CN102911190B - 乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物及其用途 - Google Patents
乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物及其用途 Download PDFInfo
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Abstract
本发明公开了一种乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物及其用途，属生物无机化学领域。它有如下结构：M=Cu、Zn、Ni、Co。该类金属配合物对刀豆尿素酶有明显的抑制作用，可以作为制备刀豆尿素酶抑制剂药物。
Description
技术领域
本发明涉及乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物及其制备方法与用途，属生物无机化学领域。
背景技术
尿素酶是一种人和动物胃肠道及泌尿道细菌感染中常见的酶，它既是人和动物中某些致病菌的致病因子之一，又是某些氮源性腐败物转化所必须具备的酶之一。研究表明尿素酶是尿道和消化道中病原菌重要的致病因子,与消化道和尿道疾病的预防、诊断和治疗密切相关。尿素酶抑制剂的研究在药物研发史上有重要地位。许多尿素酶抑制剂已经上市，并用于治疗系列疾病。尿素酶抑制剂已经广泛被认为是治疗胃溃疡的靶点药物。
N-取代硫脲类衍生物是一类用途广泛的化合物，其结构中的非对称单元是许多酶抑制剂和生物模拟肽的常见结构特征。在农药上应用广泛，其中许多可用作除草剂、杀虫剂和植物生长调节剂等。在医药、生物领域中也具有十分重要的地位，它除了具有广谱的抗菌性之外，对白血病、肿瘤也有很好的药效。最新研究表明，此类化合物与金属离子配位可增强其抑制性。目前，人们已将其作为一种具有开发潜力的生物靶标，开展合理的分子设计，以寻求具有广谱生物活性、高选择性、低毒性、短残效期的新型硫脲类化合物。因此，对此类化合物进行深入研究具有十分重要的理论价值和应用价值。
发明内容
本发明的目的在于提供一种新型乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物；另一目的在于提供其在制备药物方面的用途。
本发明的技术方案如下：
该乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物有如下结构：
M = Cu、Zn、Ni、Co。
制备上述金属配合物的方法由下列步骤组成：
步骤1 将氨基硫脲溶解在热的乙醇/水的混合溶剂中，搅拌下，滴加等物质量的2-羟基萘甲醛的乙醇/水溶液，加热回流反应，然后冷却至室温，用乙醇和水分别洗涤，减压过滤，得到固体化合物，将得到的固体化合物重结晶提纯，得到2-羟基萘甲醛基缩氨基硫脲(H2L)。
步骤2 将步骤1得到的2-羟基萘甲醛基缩氨基硫脲(H2L)溶解在热的乙醇/水的混合溶剂中，在搅拌下加入醋酸盐的无水乙醇溶液，同时滴加1,10-菲罗啉(邻菲咯啉)的无水乙醇溶液。搅拌加热至40-80 °C反应，经冷却，过滤，得清液。将清液静置数天后，析出固体，即为乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物。
所述醋酸盐为醋酸铜、醋酸锌、醋酸镍或醋酸钴。
上述制备方法中所述的乙醇/水的体积比为1:1。
上述制备方法步骤2中所述2-羟基萘甲醛基缩氨基硫脲、醋酸盐、邻菲咯啉的摩尔比为1:1:1。
经试验研究，本发明合成的乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物，对尿素酶具有明显的抑制作用，结果见表1，可以作为制备刀豆尿素酶抑制剂药物。
附图说明
图1为实施例1制得的铜配合物晶体结构图；
图2为实施例1制得的铜配合物荧光发射光谱对比图，其中，a为本发明金属配合物，b为配体H2L，c为邻菲咯啉；
图3为实施例2制得的锌配合物荧光发射光谱对比图，其中，a为本发明金属配合物，b为配体H2L，c为邻菲咯啉；
图4为实施例3制得的镍配合物荧光发射光谱对比图，其中，a为本发明金属配合物，b为配体H2L，c为邻菲咯啉；
图5为实施例4制得的钴配合物荧光发射光谱对比图，其中，a为本发明金属配合物，b为配体H2L，c为邻菲咯啉。
具体实施方式
实施例一：乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合铜配合物的制备
1、在100mL圆底烧瓶中，将氨基硫脲(0.91 g, 10.0 mmol)溶解在50 ml热的乙醇/水（体积比为1:1）的混合溶剂中，在激烈搅拌下，缓慢滴加等物质量的2-羟基萘甲醛的乙醇/水溶液（体积比为1:1）。然后加热回流4h后，冷却至室温，减压过滤，用乙醇和水分别洗涤，得到淡黄色的固体，将得到的固体溶于无水乙醇重结晶提纯，得到2-羟基萘甲醛基缩氨基硫脲(H2L)，产率47%。 Anal. Calc.
for C12H11N3OS: C, 58.8; H, 4.5; N, 17.1.
