CN105968134A - 一种Keggin结构杂多酸含磷有机盐类化合物、制备方法和应用 - Google Patents
一种Keggin结构杂多酸含磷有机盐类化合物、制备方法和应用 Download PDFInfo
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- YAGKRVSRTSUGEY-UHFFFAOYSA-Q hydron;iron(3+);hexacyanide Chemical compound [H+].[H+].[H+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] YAGKRVSRTSUGEY-UHFFFAOYSA-Q 0.000 description 1
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- C07F9/02—Phosphorus compounds
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- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract
一种Keggin结构杂多酸含磷有机盐类化合物、制备方法和应用，属于化学合成和药物应用领域。本发明化合物通式为A7PTi2W10O40，A为含磷和氮的有机阳离子，为具有Keggin结构的杂多酸化合物。通过钨酸钠、磷酸二氢钠溶解蒸馏水中，滴加四氯化钛，回流反应，过滤，向滤液中加入碱金属盐或氨基酸盐得白色沉淀物，沉淀物用热水重结晶，然后与含A基团的化合物或A化合物，调节至酸性，加热搅拌即可。化合物可作为制备抗艾滋病毒药物。
Description
技术领域
本发明属于化学合成和药物应用领域，具体涉及Keggin结构杂多酸含磷有机盐类化合物及其制备与该类化合物在制备抗艾滋病毒药物领域的应用。
背景技术
艾滋病(Acquired Immune Deficiency Syndrom,AIDS)是人类免疫缺陷病毒(Immunodeficiency Virus,HIV)引起的致死性传染病。自1981年在美国首次发现艾滋病以来，现今已在全球广泛流传。目前，尚无有效的疫苗和能根治的药物。近年来，相继报道一些较有希望的抗艾滋病药物，一是以抑制艾滋病毒逆转录酶为靶点的核苷类药物，另一个是以抑制艾滋病毒前体蛋白裂解为靶点的蛋白酶抑制剂。但这些药物都存在着较严重的毒性、耐药性和价格昂贵等缺点，作为有效药物的前景并不乐观。因此新型低毒高效的抗艾滋病药物研究刻不容缓。
杂多化合物的药物化学研究自70年代就有报道。80年代初，首次发现钨锑杂多化合物(NH4)17Na[NaSb9W21O86]，Moskovitz等人对其作为临床使用抗艾滋病药物的可行性进行了研究和论证，发现其能竞争性的抑制艾滋病毒的逆转录酶，但随后发现其能产生严重的毒副作用而停止临床使用。90年代初，Yamase等人报道了Keggin结构钨系杂多化合物，并发现其抗艾滋病毒(HIV-1)活性且毒性较低，其中较突出的是K7PTi2W10O40。近些年，美国的C.L.Hill报道含铌的杂多化合物(K7[P2W17(NbO2)O61]、K7[P2W17NbO62])能抑制艾滋病毒的蛋白酶。
磷属第五主族元素，是化学和生物学中最为重要的“软件元素”之一。进入本世纪后，生物学和生物化学领域几乎所有最重大的成就都与含磷和碳的化合物有着密切的联系，从而为磷化合物应用于医药领域开辟了十分诱人的天地，尤其是含磷有机化合物。由于其特殊生理性质，在抗肿瘤及抗病毒等领域广泛应用。杂环碱类膦酰烷基衍生物能抑制嘌呤核苷磷酸化酶，具有选择性的广谱抗DNA病毒和逆转病毒的作用。氨磷汀作为一种良好的抗肿瘤药物，可以在不影响治疗效果的前提下，保护病人的正常组织。含磷药物替诺福韦是一种新型核苷酸类逆转录酶抑制剂，可有效对抗多种病毒，用于治疗病毒感染性疾病，已被世界卫生组织推荐为艾滋病抗病毒一线药物。
迄今，在现有文献报道中还没有Keggin结构杂多酸含磷有机盐类药物作为有效成分在抗艾滋病毒方面的报道。
发明内容
本发明的目的之一在于提供一种抗病毒活性高、毒性低、价格低廉的抗艾滋病毒类药物化合物、制备方法。
