CN116602961A - 一类rumbrin类化合物在制备抗HIV药物中的用途 - Google Patents
一类rumbrin类化合物在制备抗HIV药物中的用途 Download PDFInfo
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Abstract
本发明属于生物医药领域，涉及到一类如通式(I)所示的rumbrin类化合物及其药学上可接受的盐在制备抗HIV药物中的应用。
Description
技术领域
本发明涉及生物医药领域，具体涉及到一类rumbrin类化合物或其医学上可接受的盐、含有这些化合物的药用组合物在抗HIV病毒等方面的应用。
背景技术
艾滋病(AIDS)又称获得性免疫缺陷综合征，是由人类免疫缺陷病毒(HIV)特异性感染和杀伤人体主要淋巴细胞所导致的传染性疾病，个体感染后由于免疫系统被破坏，易发生机会性感染和恶性肿瘤，病死率较高，且目前无彻底治愈的方法[1]。1987年首个抗HIV药物上市[2]，但是多年来随着艾滋病感染人数的急剧增加，全球在抗HIV药物领域投入了大量人力、财力，该领域始终是药物研发的热点之一。
艾滋病严重危害着人类的健康和社会的稳定，至今尚无有效治愈方法。高效抗反转录病毒治疗(highly active antiretroviral therapy，HAART)是目前AIDS的主要治疗方法，须终生服药。目前，AIDS治疗药物主要针对HIV生活周期中的3个关键酶，即反转录酶(reverse transcriptase，RT)、蛋白酶、整合酶(integrase，IN)，以及HIV入侵过程[3]。根据作用靶点的不同，可将抗HIV药物分为核苷类反转录酶抑制剂(nucleoside reversetranscriptase inhibitors，NRTI)、非核苷类反转录酶抑制剂(nonnucleoside reversetranscriptase inhibitors， NNRTI)、蛋白酶抑制剂(protease inhibitors，PI)、融合抑制剂(fusion inhibitors)、入胞抑制剂(entry inhibitors)或辅受体拮抗剂(CCR5 co-receptor antagonist)、整合酶抑制剂(HIV integrasestrand transfer inhibitors)六大类[4]。
Rumbrin最早是从澳大利亚土壤真菌Auxarthron umbrinum DSM3193中分离鉴定的真菌聚酮类化合物[5]。目前对rumbrin研究不多，已有的研究结果显示rumbrin类化合物在大脑细胞保护和肿瘤细胞毒活性方面具有良好活性。比如，rumbrin可以通过阻止细胞膜脂质过氧化和拮抗细胞内过载的钙离子来减轻组织损伤，与上市药品氟桂利嗪有着相当的细胞保护活性(1.3–40μg/mL，50％以上细胞有活力)，而抗脂质过氧化活性则表现出更显著的效果 (IC50＝0.47μg/mL vs 11.5μg/mL)[6]。此外，毒性实验结果显示A.umbrinum发酵物的甲醇粗提物水溶液以200mg/kg的剂量连续三天对小鼠给药没有明显毒性[7]。另一方面，rumbrin 结构类似物对癌细胞表现出显著的细胞毒活性[8][9][10]，但对人正常肺细胞没有细胞毒活性，细胞活性基本保持在90-100％[11]。到目前为止，还未见其有关抗HIV活性的报道。
本发明的发明人发现一类结构已知的rumbrin类化合物具有显著的抗HIV活性。文献检索显示，该类化合物的抗HIV活性未见文献报道，是一类新型抗HIV化合物，具有作为抗HIV候选药物开发的潜在应用价值。
参考文献:
[1]王霞,马洪涛,温瑞兴.抗HIV药物及其靶点的研究进展[J].中国中药杂志,2009, 34(11):1454-1459.
[2]冯婧劼,张庆文,徐云根.抗HIV-1药物及其复方制剂研究新进展[J].药学进展,2012, 36(12):539-546.
[3]杨文思,王洋.艾滋病治疗药物—HIV抑制剂作用机制及研究进展[J].现代生物医学进展,2012,12(23):4560-4565.
[4]Mehellou Y,De Clercq E.Twenty-six years of anti-HIV drugdiscovery:where do we stand and where do we go[J].J Med Chem,2010,53(2):521-538.
[5]Yamagishi Y,Shindo K,Kawai H.Rumbrin.a New CytoprotectiveSubstance Produced by Auxarthron umbrinum.II.Physico-Chemical Properties andStructure Determination[J].The Journal of Antibiotics,1993,46(6):888–891.
[6]Erik B,Jacqueline H,Walter J,et al.New Anti-Ischaemic Drugs:Cytoprotective Action with No Primary Haemodynamic Effects[J].Trends inPharacological Sciences 1989,10(10):397–400.
[7]Yamagishi Y,Matsuoka M,Odagawa A,et al.Rumbrin,a NewCytoprotective Substance Produced by Auxarthron umbrinum.I.Taxonomy,Production, Isolation and Biological Activities[J].The Journal ofAntibiotics,1993,466(6): 884–887.
