV潜伏激活药物开发提供了重要的线索和先导化合物。
附图说明
图1至5分别为化合物2的核磁共振氢谱、碳谱和DEPT135谱、HSQC谱、HMBC谱、1H-1HCOSY谱图。
图5至10分别为化合物3的核磁共振氢谱、碳谱和DEPT135谱、HSQC谱、HMBC谱、1H-1HCOSY谱图。
图11为OA及其衍生物(1-3)的HIV潜伏激活活性评价结果及化合物3的初步机制研究。
具体实施方式
本发明得到了项目名称为“南方海洋科学与工程广东省实验室(珠海)”(编号SML2021SP301)的资助。
下面结合实施例对本发明作进一步详细描述，但本发明的实施方式不限于此。
下列实施例中所涉及化学试剂均可从商业渠道获得。
设备及试剂：
旋光度由Perkin-Elmer 341旋光仪测得。通过压片法在Bruker Tensor 37红外分光光度计中确定红外光谱。在Bruker AM-400/500光谱仪上测量了25℃下的NMR(核磁共振)谱。HRESIMS(高分辨电喷雾电离质谱)在Finnigan-LCQ Deca仪器上测量。采用岛津LC-20AT液相色谱、SPD-M20A型PDA检测器、Phenomenex Lux cellulose-2chiral柱(250×10mm,S-5μm,12nm)联用，组合成半制备型HPLC分离系统。硅胶(300-400目，青岛海阳化工有限公司)，反相C18(Rp-C18)硅胶(12nm，S-50μm、YMC有限公司)柱层析。所有溶剂均为分析纯(广州化学试剂有限公司)。通过岛津LC-20AT系列液相色谱系统和Inertsil ODS-SP柱(4.6mm×150mm,5μm or 4.6mm×100mm,5μm)测定样品的纯度。样品用90:10乙腈/水混合洗脱剂以3mL/min的流速洗脱。所有生物评价化合物的纯度大于95％。
大田软海绵酸OA从甲藻Prorocentrum lima PL11培养液中分离得到。
实施例1：化合物2的制备
将化合物OA1(10mg,0.0124mmol)溶于新蒸馏的吡啶(2mL)中，加入过量的丁酸酐。反应体系在室温下搅拌2小时。然后用2mL水淬灭。反应混合液真空旋蒸挥干溶剂后，通过半制备高效液相色谱(Phenomenex Lux cellulose-2chiral column,MeCN/H2O＝90:10,3mL/min)纯化，得到化合物2(3.6mg,tR 12.5min)。
结构确证：
白色粉末；OH-2,7,24,27-Tetrabutyrylated derivative of OA(2):Colorlessoil；
UV(MeCN):λmax(logε)196(4.84)nm；IR(KBr)νmax 2930,1737,1459,1381,1225,1181,1080,1000,975,878cm-1；1H NMR(CDCl3,500MHz)δH 5.74(1H,dd,J＝15.5,8.0Hz,H-14),5.62(1H,m,H-27),5.56(1H,dd,J＝15.5,7.4Hz,H-15),5.41(1H,brd,J＝10.3Hz,H-24),5.22(1H,s,H-9),5.02(2H,s,H-41a and 41b),4.78(1H,dd,J＝11.8,4.2Hz,H-7),4.42(1H,m,H-16),4.11(1H,d,J＝9.5Hz,H-26),4.10(1H,m,overlap,H-4),3.86(1H,m,H-22),3.69(1H,m,H-12),3.65(1H,m,H-38a),3.55(1H,m,H-38b),3.55(1H,t,J＝9.3Hz,H-23),3.30(1H,dd,J＝9.7,1.3Hz,H-30),2.38(1H,overlap,H-13),2.34(1H,m,H-3a),2.12(1H,m,overlap,H-17a),2.05(1H,m,H-6a),2.00(1H,m,H-32a),1.96(1H,m,H-18a),1.94(2H,m,overlap,H-11a and 20a),1.89(1H,m,overlap,H-3b),1.87(1H,m,overlap,H-36a),1.82-1.79(4H,m,overlap,H-11b,18b,20b,and21),1.75(2H,m,H-5a and 6b),1.73(2H,m,H-21a and 32b),1.68(3H,s,H-43),1.63(1H,m,overlap,H-35a；3H,s,H-44),1.59-1.56(5H,m,overlap,H-5b,17b,29,33b,and 36b),1.52-1.50(3H,m,overlap,H-28a,37a,and 37b),1.44(1H,m,overlap,H-35b),1.40(1H,m,overlap,H-33a),1.37(1H,m,overlap,H-21b),1.10(3H,d,J＝6.5Hz,H-42),1.09(3H,d,J＝6.5Hz,H-40),1.04(1H,m,overlap,H-28b),0.88(3H,d,J＝6.5Hz,H-39),for 