本发明的目的之二在于提供一种制备上述药物的方法。
本发明的一种Keggin结构杂多酸含磷有机盐类化合物，其特征在于，通式为A7PTi2W10O40，A为替诺福韦、阿德福韦、环磷酰胺等含磷和氮的有机阳离子，为具有Keggin结构的杂多酸化合物；其阴离子PTi2W10O40结构中P为中心原子，通常以四面体(PO4)构型与四个氧原子连接，配原子Ti和W以八面体配位与周围六个氧原子结合。这种杂多酸化合物中的杂多酸阴离子具有如下一般特征：阴离子结构为笼型，分子量约为2605。该类化合物多数为粉末状固体，易溶于水或极性溶剂中，对酸碱稳定性较强。
进一步优选A阳离子选自C9H15N5PO4、C8H13N5PO4、C11H19NPO3、C11H18NPBrO3、C7H18N2PCl2O3或C5H16N2PSO3。
杂多酸含磷有机盐类化合物的制备方法，包括以下步骤：将二水钨酸钠、磷酸二氢钠溶解蒸馏水中，滴加四氯化钛，回流反应，过滤，向滤液中加入碱金属盐或氨基酸盐得白色沉淀物，沉淀物用热水重结晶，得到化合物B7PTi2W10O40，其中B为碱金属或氨基酸阳离子；将B7PTi2W10O40溶于蒸馏水中，加入含A基团的化合物或A化合物，调节至酸性，加热搅拌，得到固体A7PTi2W10O40。
其中优选：将二水钨酸钠：磷酸二氢钠：蒸馏水中：四氯化钛：碱金属盐或氨基酸盐的用量关系为91mmol：43mmol：100mL：16mmol：4.1mol。
采用本发明的一种Keggin结构杂多酸含磷有机盐类化合物作为制备抗艾滋病毒药物时，具有活性高，具有较低的细胞毒性，安全性高。
附图说明
图1为PTi2W10O40 7-X射线单晶衍射结构图；
图2为化合物在TZM-bl细胞上抗HIV-1药效图；
图3为CCK8法细胞毒性结果图。
具体实施方式
下面结合实施例对本发明作进一步说明，但本发明并不限于以下实施例。
实施例1(PZ-1的制备)
二水钨酸钠91mmol、磷酸二氢钠43mmol溶解在100mL的蒸馏水中，滴加16mmol的四氯化钛，回流反应30min，过滤，向滤液中加入4.1mol固体KCl得白色沉淀物，沉淀物用热水重结晶，得到固体K7PTi2W10O40。将10mmol K7PTi2W10O40溶于100mL水中，加入100mmol替诺福韦，调节pH值为4.0，加热至60℃，反应3h，放置一段时间后得到白色固体(C9H15N5PO4)7PTi2W10O40。
1H NMR(400MHz,DMSO-d6):δH(ppm)1.020(d,3H),3.590(m,2H),3.909(m,1H),4.255(m,2H),8.133(s,1H),8.147(s,1H),9.271(s,3H),10.960(s,2H).元素分析(4622.24):calcd(％):C,16.36；N,10.61；P,5.36；Ti,2.07；W,39.76；found(％):C,16.43；N,10.68；P,5.33；Ti,2.02；W,39.69.PTi2W10O40 7-X射线单晶衍射结构图见图1，晶体基本参数见表1。
实施例2(PZ-2的制备)
二水钨酸钠91mmol、磷酸二氢钠43mmol溶解在100mL的蒸馏水中，滴加16mmol的四氯化钛，回流反应30min，过滤，向滤液中加入4.1mol固体KCl得白色沉淀物，沉淀物用热水重结晶，得到固体K7PTi2W10O40。将10mmol K7PTi2W10O40溶于100mL水中，加入100mmol阿德福韦，调节pH值为4.0，加热至60℃，反应3h，放置一段时间后得到白色固体(C8H13N5PO4)7PTi2W10O40。
1H NMR(400MHz,DMSO-d6):δH(ppm)3.260(s,2H),3.729(t,2H),4.195(t,2H),7.957(s,1H),8.021(s,1H),9.160(s,3H),10.754(s,2H).元素分析(4524.10):calcd(％):C,14.85；N,10.83；P,5.48；Ti,2.12；W,40.63；found(％):C,14.95；N,10.89；P,5.43；Ti,2.16；W,40.56.PTi2W10O40 7-X射线单晶衍射结构图见图1，晶体基本参数见表1。
实施例3(PZ-3的制备)
