FMNH催化O6-4-硝基苄基鸟嘌呤还原机理的研究
Mechanism Study of the Reduction of O6-4-Nitrobenzyl-Guanine Catalysed by FMNH

作者: 肖家斌 , 孙国辉 :北京工业大学生命科学与生物工程学院,北京;

关键词: AGT抑制剂前体药物硝基还原酶质子电子耦合转移AGT Inhibitor Prodrug Nitroreductase Proton Coupled Electron Transfer

摘要:
使用密度泛函理论(DFT)对O6-烷基鸟嘌呤-DNA-烷基转移酶(AGT)抑制剂的硝基类前体药物在硝基还原酶(NTR)作用下的还原机理进行了研究。结果显示,在反应的六个过渡态中,生成亚硝基反应的过渡态(TS2)和生成苯胺反应的过渡态(TS5)为反应的两个控速步骤。整个还原反应过程中水参与的质子电子耦合转移在过渡态TS2和TS6降低了反应的活化能,推测水介导的质子电子耦合转移为这两步反应的优势途径。通过绘制反应势能曲线阐明了硝基芳烃类前体药物还原机理及其反应所涉及的热力学问题,为制备高效低毒的AGT抑制剂的前体药物提供理论基础。

Abstract: The reduction mechanism of O6-Alkylguanine DNA Alkyltransferase inhibitor of the nitro group of the pro-drug in the Nitro Reductase (NTR) was studied by using the Density Functional Theory (DFT). The results showed that the transitions of TS2 (yielding nitroso compound) and TS5 (yielding aniline compound) were the rate-limiting steps among the six reaction transition states. Single water molecule-mediated proton coupled electron transfer can lower the reactive activation energy of TS2 and TS6; thus it is speculated that water-mediated proton coupled electron transfer is the optimal reaction pathway of TS2 and TS6. The reduction mechanism of the prodrug of nitro aromatic compound and the involved reaction thermodynamics can be clearly presented by the potential energy curve. This study can provide a theoretical basis for designing more efficient hypoxia-activated AGT inhibitors with less side effects.

文章引用: 肖家斌 , 孙国辉 (2016) FMNH催化O6-4-硝基苄基鸟嘌呤还原机理的研究。 药物资讯, 5, 25-32. doi: 10.12677/PI.2016.52005

参考文献

[1] Zhao, L.J., Ma, X.Y. and Zhong, R.G. (2012) Comparative Theoretical Investigation of the Formation of DNA Interstrand Crosslinks Induced by Two Kinds of N-Nitroso Compounds: Nitrosoureas and Nitrosamines. Journal of Physical Organic Chemistry, 25, 1153-1167.
http://dx.doi.org/10.1002/poc.2970

[2] Georgieva, P. and Himo, F. (2008) Density Func-tional Theory Study of the Reaction Mechanism of the DNA Repairing Enzyme Alkylguanine Alkyltransferase. Chemical Physics Letters, 463, 214-218.
http://dx.doi.org/10.1016/j.cplett.2008.08.043

[3] 马昕燕. 氯乙基亚硝基脲导致DNA股间交联及其修复机制的理论研究[D]: [硕士学位论文]. 北京: 北京工业大学生命科学与生物工程学院, 2013.

[4] Apisarnthanarax, N., Wood, G.S., Stevens, S.R., et al. (2012) Phase I Clinical Trial of O6-Benzylguanine and Topical Carmustine in the Treatment of Cutaneous T-Cell Lymphoma, Mycosis Fungoides Type. Archives of Dermatology, 148, 613-620.
http://dx.doi.org/10.1001/archdermatol.2011.2797

[5] Wilson, K.A. and Wetmore, S.D. (2014) Complex Conforma-tional Heterogeneity of the Highly Flexible O6-Benzyl- guanine DNA Adduct. Chemical Research in Toxicology, 27, 1310-1325.
http://dx.doi.org/10.1021/tx500178x

[6] Sarlauskas, J., Miseviciene, L., Maroziene, A., et al. (2014) The Study of NADPH-Dependent Flavoenzyme-Catalyzed Reduction of Benzo[1,2-c]1,2,5-Oxadiazole N-Oxides (Benzofuroxans). International Journal of Molecular Sciences, 15, 23307-23331.
http://dx.doi.org/10.3390/ijms151223307

[7] Sarlauskas, J., Peciukaityte, A.M., Miseviciene, L., et al. (2016) Naphtho[1’,2’:4,5]imidazo[1,2-a]pyridine-5, 6-diones: Synthesis, Enzymatic Reduction and Cytotoxic Activity. Bioorganic & Medicinal Chemistry Letters, 26, 512-517.
http://dx.doi.org/10.1016/j.bmcl.2015.11.084