2,7,24,27-O-butyryl:2.39-2.20(8H,m,overlap,H-2′,H-2″,H-2″′,and H-2″″),1.73-1.53(8H,m,overlap,H-3′,H-3″,H-3″′,and H-3″″),1.00-0.88(12H,t,overlap,H-4′,H-4″,H-4″′,and H-4″″)；13C NMR(CDCl3,125MHz)δC 172.1(C-1),140.5(C-25),139.0(C-12),133.7(C-14),131.4(C-15),120.7(C-9),112.4(C-41),105.9(C-19),95.6(C-8and 34),83.3(C-26),79.6(C-2),79.0(C-16),74.5(C-30),74.1(C-23),72.2(C-7),71.5(C-12),71.4(C-24),70.3(C-22),66.8(C-27),65.7(C-4),60.4(C-38),42.9(C-3),41.1(C-13),36.8(C-18),35.9(C-35),33.4(C-28),32.7(C-11and 20),31.7(C-5),31.1(C-29),30.5(C-17),30.3(C-33),27.3(C-31),26.3(C-32),26.2(C-21),25.4(C-37),23.9(C-6),22.9(C-43),22.1(C-44),18.2(C-36),16.3(C-40),16.2(C-42),10.6(C-39).For 2,7,24,27-O-butyryl:173.2,173.0,172.6,172.6(C-1′,C-1″,C-1″′,and C-1″″)；36.5,36.2,36.2,36.2(C-2′,C-2″,C-2″′,and C-2″″)；18.7,18.6,18.5,18.5(C-3′,C-3″,C-3″′,and C-3″″)；13.7,13.7,13.6,13.5(C-4′,C-4″,C-4″′,C-4″″)；HRESIMS m/z 1085.6418[M+H]+(calcd for C60H93O17 +,1085.6413)。
实施例2：化合物3的制备
将化合物OA 1(10mg,0.0124mmol)溶于新蒸馏的吡啶(2mL)中，加入过量的噻吩甲酰氯。反应体系在室温下搅拌1小时。然后用2mL水淬灭。反应混合液真空旋蒸挥干溶剂后，通过半制备高效液相色谱(Phenomenex Lux cellulose-2chiral column,MeCN/H2O＝90:10,3mL/min)纯化，得到化合物3(4.2mg,tR 11.3min)。
结构确证：
白色粉末；OH-2,7,24,27-Tetra-(thiophene-2-carbonylated)-derivative ofOA(3):Colorless oil；
UV(MeCN):λmax(logε)270(4.05),251(4.09),194(4.10)nm；IR(KBr)νmax 2926,1712,1525,1417,1362,1259,1080,999,976,746cm cm-1；1H NMR(CDCl3,500MHz)δH 5.84(1H,m,H-27),5.77(1H,dd,J＝14.8,7.3Hz,H-14),5.57(1H,d,J＝9.0Hz,H-24),5.54(1H,overlap,H-15),5.23(1H,s,H-9),5.10(1H,s,H-41a),5.06(1H,s,H-41b),4.88(1H,dd,J
11.0,4.0Hz,H-7),4.47(1H,m,H-16),4.29(1H,d,J＝9.0Hz,H-26),4.24(1H,m,H-4),4.05(1H,m,H-22),3.74(2H,overlap,H-12and H-23),3.65(1H,m,H-38a),3.54(1H,m,H-38b),3.35(1H,d,J＝10.2Hz,H-30),2.50(1H,m,overlap,H-3a),2.42(1H,m,overlap,H-13),2.17(1H,m,overlap,H-6a),2.08(1H,m,overlap,H-3b),2.05(1H,m,overlap,H-17a),2.02(1H,m,overlap,H-11a),2.00(1H,m,H-32a),1.93(2H,m,H-6b and 18a),1.83(2H,m,overlap,H-11b and 36a),1.82(1H,m,overlap,H-31),1.78(2H,m,overlap,H-21a and32b),1.75(1H,m,overlap,H-18b；3H,s,H-44),1.67-1.65(5H,m,overlap,H-5a,5b,20a,28a,and