Found: C, 58.6; H, 4.4; N, 17.3%. IR (KBr, cm-1): 3444, 3258, 3162,
1608, 1519, 1465, 1392, 1323, 1276, 1237, 1185, 1117, 950, 819, 748, 645, 600,
487, 446. UV–visible [DMSO–H2O (1:1 v/v), λ/nm]:
365, 330, 265.
2、将2-羟基萘甲醛基缩氨基硫脲(0.12 g, 0.5 mmol)溶于80ml热的乙醇/水的混合溶剂中（体积比为1:1），在搅拌下加入Cu(OAc)2·H2O(0.10 g, 0.5
mmol)的无水乙醇溶液，同时滴加邻菲咯啉(0.09g, 0.5 mmol)的无水乙醇溶液。搅拌加热至50-60 °C，反应3h后冷却，过滤，得黑色清液，将清液静置8天后，析出黑色晶体，产率41%。Anal.
Calc. for C50H40Cu2N10O3S2:
C, 58.8; H, 4.5; N, 17.1. Found: C, 58.6; H, 4.4; N, 17.3%. IR (KBr, cm-1):
3335, 3111, 1613, 1500, 1387, 1334, 1184, 1092, 1045, 960, 872, 756, 719, 625,
576, 526, 487, 600, 487, 446. UV-visible [DMSO-H2O (1:1 v/v), λ/nm]:
415, 335。经X-射线衍射分析其结果为：C50H40Cu2N10O3S2。其晶体结构见图1，荧光发射光谱见图2，晶体学数据见表2，主要的键长和键角见表3。
实施例二：乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合锌配合物的制备
制备方法同实施例一。醋酸锌代替醋酸铜，得到橘黄色粉末状目标化合物，产率61%。Anal.
Calc. for C50H40Zn2N10O3S2:
C, 58.7; H, 3.9; N, 13.7. Found: C, 58.4; H, 3.7; N, 13.9%. IR (KBr, cm-1):
3419, 3131, 1607, 1487, 1423, 1386, 1332, 1170, 1091, 1039, 954, 836, 755, 719,
684, 611, 440. UV-visible [DMSO-H2O (1:1 v/v), λ/nm]:
405, 335. 其荧光发射光谱见图3。
实施例三：乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合镍配合物的制备
制备方法同实施例一。醋酸镍代替醋酸铜，得到棕绿色粉末状目标化合物，产率52%。Anal.
Calc. for C50H40Ni2N10O3S2:
C, 59.4; H, 4.0; N, 13.9. Found: C, 58.8; H, 3.7; N, 14.1%. IR (KBr, cm-1):
3331, 3151, 1663, 1607, 1533, 1486, 1393, 1328, 1191, 1096, 1046, 967, 832,
741, 614, 515. UV-visible [DMSO-H2O (1:1 v/v), λ/nm]:
420, 385, 320. 其荧光发射光谱见图4。
实施例四：乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合钴配合物的制备
制备方法同实施例一。醋酸钴代替醋酸铜，得到棕黑色粉末状目标化合物，产率 56%。Anal.
Calc. for C50H40Co2N10O3S2:
C, 59.4; H, 4.0; N, 13.9. Found: C, 59.1; H, 3.8; N, 14.2%. IR (KBr, cm-1):
3309, 3180, 1657, 1607, 1519, 1436, 1394, 1338, 1191, 1098, 1043, 967, 828,
749, 665, 606, 494, 447. UV-visible [DMSO-H2O (1:1 v/v), λ/nm]:
430. 其荧光发射光谱见图5。
实施例五：乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉金属配合物体外抑制尿素酶活性研究
抑制尿素酶(Urease)活性实验：刀豆(jack bean)尿素酶购自Sigma-Aldrich公司(St. Louis, Mo, USA)，用DMSO和水(v/v，1:1)的混合溶剂配制各种浓度的待测化合物。将含有尿素酶(25 µL，10 kU·L-1)和各种浓度的待测化合物(25 µL )的混合溶液放置在化验盘(96-well)中，37 oC下预培养1 h。再加入含有尿素酶（500mM）的Hepes缓冲溶液(0.2 ml，100mM； pH = 6.8)和浓度为0.002%的酚红指示剂，并在37 oC下进行培养。反应时间通过微盘读卡器(570 nm)来测量，这需要形成充足的碳酸铵，使Hepes缓冲溶液的pH值从6.8提高到7.7，测试终点依据酚红指示剂的颜色变化。
半数抑制浓度（IC50）定义为当抑制率为50%时的药物浓度。
测得的IC50见表1所示：
表1 本发明所列配合物1-4的刀豆尿素酶的抑制IC50值(μM)
| 化合物 | IC50 (μM) |
