CN109456364A - 用作dna裂解剂的化合物 - Google Patents
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- 238000000354 decomposition reaction Methods 0.000 title claims abstract description 35
- 150000001875 compounds Chemical class 0.000 title claims abstract description 9
- 239000000126 substance Substances 0.000 abstract description 24
- 238000005336 cracking Methods 0.000 abstract description 6
- 230000005284 excitation Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 description 36
- 238000000034 method Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 5
- 101710163270 Nuclease Proteins 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229940075397 calomel Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000005281 excited state Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 230000033116 oxidation-reduction process Effects 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101000702488 Rattus norvegicus High affinity cationic amino acid transporter 1 Proteins 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 238000004020 luminiscence type Methods 0.000 description 1
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- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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Abstract
本发明提供一种可用作DNA裂解剂的化合物，其中该化合物在光激发下具有远超现有大多数化学DNA裂解剂的还原电势，能够提供更强的裂解性能。
Description
技术领域
本发明涉及生物化学领域，尤其涉及一种新的DNA裂解剂。进一步地，本发明提供的新的DNA裂解剂还可能被用于制备抗肿瘤药物和/或光敏化试剂。
背景技术
常见的DNA裂解剂可以分为两种：生物裂解剂，如核酸酶等，和化学裂解剂(或化学核酸酶)。一般地，生物裂解剂，如核酸酶多提取自自然界生物体，或在其基础上改进而来。例如，自E.coli中分离的用于限制性酶切的EcoR I内切酶。常见生物性DNA裂解剂的反应条件较为苛刻和复杂，往往除需要Mg2+外，还需要S-腺苷-L甲硫氨酸、ATP等，且其最适反应温度多在37℃左右。此外，由于很多生物源核酸酶为多肽，容易失活和失去DNA切割或裂解活性。上世纪八十年代，研究人员首次发现Ru(II)联吡啶配合物具有光诱导的DNA裂解功能。此类DNA裂解剂具有多种潜在应用：(1)用于对DNA某些位点的特异性剪切；(2)用作核酸非放射性的发光或电化学发光标记物，如作为DNA“分子光开关”等；(3)合成出对某些与基因突变有关疾病，如癌症等疾病，的治疗药物。化学DNA裂解剂同时具有生物性DNA裂解剂的高度特异性，和允许研究人员预先设计DNA裂解位点的可设计性(或可编程性)，在DNA分子光开关、结构探针、光探针、光裂解试剂、抗肿瘤药物、光敏化试剂等方面具有巨大的应用潜力。然而，化学DNA裂解剂的应用前景取决于其裂解能力。现有的Ru(II)联吡啶配合物的光激发下还原电势较低，这限制了现有的Ru(II)联吡啶配合物的实际应用。
发明内容
本发明的主要优势在于其提供一种新的化学DNA裂解剂，其具有远超现有化学DNA裂解剂的还原电势，其中本发明化学DNA裂解剂下述结构式：
其中前者的理论还原电势为1.624V，后者的理论还原电势为1.680V，均超过现有的Ru(II)联吡啶配合物的还原电势。换句话说，本发明提供一种具有高裂解能力的化学DNA裂解剂。进一步地，本发明化学DNA裂解剂可用作DNA光裂解试剂、抗肿瘤药物和/或光敏化试剂。
具体实施方式
依本发明较佳实施例，本发明提供一种化学DNA裂解剂，其具有下述结构式：
其中结构式I的理论还原电势为1.624V，结构式II的理论还原电势为1.680V，均超过现有的Ru(II)联吡啶配合物的还原电势。换句话说，本发明结构式I和结构式II的化学DNA裂解剂均具有高DNA光裂解能力。进一步地，本发明结构式I和结构式II的化学DNA裂解剂均可用作DNA光裂解试剂、抗肿瘤药物和/或光敏化试剂。
下述示例用于举例说明本发明结构式I和结构式II的化学DNA裂解剂的还原电势及其计算方法。本领域技术人员能够理解，采用何种方法检测或计算化学DNA裂解剂的还原电势，并不构成对本发明范围的限制。对本领域技术人员显而易见的是，存在其它检测或计算方法来确定本发明化学DNA裂解剂的还原电势。
示例1：具有结构式I的化学DNA裂解剂的还原电势及其计算
采用UB3LYP方法，钌原子采用LanL2DZ基组，其它原子采用6-31G(d)基组，优化得到具有结构式I的化合物。对此化合物，溶液中的数据采用连续极性导体模型(CPCM)和默认参数进行计算得到。优化得到的三重态分子，作为分子的最低三重激发态(T1)。液相中的吉布斯自由能采用CPCM模型通过单点计算得到。对于激发态配合物的热力学数据，采用单点计算的方法获得。所有计算采用Gaussian 09程序包(Revision D.01)。