二水钨酸钠91mmol、磷酸二氢钠43mmol溶解在100mL的蒸馏水中，滴加16mmol的四氯化钛，回流反应30min，过滤，向滤液中加入4.1mol固体KCl得白色沉淀物，沉淀物用热水重结晶，得到固体K7PTi2W10O40。将10mmol K7PTi2W10O40溶于100mL水中，加入100mmol二乙基(α-氨基苄基)膦酸酯盐酸盐，调节pH值为7.0，加热至60℃，反应3h，放置一段时间后得到白色固体(C11H19NPO3)7PTi2W10O40。
1H NMR(400MHz,DMSO-d6):δH(ppm)1.090(t,3H),1.245(t,3H),3.821-4.116(m,4H),4.939(d,1H),7.412-7.569(m,5H),9.093(s,3H).元素分析(4314.52):calcd(％):C,21.42；N,2.27；P,5.74；Ti,2.22；W,42.60；found(％):C,21.53；N,2.32；P,5.77；Ti,2.20；W,42.53.PTi2W10O40 7-X射线单晶衍射结构图见图1，晶体基本参数见表1。
实施例4(PZ-4的制备)
二水钨酸钠91mmol、磷酸二氢钠43mmol溶解在100mL的蒸馏水中，滴加16mmol的四氯化钛，回流反应30min，过滤，向滤液中加入4.1mol固体KCl得白色沉淀物，沉淀物用热水重结晶，得到固体K7PTi2W10O40。将10mmol K7PTi2W10O40溶于100mL水中，加入100mmol二乙基(α-氨基-4-溴苄基)膦酸酯盐酸盐，调节pH值为7.5，加热至60℃，反应3h，放置一段时间后得到白色固体(C11H18NPBrO3)7PTi2W10O40。
1H NMR(400MHz,DMSO-d6):δH(ppm)1.107(t,3H),1.247(t,3H),3.888-4.127(m,4H),5.006(d,1H),7.503-7.684(m,4H),9.174(s,3H).元素分析(4858.91):calcd(％):C,19.02；N,2.02；P,5.10；Br,11.51；Ti,1.97；W,37.83；found(％):C,19.11；N,2.03；P,5.15；Br,11.57；Ti,1.91；W,37.78.PTi2W10O40 7-X射线单晶衍射结构图见图1，晶体基本参数见表1。
实施例5(PZ-5的制备)
二水钨酸钠91mmol、磷酸二氢钠43mmol溶解在100mL的蒸馏水中，滴加16mmol的四氯化钛，回流反应30min，过滤，向滤液中加入4.1mol固体KCl得白色沉淀物，沉淀物用热水重结晶，得到固体K7PTi2W10O40。将10mmol K7PTi2W10O40溶于100mL水中，加入100mmol环磷酰胺，调节pH值为4.0，加热至60℃，反应3h，放置一段时间后得到白色固体(C7H18N2PCl2O3)7PTi2W10O40。
1H NMR(400MHz,D2O):δH(ppm)1.855(m,2H),3.267(t,2H),3.380(t,4H),3.635(t,4H),4.354(t,2H).元素分析(4565.47):calcd(％):C,12.88；N,4.29；P,5.43；Cl,10.87；Ti,2.10；W,40.27；found(％):C,12.95；N,4.32；P,5.46；Cl,10.81；Ti,2.06；W,40.36.PTi2W10O40 7-X射线单晶衍射结构图见图1，晶体基本参数见表1。
实施例6(PZ-6的制备)
二水钨酸钠91mmol、磷酸二氢钠43mmol溶解在100mL的蒸馏水中，滴加16mmol的四氯化钛，回流反应30min，过滤，向滤液中加入4.1mol固体KCl得白色沉淀物，沉淀物用热水重结晶，得到固体K7PTi2W10O40。将10mmol K7PTi2W10O40溶于100mL水中，加入100mmol氨磷汀，调节pH值为4.0，加热至60℃，反应3h，放置一段时间后得到白色固体(C5H16N2PSO3)7PTi2W10O40。
