作为缺氧选择性细胞毒素的三环[1,2,4]三嗪1,4-二氧化物
Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia selective cytotoxins.
作者信息
Hay Michael P, Hicks Kevin O, Pchalek Karin, Lee Ho H, Blaser Adrian, Pruijn Frederik B, Anderson Robert F, Shinde Sujata S, Wilson William R, Denny William A
机构信息
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
出版信息
J Med Chem. 2008 Nov 13;51(21):6853-65. doi: 10.1021/jm800967h. Epub 2008 Oct 11.
Abstract
A series of novel tricyclic triazine-di- N-oxides (TTOs) related to tirapazamine have been designed and prepared. A wide range of structural arrangements with cycloalkyl, oxygen-, and nitrogen-containing saturated rings fused to the triazine core, coupled with various side chains linked to either hemisphere, resulted in TTO analogues that displayed hypoxia-selective cytotoxicity in vitro. Optimal rates of hypoxic metabolism and tissue diffusion coefficients were achieved with fused cycloalkyl rings in combination with both the 3-aminoalkyl or 3-alkyl substituents linked to weakly basic soluble amines. The selection was further refined using pharmacokinetic/pharmacodynamic model predictions of the in vivo hypoxic potency (AUC req) and selectivity (HCD) with 12 TTO analogues predicted to be active in vivo, subject to the achievement of adequate plasma pharmacokinetics.
摘要
已设计并制备了一系列与替拉扎明相关的新型三环三嗪二氮氧化物（TTOs）。一系列结构排列包括与三嗪核心稠合的环烷基、含氧和含氮饱和环，再加上连接到任一半球的各种侧链，产生了在体外显示出缺氧选择性细胞毒性的TTO类似物。通过将稠合环烷基环与连接到弱碱性可溶性胺的3-氨基烷基或3-烷基取代基相结合，实现了最佳的缺氧代谢速率和组织扩散系数。利用药代动力学/药效学模型对体内缺氧效力（AUC req）和选择性（HCD）进行预测，对12种预计在体内具有活性的TTO类似物进行了进一步筛选，前提是要实现足够的血浆药代动力学。
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本文引用的文献
1
Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group.
J Clin Oncol. 2010 Jun 20;28(18):2989-95. doi: 10.1200/JCO.2009.27.4449. Epub 2010 May 17.
2
Tirapazamine: from bench to clinical trials.
Curr Clin Pharmacol. 2006 Jan;1(1):71-9. doi: 10.2174/157488406775268192.
3
Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells.
Cancer Res. 2008 Jan 1;68(1):257-65. doi: 10.1158/0008-5472.CAN-06-4497.
4
Hypoxia-selective 3-alkyl 1,2,4-benzotriazine 1,4-dioxides: the influence of hydrogen bond donors on extravascular transport and antitumor activity.
J Med Chem. 2007 Dec 27;50(26):6654-64. doi: 10.1021/jm701037w. Epub 2007 Dec 6.
5
Pharmacokinetic/pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport.
J Med Chem. 2007 Dec 13;50(25):6392-404. doi: 10.1021/jm070670g. Epub 2007 Nov 15.
6
DNA strand damage product analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for O(2).
J Am Chem Soc. 2007 Oct 24;129(42):12870-7. doi: 10.1021/ja074432m. Epub 2007 Sep 27.
7
Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine.
Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):560-71. doi: 10.1016/j.ijrobp.2007.05.049.
8
Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins.
Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S61-3. doi: 10.1016/j.ijrobp.2007.05.043.
9
HIF-1 mediates the Warburg effect in clear cell renal carcinoma.
J Bioenerg Biomembr. 2007 Jun;39(3):231-4. doi: 10.1007/s10863-007-9081-2.
10
Glycolysis in cancer: a potential target for therapy.
Int J Biochem Cell Biol. 2007;39(7-8):1358-66. doi: 10.1016/j.biocel.2007.03.021. Epub 2007 Apr 4.
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