[8]Benjamin R C,Robert J C,Ernest L,et al.Polyenylpyrroles andPolyenylfurans from an Australian Isolate of the Soil Ascomycete Gymnoascusreessii[J]. Organic Letters,2006,8(4):701–704.
[9]Robert S C,Matthew C W.Total Synthesis of Gymnoconjugatins A and B[J]. Journal of Chemistry,2006,71(26):9841–9846.
[10]Benjamin R C,Ernest L,Jennifer H G,et al.The Effect of HalideSalts on the Production of Gymnoascus Reessii Polyenylpyrroles[J].The Journalof Natural Products,2007,70(4):665–667.
[11]Fang Z,Liao P C,Yang Y L,et al.Synthesis and BiologicalEvaluation of Polyenylpyrrole Derivatives as Anticancer Agents Acting throughCaspases-Dependent Apoptosis[J].Journal of Medicinal Chemistry,2010, 53(22):7967–7978.
发明内容
本发明解决的技术问题是提供一类rumbrin类化合物及其药学上可接受的盐，以及其药物组合物在制备抗HIV病毒药物中的应用。
为解决本发明的技术问题，提供了如下技术方案：
本发明技术方案的第一方面是提供了一类Rumbrin类化合物及其药学上可接受的盐在预防、缓解和/或治疗HIV药物中的应用，其特征在于，所述化合物选自如下群组：
本发明技术方案的第二方面是提供了一种药物组合物在预防、缓解和/或治疗HIV药物中的应用，其特征在于，由有效剂量的第一方面中所述的化合物或其医学上可接受的盐和药学上可接受的载体或辅料组成。
本发明还涉及含有作为活性成分的本发明化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1～95％重量的本发明化合物。在单元剂型中本发明化合物一般含量为0.1～100mg，优选的单元剂型含有4～50mg。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目时，如果需要，可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为人药或兽药使用的适当的使用形式或剂量形式。
本发明化合物或含有它的药物组合物可以以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔黏膜、皮肤、腹膜或直肠等。本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其它剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂，也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
例如为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子，如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的载体。关于载体的例子，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、单硬脂酸甘油酯、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将本发明化合物与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明化合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇酯、脂肪酸等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成份的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围：本发明的化合物的用量为0.001～150mg/kg体重，优选为0.1～100mg/kg体重，更优选为1～60mg/kg体重，最优选为2～30mg/kg体重。成人患者服用的本发明化合物每日为10～500mg，优选为10～100mg，可一次服用或分2～3 次服用；儿童服用的剂量按照每kg体重5～30mg，优选为10～20mg/kg体重。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药，这受限于给药医生的临床经验以及治疗手段的给药方案。本发明的化合物或组合物可单独服用，或与其它治疗药物或对症药物合并使用。
有益技术效果：
本发明的发明人在对真菌A.umbrinum的次级代谢产物进行活性研究过程中，发现rumbrin类化合物具有显著抗HIV病毒活性。对这类化合物的抗病毒活性进行进一步的评价，发现该类化合物对HIV-1病毒复制具有强抑制活性。对HIV-1病毒抑制活性最高的化合物的 IC50值可以达到20.93±0.15nM。
具体实施方式
下面的实验实施例可进一步说明本发明，但不以任何方式限制本发明。
实施例1：对野生株进行发酵，并经提取分离可得到化合物1-8，具体操作过程如下：
对商业化的菌株Auxarthron umbrinum DSM3193分3组在富含棉籽粉的培养基中培养， 3天后分别饲喂3种不同的底物，吡咯-2-羧酸、4-氟-吡咯-2-羧酸和4-溴-吡咯-2-羧酸，7天后收集菌丝体，并加入适量EtOAc超声提取(1h/次×3次)，旋蒸得到粗膏，3组菌株分别得到M1，M2和M3等3个粗膏。对各个粗膏进行中压分离以及高效液相色谱HPLC纯化得到化合物1-8。