1H NMR(400MHz,D2O):δH(ppm)2.105(m,2H),2.969(t,2H),3.187(t,2H),3.242(t,2H),3.417(t,2H).元素分析(4111.31):calcd(％):C,10.22；N,4.77；P,6.03；S,5.46；Ti,2.33；W,44.71；found(％):C,10.33；N,4.82；P,5.98；S,5.42；Ti,2.11；W,39.66.PTi2W10O40 7-X射线单晶衍射结构图见图1，晶体基本参数见表1。
实施例7(细胞水平的抗HIV-1药效学实验)
以TZM-bl细胞为模型，用HIV-1感染细胞，对染毒细胞给药后观察化合物对病毒复制的抑制作用。
将TZM-bl细胞(Hela细胞表达CD4、CXCR4和CCR5，含Tat启动的荧光素酶和LacZ基因)接种于96孔板，37℃培养箱培养24h后，弃去上清，加入pSG3假病毒上清(即用HIV-1感染细胞)，病毒上清中加入DEAE(终浓度10μg/mL)，同时加入系列浓度分别为10、1、0.1、0.01、0.001μg/mL的杂多酸含磷有机盐类化合物溶液，培养48h后，弃去上清，加入固定液室温固定5min，PBS清洗后加入显色液(含4mM氰亚铁酸钾，4mM氰铁酸钾，2mM MgCl2，0.4mg/mL X-gal)，37℃培养箱中培养50min，PBS清洗，在显微镜下计数蓝斑数，计算得出抑制率及IC50，显示其抑制病毒复制的活性很高，结果见附图2和表2。
实施例8(细胞水平的毒性实验)
CCK-8细胞毒性试验：采用TZM-bl细胞验证化合物的细胞毒性。将TZM-bl细胞接种于96孔板，37℃培养箱培养24h后，加入不同浓度梯度的杂多酸含磷有机盐类化合物。继续培养48h后，采用CCK-8细胞增殖检测试剂，培养30min，酶标仪检测OD值。计算不同化合物对细胞增殖的抑制率，结果显示该化合物具有较低的细胞毒性，安全性高，结果见图3和表3。
表1.杂多阴离子PTi2W10O40 7-的晶体基本参数
表2.化合物在TZM-bl细胞上抗HIV-1药效
表3.CCK8法细胞毒性结果
Claims (6)
1.一种Keggin结构杂多酸含磷有机盐类化合物，其特征在于，通式为A7PTi2W10O40，A为含磷和氮的有机阳离子，为具有Keggin结构的杂多酸化合物。
2.按照权利要求1所述的一种Keggin结构杂多酸含磷有机盐类化合物，其特征在于，阴离子PTi2W10O40结构中P为中心原子，通常以四面体PO4构型与四个氧原子连接，配原子Ti和W以八面体配位与周围六个氧原子结合。
3.按照权利要求1所述的一种Keggin结构杂多酸含磷有机盐类化合物，其特征在于，A阳离子选自C9H15N5PO4、C8H13N5PO4、C11H19NPO3、C11H18NPBrO3、C7H18N2PCl2O3或C5H16N2PSO3。
4.权利要求1所述的一种Keggin结构杂多酸含磷有机盐类化合物的制备方法，其特征在于，将二水钨酸钠、磷酸二氢钠溶解蒸馏水中，滴加四氯化钛，回流反应，过滤，向滤液中加入碱金属盐或氨基酸盐得白色沉淀物，沉淀物用热水重结晶，得到化合物B7PTi2W10O40，其中B为碱金属或氨基酸阳离子；将B7PTi2W10O40溶于蒸馏水中，加入含A基团的化合物或A化合物，调节至酸性，加热搅拌，得到固体A7PTi2W10O40。
5.按照权利要求4的方法，其特征在于，其中优选：将二水钨酸钠：磷酸二氢钠：蒸馏水：四氯化钛：碱金属盐或氨基酸盐的用量关系为91mmol：43mmol：100mL：16mmol：4.1mol。
6.权利要求1所述的一种Keggin结构杂多酸含磷有机盐类化合物作为制备抗艾滋病毒药物的应用。
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| CN116212955A (zh) * | 2023-03-17 | 2023-06-06 | 中国科学院宁波材料技术与工程研究所 | 一种含钛多金属氧酸盐及其制备和在co2高值化转化中的应用 |
| CN116212955B (zh) * | 2023-03-17 | 2024-05-14 | 中国科学院宁波材料技术与工程研究所 | 一种含钛多金属氧酸盐及其制备和在co2高值化转化中的应用 |
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