H-29),1.60(3H,s,H-43),1.58(1H,m,overlap,H-35a),1.53-1.51(5H,m,overlap,H-17b,33a,36b,37a,and 37b),1.42(1H,m,H-35b),1.39-1.37(2H,m,overlap,H-21b and 33b),1.27(1H,m,H-20b),1.15(1H,m,overlap,H-28b；3H,d,J＝6.5Hz,H-40),1.10(3H,d,J＝6.5Hz,H-42),0.89(3H,d,J＝6.5Hz,H-39),for 2,7,24,27-O-thiophene-2-carbonyl:7.70-7.84(4H,m,overlap,H-3′,H-3″,H-3″′,and H-3″″),7.49-7.56(4H,m,overlap,H-5′,H-5″,H-5″′,and H-5″″),7.04-7.10(4H,m,overlap,H-4′,H-4″,H-4″′,andH-4″″)；13C NMR(CDCl3,125MHz)δC 176.6(C-1),139.9(C-25),139.6(C-12),133.6(C-14),131.4(C-15),120.2(C-9),113.3(C-41),106.0(C-19),95.6(C-8),95.5(C-34),83.4(C-26),80.4(C-2),79.1(C-16),74.5(C-30),74.0(C-23),73.6(C-7),72.6(C-24),71.6(C-12),70.3(C-22),67.8(C-27),65.9(C-4),60.5(C-38),42.9(C-3),41.0(C-13),36.7(C-18),35.8(C-35),33.5(C-28),32.4(C-11),31.9(C-5),31.6(C-20),31.1(C-29),30.3(C-17and 33),27.4(C-31),26.2 26.2(C-21and 32),25.4(C-37),24.0(C-6),22.9(C-43),22.7(C-44),18.7(C-36),16.3(C-40),16.0(C-42),10.6(C-39).For 2,7,24,27-O-thiophene-2-carbonyl:161.6,161.6,161.3,161.0(C-1′,C-1″,C-1″′,and C-1″″)；133.9,133.9,133.6,133.3(C-3′,C-3″,C-3″′,and C-3″″)；133.9-133.0(C-2′,C-2″,C-2″′,and C-2″″)；132.8,132.7,132.5,132.5(C-5′,C-5″,C-5″′,and C-5″″)；128.0,127.7,127.7,127.6(C-4′,C-4″,C-4″′,and C-4″″)；HRESIMS m/z 1245.4039[M+H]+(calcd for C64H77O17S4 +,1245.4044)。
实施例3：基于流式细胞术的HIV潜伏逆转活性筛选实验-考察化合物对HIV的潜伏激活作用
Jurkat 2D10细胞模型为基于Jurkat细胞建立的含稳定转染HIV基因元件的HIV潜伏模型细胞，本实验采用该细胞模型进行研究。Jurkat 2D10细胞接种于24孔板中，密度为2×105个细胞/孔。空白对照组给予含有DMSO的完全培养基，阳性药组给药prostratin，化合物组给药相应浓度化合物(DMSO配制)。继续培养24h后，细胞被收集，然后用PBS清洗两次，最后用流式细胞仪ATTUNE NXT(Thermo,USA)对2D10细胞活力和表达绿色荧光蛋白GFP细胞的比例进行分析。
结果如图11A和11B所示，图11A显示OA结构修饰制得的衍生物2和3的细胞毒作用都显著较低(细胞存活率达到80％)，其中OA衍生物3同时具有显著的HIV潜伏激活活性，而且活性强于原型化合物OA。图11B显示OA衍生物3的EC50达46±13.5nM。
实施例4：采用荧光报告实验进一步考察OA衍生物3的HIV的潜伏激活作用
NH1和NH2为基于Hela细胞建立的含稳定转染HIV基因元件的HIV基因转录模型细胞，本实验采用该细胞模型进行研究。对数期NH1和NH2细胞接种于24孔板中，密度为2×105个细胞/孔，培养12h。空白对照组给予含有DMSO的完全培养基，化合物组给药相应浓度化合物3，继续培养12h。细胞裂解后用试剂盒E1501进行检测。
如图11C和11D所示，OA衍生物3能够浓度依赖的激活潜伏HIV，该实验对OA衍生物7的活性进一步验证。
实施例5：采用免疫共沉淀实验探究OA衍生物3的HIV的潜伏激活作用初步机制