基于热力学循环原理，采取下述方案1，计算具有结构式I的化学DNA裂解剂的还原电势，其中具有结构式I的化学DNA裂解剂的标准氧化还原电位相对于标准汞电极(SCE)可以用下述方程(1)得到。标准氢电极(SHE)的吉布斯自由能变值 相当于下述方程(8)的吉布斯自由能变值。因为标准甘汞电极相对于氢电极的电位是-0.2412V，SCE的吉布斯自由能变值(相当于下述方程(9)的自由能变值)是由标准氢电极的吉布斯自由能变值加上0.2412eV得到：
方案1：热力学循环方法计算溶液中的氧化还原电势：
其中，
ΔGo(2)＝Go[Ru(tap)2tanp](n+1)+(aq)-Go[Ru(tap)2tanp](n+1)+(gas) (6)
ΔGo(1)＝Go[Ru(tap)2tanp]n+(aq)-Go[Ru(tap)2tanp]n+(gas) (7)
其中，所有相关的自由能变值均在标准条件下计算得到。例如：温度为298.15K，压力为1个标准大气压，溶液为1mol/L(水为溶剂)；气体为298.15K，1个标准大气压。结构式I的化学DNA裂解剂的还原电势所需要的数据如表1：
表1：
其中计算得到的具有结构式I的化学DNA裂解剂的还原电势为1.624V。
示例2：具有结构式II的化学DNA裂解剂的还原电势及其计算
采用UB3LYP方法，钌原子采用LanL2DZ基组，其它原子采用6-31G(d)基组，优化得到具有结构式II的化合物。对此化合物，溶液中的数据采用连续极性导体模型(CPCM)和默认参数进行计算得到。优化得到的三重态分子，作为分子的最低三重激发态(T1)。液相中的吉布斯自由能采用CPCM模型通过单点计算得到。对于激发态配合物的热力学数据，采用单点计算的方法获得。所有计算采用Gaussian 09程序包(Revision D.01)。
基于热力学循环原理，采取下述方案2，计算具有结构式II的化学DNA裂解剂的还原电势，其中具有结构式II的化学DNA裂解剂的标准氧化还原电位相对于标准汞电极(SCE)可以用下述方程(1)得到。标准氢电极(SHE)的吉布斯自由能变值 相当于下述方程(8)的吉布斯自由能变值。因为标准甘汞电极相对于氢电极的电位是-0.2412V，SCE的吉布斯自由能变值(相当于下述方程(9)的自由能变值)是由标准氢电极的吉布斯自由能变值加上0.2412eV得到：
方案2：热力学循环方法计算溶液中的氧化还原电势：
其中，
ΔGo(2)＝Go[Ru(dcp)2phhat](n+1)+(aq)-Go[Ru(dcp)2phhat](n+1)+(gas) (6)
ΔGo(1)＝Go[Ru(tap)2phhat]n+(aq)-Go[Ru(dcp)2phhat]n+(gas) (7)
其中，所有相关的自由能变值均在标准条件下计算得到。例如：温度为298.15K，压力为1个标准大气压，溶液为1mol/L(水为溶剂)；气体为298.15K，1个标准大气压。结构式II的化学DNA裂解剂的还原电势所需要的数据如表2：
表2：
其中计算得到的具有结构式II的化学DNA裂解剂的还原电势为1.680V。
Claims (1)
1.一种用作DNA裂解剂的化合物，其特征在于，具有以下结构通式：
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012028874A1 (en) * | 2010-09-01 | 2012-03-08 | University Of Sheffield | Cytotoxic luminescent metal complexes |
| CN105884833A (zh) * | 2014-12-24 | 2016-08-24 | 江南大学 | 一种含4，4’-二溴-2，2’-联吡啶的新型钌配合物的制备方法及其抗肿瘤活性 |
| CN105884834A (zh) * | 2014-12-24 | 2016-08-24 | 江南大学 | 含苯并唑类的咪唑并[1,10]菲咯啉的新型Ru(Ⅱ)配合物的制备方法及其光裂解活性 |
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- 2018-09-07 CN CN201811055158.3A patent/CN109293703A/zh active Pending
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012028874A1 (en) * | 2010-09-01 | 2012-03-08 | University Of Sheffield | Cytotoxic luminescent metal complexes |
| CN105884833A (zh) * | 2014-12-24 | 2016-08-24 | 江南大学 | 一种含4，4’-二溴-2，2’-联吡啶的新型钌配合物的制备方法及其抗肿瘤活性 |
| CN105884834A (zh) * | 2014-12-24 | 2016-08-24 | 江南大学 | 含苯并唑类的咪唑并[1,10]菲咯啉的新型Ru(Ⅱ)配合物的制备方法及其光裂解活性 |
Non-Patent Citations (3)
| Title |
|---|
| TI-FANG MIAO等: "Theoretical studies on DNA-photocleavage efficiencies of Ru(II) polypyridyl complexes", 《DALTON TRANS.》 * |
| TI-FANG MIAO等: "Theoretical Studies on DNA-Photocleavage Efficiency and Mechanism of Functionalized Ru(II) Polypyridyl Complexes", 《J. PHYS. CHEM. A》 * |
| 张建夫等: "Ru(Ⅱ)多吡啶配合物DNA光裂解性质的密度泛函研究", 《原子与分子物理学报》 * |
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