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アイテム
新規環状ナフタレンジイミドとDNAとの結合解析に関する研究
https://doi.org/10.18997/00004324
https://doi.org/10.18997/000043248c52b931-dacb-4afe-b90e-4f77e3d510cf
| 名前 / ファイル | ライセンス | アクション |
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kou_k_402.pdf (4.0 MB)
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| アイテムタイプ | 学位論文 = Thesis or Dissertation(1) | |||||||
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| 公開日 | 2016-01-21 | |||||||
| 資源タイプ | ||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||
| 資源タイプ | doctoral thesis | |||||||
| タイトル | ||||||||
| タイトル | Binding Analysis of Novel Cyclic Naphthalene Diimide with DNA | |||||||
| 言語 | en | |||||||
| タイトル | ||||||||
| タイトル | 新規環状ナフタレンジイミドとDNAとの結合解析に関する研究 | |||||||
| 言語 | ja | |||||||
| 言語 | ||||||||
| 言語 | eng | |||||||
| 著者 |
Islam, Md. Monirul
× Islam, Md. Monirul
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| 抄録 | ||||||||
| 内容記述タイプ | Abstract | |||||||
| 内容記述 | In recent times, DNA structures are one of the attractive research targets because of their vital biological roles and remarkable therapeutic applications. Specially, G-quadruplex DNA structures are a very interesting target because of promoter regions, human telomeres and aptemers are closely associated with the genetic integrity, cell proliferation, aging and cancer. Fundamental understanding of the interactions of small-molecule ligands or proteins with DNA sequences and their structural effect, binding affinities, thermodynamic, kinetic and thermal stability are very crucial. This doctoral thesis has uncovered the interaction studies of novel cyclic naphthalene diimide derivatives (cNDIs, 1,2) & non-cyclic naphthalene diimide (NDI 3) with double stranded DNA (dsDNA) such as calf thymus DNA (CT-DNA), poly[d(A-T)]2, or poly[d(G-C)]2 and G-quadruplexes DNA such as human telomere DNA (a-core & a-coreTT), promoter region’s DNA (c-kit & c-myc) and thrombin-binding aptamer (TBA). Firstly, I have studied the interaction of newly synthesized cNDIs 1,2 with various types of dsDNA to observe the cyclic linker chain effect binding to dsDNA. Secondly, I have studied the interaction of 2 with various types of G-quadruplexes DNA to observe the specific binding to G-quadruplexes DNA structure. I have studied the interaction of NDI 3 with dsDNA and G-quadruplexes DNA as a control. The interaction of three different types of dsDNA and seven different types G-rich oligonucleotides studied with newly synthesize 1,2 and NDI 3 by the physicochemical and biochemical method such as UV-Vis spectroscopy, Circular dichroism (CD)spectroscopy, Topoisomerase I assay, Stopped-flow kinetics, Thermal melting studies, TRAP assay and FRET-melting assay experiments. The binding studies between cNDIs 1,2 and DNA duplexes showed affinities in the order of 105?106 M-1 using UV-Vis spectroscopic titration with a stoichiometry of one cNDI molecule covered four DNA base pairs as a bis-threading intercalation mode of binding. The induced CD signal was observed on cNDIs chromophore upon the addition of CT-DNA. Topo I isomerase assay showed that 2 can unwind circular dsDNA, it’s also indicated the bis-intercalation binding of cNDIs with dsDNA. According to the van’t Hoff and Gibbs free energy equation, thermodynamic parameters (ΔG, ΔH, and ΔS) indicated that entropy-dependent hydrophobic and endothermic interactions played a major role in the reaction between cNDIs and CT-DNA. Stopped-flow analysis showed that 2 slowly dissociate from GC base pairs. The salt ion effect analysis showed that upon the increasing salt concentration reduced cNDIs binding with dsDNA. Compound 1 showed much slower dissociation, a higher binding selectivity and a more entropically favorable interaction to dsDNA than 2 because of its longer linker chain. The binding interactions between G-quadruplex DNA structure and cNDIs showed the affinities in the range of 106-107 M-1 orders with a 2:1 stoichiometry. Compound 2 showed highest binding affinities to human telomere a-core G-quadruplex DNA with 270 times selectivity than dsDNA. The CD spectra of G-quadruplex DNA changed upon the addition of cNDIs suggesting the end staking interaction of cNDIs on G-tetrad plane. The thermal melting studies indicated that 2 stabilized to G-quadruplexes DNA with preference of human telomeric a-core TT. The FRET melting assay also showed that 2 highly stabilized with F21T which is an ancestor of human telomere G-quadruplex DNA. Compound 2 revealed an effective inhibitor against telomerase activity with an IC50 value of 0.9 μM. Briefly, the finding of this doctoral thesis will contribute to generate new idea to design and development suitable DNA binding ligands. The interesting data in the chapter4 indicated that 2 is the suitable candidate drug target to G-quadruplexes DNA, it deserves for further investigation with cancer cell line. | |||||||
| 目次 | ||||||||
| 内容記述タイプ | TableOfContents | |||||||
| 内容記述 | I: Introduction and Background||II: Synthesis of cyclic naphthalene diimide 1, 2 and 3||III: Thermodynamics and Kinetic Studies in the Binding Interaction of Cyclic Naphthalene Diimide Derivatives with Double Stranded DNAs||IV: A Selective G-Quadruplex DNA-Stabilizing Ligand Based on a Cyclic Naphthalene Diimide Derivative||V: Conclusion and perspective | |||||||
| 備考 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 九州工業大学博士学位論文 学位記番号:工博甲第402号 学位授与年月日:平成27年9月25日 | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Cyclic Naphthalene Diimide | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Binding studies | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | G-quadruplexes DNA | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Double stranded DNA | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Anticancer drug | |||||||
| アドバイザー | ||||||||
| 竹中, 繁織 | ||||||||
| 学位授与番号 | ||||||||
| 学位授与番号 | 甲第402号 | |||||||
| 学位名 | ||||||||
| 学位名 | 博士（工学） | |||||||
| 学位授与年月日 | ||||||||
| 学位授与年月日 | 2015-09-25 | |||||||
| 学位授与機関 | ||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||
| 学位授与機関識別子 | 17104 | |||||||
| 学位授与機関名 | 九州工業大学 | |||||||
| 学位授与年度 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 平成27年度 | |||||||
| 出版タイプ | ||||||||
| 出版タイプ | VoR | |||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||
| アクセス権 | ||||||||
| アクセス権 | open access | |||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||
| ID登録 | ||||||||
| ID登録 | 10.18997/00004324 | |||||||
| ID登録タイプ | JaLC | |||||||