实验方法：1、洗涤anti-Flag(M2)Affinity Gel：根据细胞量吸取一定量的Affinity Gel，加入1mL预冷的buffer D 0.3(现用时加入DTT和PMSF)洗涤，4℃条件下1000g离心1min，尽量吸弃上清洗涤液，然后重复上述洗涤步骤；2、Affinity Gel结合核抽提总蛋白(NE)：加NE到洗涤过的Affinity Gel，充分混匀，并在摇床4℃旋转孵育过夜，使Affinity Gel上的anti-Flag抗体充分与目的融合蛋白结合；3、洗涤杂质：将上述样品4℃条件下1000g离心1min，上清收集在另外的管中(结果异常时便于分析原因)，加入1mL预冷的buffer D 0.3，4℃摇床下摇3min，1000g离心1min，重复此步骤2次；再加入bufferD 0.1，4℃摇床摇3min，1000g离心1min，重复此步骤1次，(最后一次加buffer D 0.1后，先吸掉大部分上清，再用扁嘴枪头沿管壁伸到Affinity Gel中去吸掉上清)；4、Flag Peptides竞争性洗脱目的结合蛋白：加入8μL的含1×Flag Peptides的buffer D 0.1到Affinity Gel中，用手指轻轻弹匀，在室温下孵育30min，以使目的蛋白被充分地洗脱下来；5、离心：用70％乙醇擦拭样品管底部，用粗的注射针先扎盖子，然后扎下样品管底部，再改用1mL注射针将针斜面插入到样品管底一半处，下套一个1.5mL的离心管于4℃下3000g离心1min；收集洗脱下的样品；6、再次加入7μL的含1×Flag Peptides的buffer D 0.1到Affinity Gel中，室温下孵育10min，离心收集样品，再加入4×SDS-PAGE上样缓冲液100℃煮样10min，Western blot检测实验结果。NH1和NH2为基于Hela细胞建立的含稳定转染HIV基因元件的HIV基因转录模型细胞，本实验采用该细胞模型进行研究。对数期NH1和NH2细胞接种于24孔板中，密度为2×105个细胞/孔，培养12h。空白对照组给予含有DMSO的完全培养基，化合物组给药相应浓度化合物3，继续培养12h。细胞裂解后用试剂盒E1501进行检测。
在被HIV感染的CD4+T细胞中，正性转录延伸因子b(P-TEFb)是刺激HIV-1基因表达的关键，它一种进化上保守的异二聚体细胞周期蛋白依赖性激酶(Cdk9/CycT1)。它被病毒转录反式激活子(Tat)招募，形成Tat-TAR-P-TEFb复合物，该复合物能够磷酸化RNA聚合酶II的C末端结构域(CTD)，最终促进HIV-1转录延长。而当感染的CD4+T细胞在潜伏期时，P-TEFb被隔离在抑制性7SK小核核糖核蛋白(7SK snRNP)复合物中，该复合物由7SK snRNA、P-TEFa、HEXIM1、LARP7和MePCE组成，P-TEF b的激酶活性被HEXIM1以7SK snRNA-依赖性方式抑制。这一机制有助于维持HIV前病毒潜伏期，因此7SK snRNP复合物的解离释放活性P-TEFb被用于LRA的研究。为了确定OA衍生物3是否诱导7SK snRNP复合物的解离，发明人在用OA衍生物3或DMSO处理的F1C2细胞中进行了抗flag免疫沉淀，并检查了免疫沉淀物中7SKsnRNP的成分。如图11E所示，用OA衍生物3处理后，MePCE、LARP7和HEXIM1在细胞核中的总表达没有改变。然而，OA衍生物3可以显著减少MePCE、LARP7或HEXIM1与CDK9之间的相互作用，而不减少CycT1和CDK9间的相互作用。这些结果表明，OA衍生物3可以促进活性P-TEFb从7SKsnRNP释放，以重新激活HIV-1基因转录延长。
以上是对本发明所作的进一步详细说明，不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的简单推演或替换，都在本发明的保护范围之内。
Claims (9)
1.一类大田软海绵酸衍生物，具有38个碳长链脂肪酸形成的聚醚类分子骨架，其结构式如式Ⅰ所示：
或式Ⅰ所示化合物药学上可接受的盐、立体异构体、溶剂化物、配合物、酯化物、酰胺化物。
2.根据权利要求1所述的一类大田软海绵酸衍生物，其特征在于，所述药学上可接受的盐选自化合物的酸或碱加成盐。
3.一种HIV潜伏激活组合物，包括载体和活性成分，其特征在于，所述活性成分选自权利要求1或2所述一类大田软海绵酸衍生物中的至少一种。
4.根据权利要求3所述的HIV潜伏激活组合物，其特征在于，所述组合物为口服制剂、注射制剂、吸入制剂或透皮制剂。
5.一种治疗HIV潜伏感染的组合物，包括载体、HIV抑制剂和HIV潜伏激活剂，其特征在于，所述HIV潜伏激活剂选自权利要求1或2所述一类大田软海绵酸衍生物中的至少一种。
6.根据权利要求5所述的组合物，其特征在于，所述组合物为口服制剂、注射制剂、吸入制剂或透皮制剂。
7.根据权利要求5或6所述的组合物，其特征在于，所述HIV抑制剂选自齐多夫定、扎西他滨、依非韦伦、利匹韦林、奈非那韦、安泼那韦中的至少一种。
8.权利要求1或2所述一类大田软海绵酸衍生物在制备HIV潜伏激活剂中的应用。
9.权利要求1或2所述一类大田软海绵酸衍生物的制备方法，包括使用大田软海绵酸OA为原料，在其C-2,7,24,27位羟基进行酯化反应得到化合物2和3。
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