[8] Johnson, K.M., Parsons, Z.D., Barnes, C.L., et al. (2014) Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia Selective DNA-Oxidizing Agent 3-Amino- 1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine). Journal of Organic Chemistry, 79, 7520-7531.
http://dx.doi.org/10.1021/jo501252p

[9] Cai, T.Y., Liu, X.W., Zhu, H., et al. (2014) Tirapazamine Sensitizes Hepato-cellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1a. Molecular Cancer Therapeutics, 13, 630-642.
http://dx.doi.org/10.1158/1535-7163.MCT-13-0490

[10] Liapis, V., Labrinidis, A., Zinonos, I., et al. (2015) Hypox-ia-Activated Pro-Drug TH-302 Exhibits Potent Tumor Suppressive Activity and Cooperates with Chemotherapy against Os-teosarcoma. Cancer Letters, 357, 160-169.
http://dx.doi.org/10.1016/j.canlet.2014.11.020

[11] Sun, J.D., Liu, Q., Ahluwalia, D., et al. (2015) Efficacy and Safety of the Hypoxia-Activated Prodrug TH-302 in Combination with Gemcitabine and Nab-Paclitaxel in Human Tumor Xenograft Models of Pancreatic Cancer. Cancer Biology & Therapy, 16, 438-449.
http://dx.doi.org/10.1080/15384047.2014.1003005

[12] Penketh, P.G., Shyam, K., Baumann, R.P., Ishiguro, K., Patridge, E.V., Zhu, R. and Sartorelli, A.C. (2012) A Strategy for Selective O6-Alkylguanine-DNA Alkyltransferase Depletion under Hypoxic Conditions. Chemical Biology & Drug Design, 80, 279-290.
http://dx.doi.org/10.1111/j.1747-0285.2012.01401.x

[13] Zhu, R., Seow, H.A., Baumann, R.P., et al. (2012) Design of a Hypoxia-Activated Prodrug Inhibitor of O6-Alkylgua- nine-DNA Alkyltransferase. Bioorganic & Medicinal Chemistry Letters, 22, 6242-6247.
http://dx.doi.org/10.1016/j.bmcl.2012.08.008

[14] Bai, J., Zhou, Y., Chen, Q., et al. (2015) Altering the Regioselectivity of a Nitroreductase in the Synthesis of Arylhydroxylamines by Structure-Based Engineering. ChemBioChem, 16, 1219-1225.
http://dx.doi.org/10.1002/cbic.201500070

[15] Kilic, M. and Ensing, B. (2013) First and Second One-Electron Reduction of Lumiflavin in Water—A First Principles Molecular Dynamics Study. Journal of Chemical Theory and Computation, 9, 3889-3899.
http://dx.doi.org/10.1021/ct400088g

[16] Silva, J.R., Roitberg, A.E. and Alver, C.N. (2015) A QM/MM Free Energy Study of the Oxidation Mechanism of Dihydroorotate Dehydrogenase (Class 1A) from Lactococcus lactis. The Journal of Physical Chemistry B, 119, 1468- 1473.
http://dx.doi.org/10.1021/jp512860r

[17] Nguyen-Tran, H.H., Zheng, G.W., Qian, X.H., et al. (2014) Highly Selective and Controllable Synthesis of Arylhydroxylamines by the Reduction of Nitroarenes with an Electron-Withdrawing Group Using a New Nitroreductase BaNTR1. Chemical Communications, 50, 2861-2864.
http://dx.doi.org/10.1039/c3cc48590k

[18] Chua, C.K., Pumera, M. and Rulisek, L. (2012) Reduction Pathways of 2,4,6-Trinitrotoluene: An Electrochemical and Theoretical Study. The Journal of Physical Chemistry C, 116, 4243-5251.
http://dx.doi.org/10.1021/jp209631x

[19] Maia, L.B. and Moura, J. (2014) How Biology Handles Nitrite. Chemical Reviews, 114, 5273-5357.
http://dx.doi.org/10.1021/cr400518y

[20] Migliore, A., Polizzi, N.F., Therien, M.J., et al. (2014) Biochemistry and Theory of Proton-Coupled Electron Transfer. Chemical Reviews, 114, 3381-3468.
http://dx.doi.org/10.1021/cr4006654

[21] Chen, X., Ma, G., Sun, W., et al. (2014) Water Promoting Electron Hole Transport between Tyrosine and Cysteine in Proteins via a Special Mechanism: Double Proton Coupled Electron Transfer. Journal of the American Chemical Society, 136, 4515-4524.
http://dx.doi.org/10.1021/ja406340z

[22] Christofferson, A. and Wilkie, J. (2009) Mechanism of CB1954 Reduction by Escherichia coli Nitroreductase. Biochemical Society Transactions, 37, 413-418.
http://dx.doi.org/10.1042/BST0370413

分享
Top