| HL1 | / a |
| HL2 | / |
| Cu2+ | 0.37 |
| Zn2+ | / |
| Ni2 + | 2.87 |
| Co2+ | / |
| 实施例1制得的配合物1 | 18.3 ± 1.6 |
| 实施例2制得的配合物2 | / |
| 实施例3制得的配合物3 | 1.2 ± 0.1 |
| 实施例4制得的配合物4 | 10.4 ± 0.7 |
| 阳性对照AHA(乙酰氧肟酸) | 42.1 ± 0.4 |
a / 指对尿素酶没有抑制性
表2 配合物1的晶体学数据
| Empirical Formula | C50H40Cu2N10O3S2 | F(000) | 4192 |
| Formula weight | 1020.12 | θ range (o) | 1.93 to 26.00 |
| T/ K | 296(2) | hmin / hmax | -18 / 18 |
| Wavelength / Å | 0.71073 | kmin / kmax | -19 / 19 |
| Crystal shape/color | Block/black | lmin / lmax | -46 / 23 |
| Crystal size / mm | 0.23 × 0.22 × 0.17 | Data collected | 48086 |
| Crystal system | Orthorhombic | Unique data (I> 2s(I)) | 8903 |
| Space group | Pbca | Maximum and minimum transmission | 0.8368and 0.7882 |
| a / Å | 15.008(9) | parameters | 604 |
| b / Å | 16.100(10) | restraints | 12 |
| c / Å | 37.54(2) | Goodness-of-fit on F2 | 1.002 |
| V / Å 3 | 9070(10) | R1 , wR2 [I>2s (I)] | 0.0626, 0.0912 |
| Z | 8 | R1 , wR2 (all data) | 0.1974, 0.1270 |
| D / g·cm -3 | 1.494 | Largest difference peak and hole / (eÅ -3) | 0.418and -0.419 |
| μ(Mo Kα) / mm-1 | 1.086 |
表 3 配合物1的重要键长和键角
| Cu(1)-O(1) | 1.933(4) | Cu(1)-N(5) | 1.953(4) |
| Cu(1)-N(1) | 2.025(5) | Cu(1)-S(1) | 2.249(2) |
| Cu(1)-N(2) | 2.292(5) | Cu(2)-O(2) | 1.937(4) |
| Cu(2)-N(10) | 1.947(4) | Cu(2)-N(6) | 2.046(4) |
| Cu(2)-N(7) | 2.262(5) | Cu(2)-S(2) | 2.271(2) |
| C(23)-N(5) | 1.288(6) | C(24)-N(4) | 1.301(7) |
| C(24)-S(1) | 1.756(6) | C(47)-N(10) | 1.293(6) |
| C(48)-N(9) | 1.311(6) | C(48)-S(2) | 1.740(6) |
| O(1)-Cu(1)-N(5) | 93.17(19) | O(1)-Cu(1)-N(1) | 88.64(17) |
| N(5)-Cu(1)-N(1) | 177.61(19) | O(1)-Cu(1)-S(1) | 163.29(13) |
| N(5)-Cu(1)-S(1) | 85.67(16) | N(1)-Cu(1)-S(1) | 93.03(14) |
| O(1)-Cu(1)-N(2) | 97.20(18) | N(5)-Cu(1)-N(2) | 100.74(19) |
| N(1)-Cu(1)-N(2) | 77.5(2) | S(1)-Cu(1)-N(2) | 99.39(14) |
| O(2)-Cu(2)-N(10) | 91.86(19) | O(2)-Cu(2)-N(6) | 88.63(17) |
| N(10)-Cu(2)-N(6) | 173.3(2) | O(2)-Cu(2)-N(7) | 103.15(18) |
| N(10)-Cu(2)-N(7) | 95.92(19) | N(6)-Cu(2)-N(7) | 77.5(2) |
| O(2)-Cu(2)-S(2) | 154.54(12) | N(10)-Cu(2)-S(2) | 85.34(16) |
| N(6)-Cu(2)-S(2) | 97.04(13) | N(7)-Cu(2)-S(2) | 102.30(15) |
Claims (2)
1.一种乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物，其特征是，它有如下结构：
M = Ni、Co 。
2.如权利要求1所述的乙醇合2-羟基萘甲醛基缩氨基硫脲·邻菲咯啉合金属配合物的应用，其特征是，以其为活性成分，作为制备刀豆尿素酶抑制剂药物。
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