粗膏M1经ODS色谱柱进行中压制备，MeOH-H2O梯度洗脱(30:70，100:0，v/v)，得到15个馏分Fr.1–Fr.10。对Fr.6馏分进行高效液相色谱HPLC纯化，流动相体系为72％ MeOH-H2O，得到化合物1(1.8mg)2(1.8mg)和3(3.2mg)；对Fr.4馏分进行高效液相色谱HPLC纯化，流动相体系为70％MeOH-H2O，得到化合物4(2.8mg)和5(6.8mg)；对Fr.5馏分进行高效液相色谱HPLC纯化，流动相体系为53％MeCN-H2O，得到化合物6 (2.3mg)。
粗膏M2经ODS色谱柱进行中压制备，MeOH-H2O梯度洗脱(30:70，100:0，v/v)，得到7个馏分Fr.1–Fr.7。对Fr.4馏分进行高效液相色谱HPLC纯化，流动相体系为53％ MeCN-H2O，得到化合物7(2.1mg)。
粗膏M3经ODS色谱柱进行中压制备，MeOH-H2O梯度洗脱(30:70，100:0，v/v)，得到8个馏分Fr.1–Fr.10。对Fr.4馏分进行高效液相色谱HPLC纯化，流动相体系为70％ MeCN-H2O，分别得到化合物8(1.2mg)。
化合物1-8的波谱数据如下：
化合物1：红色无定形粉末；UV(MeCN)λmax:269,322,339,430nm；ESI-MS m/z 356[M-H]-；1H和13C NMR数据如表2和表4所示。
化合物2：红色无定形粉末；UV(MeCN)λmax:269,322,339,430nm；ESI-MS m/z 328[M-H]-；1H和13C NMR数据如表2和表4所示。
化合物3：红色无定形粉末；UV(MeCN)λmax(logε)268(4.36),319(4.16),334(4.25),434 (4.83)nm；IRνmax 3271,2959,2919,2851,2665,1703,1622,1536,1466,1408,1261,1096, 1033,864,801,722cm-1；ESI-MS m/z 344[M+H]+；1H和13C NMR数据如表2和表4所示。
化合物4：红色无定形粉末；UV(MeCN)λmax:269,322,339,430nm；ESI-MS m/z 294[M-H]-；1H和13C NMR数据如表2和表4所示。
化合物5：红色无定形粉末；UV(MeCN)λmax:269,322,339,430nm；ESI-MS m/z 322[M-H]-；1H和13C NMR数据如表3和表4所示。
化合物6：红色无定形粉末；UV(MeCN)λmax:265,322,339,429nm；ESI-MS m/z 330[M+H]+；1H和13C NMR数据如表3和表4所示。
化合物7：红色无定形粉末；UV(MeCN)λmax:271,326,340,436nm；ESI-MS m/z 342；1H 和13C NMR数据如表3和表4所示。
化合物8：红色无定形粉末；UV(MeCN)λmax:271,327,340,435nm；ESI-MS m/z 403[M+H]+；1H和13C NMR数据如表3和表4所示。
表2：化合物1-4的1H NMR数据
a 1-4在600MHz核磁共振波谱仪上测试，溶剂为DMSO-d6。
表3：化合物5-8的1H NMR数据
a 5和7在600MHz核磁共振波谱仪上测试，溶剂为DMSO-d6；b 6在800MHz核磁共振波谱仪上测试，溶剂为DMSO-d6；c 8在700MHz核磁共振波谱仪上测试，溶剂为DMSO-d6。
表4：化合物1-8的13C NMR数据
a 1-5和7在150MHz核磁共振波谱仪上测试，溶剂为DMSO-d6；b 6在200MHz核磁共振波谱仪上测试，溶剂为DMSO-d6；c 8在175MHz核磁共振波谱仪上测试，溶剂为DMSO-d6。
实施例2.化合物的抗HIV病毒活性评价
(1)实验方法
293T细胞(细胞浓度为2×105个/mL)与pHIT/G(0.4μg)和pNL4-3.Luc.R-E-(0.6μg) 共转染。48h后，通过过滤收集HIV-1假病毒，然后通过p24抗原捕获ELISA对病毒衣壳蛋白进行定量。所得病毒用于感染SupT1细胞(MOI＝1)，细胞浓度为2×105个/mL，然后加入待检测的连续稀释的化合物(efavirenz作为阳性对照)。在37℃、5％CO2的条件下进一步孵育48小时后，使用萤火虫荧光素酶测定系统测定抑制率。用细胞培养裂解缓冲液(Promega)裂解细胞，37℃处理20分钟。取10μL细胞裂解产物加入至40μL荧光素酶底物中，混匀， 960酶标仪测定荧光素酶活性，其活性强弱反应HIV复制水平强弱，结果见表4。
(2)实验结果
本发明研究了上述实施例中化合物1-8的抗HIV-1活性，结果发现这些化合物在10μM浓度下对HIV-1具有不同程度的抑制作用。其中化合物1、2、3、4和5的抑制率超过50％(表4)，其IC50在分别为20.93±0.15nM、53.06±4.03nM、171.07±1.24nM、250±10.0nM和3.94±0.47 μM。
表4.化合物抗HIV-1活性评价结果
Claims (4)
1.一类Rumbrin类化合物及其药学上可接受的盐在预防、缓解和/或治疗HIV药物中的应用，其特征在于，所述化合物选自如下群组：
2.一种药物组合物在预防、缓解和/或治疗HIV药物中的应用，其特征在于，由有效剂量的如下化合物或其医学上可接受的盐和药学上可接受的载体或辅料组成，所述的化合物如下所示：
3.根据权利要求2的应用，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂。
4.根据权利要求2的应用，其特征在于，所述的药物组合物选自缓释制剂、控释制剂及微粒给药系统。
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