An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

Li Z.; Shigeoka D.; Caulfield T.R.; Kawachi T.; Qiu Y.; Kamon T.; Arai M.; Tun H.W.; Yoshimitsu T.

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An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

机译：一种发现有效的脑肿瘤阿司他汀A类似物的综合方法：化学合成以及生物学，理化和中枢神经系统药代动力学分析

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(-)-Agelastatin A (AA), isolated from the coral sea axinellid sponge Agelas dendromorpha, has shown a high antineoplastic activity. We have synthesized eighteen AA analogues and analyzed their cytotoxicities towards three cancer cell lines. By the structure-activity relationship (SAR) study, we identified three novel analogues with higher or comparable cytotoxic activities to AA. They were subjected to chemoinformatic analysis, which revealed physicochemical properties favoring excellent central nervous system (CNS) penetration. CNS pharmacokinetic analysis in murine models validated the chemoinformatic prediction and revealed that these analogues indeed had better CNS penetration than AA. These novel potent AA analogues deserve further evaluation for therapeutic use against cancers, particularly primary and secondary brain tumors.

机译：（-）-Agelastatin A（AA），从珊瑚海绵状海绵体Agelas dendromorpha中分离出来，具有很高的抗肿瘤活性。我们已经合成了18种AA类似物，并分析了它们对三种癌细胞系的细胞毒性。通过结构-活性关系（SAR）研究，我们鉴定了三种对AA具有更高或相当细胞毒活性的新型类似物。他们接受了化学信息学分析，发现其理化性质有利于出色的中枢神经系统（CNS）渗透。小鼠模型中的CNS药代动力学分析验证了化学信息学预测，并显示这些类似物确实比AA具有更好的CNS渗透性。这些新颖的有效的AA类似物值得进一步评估用于治疗癌症，特别是原发性和继发性脑瘤。

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《MedChemComm》 |2013年第7期|共6页
作者
Li Z.; Shigeoka D.; Caulfield T.R.; Kawachi T.; Qiu Y.; Kamon T.; Arai M.; Tun H.W.; Yoshimitsu T.;
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正文语种 eng
中图分类化学;
关键词
approach; discovery; agelastatin;

机译：方法;发现;阿斯拉汀;

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机译：一种发现有效的脑肿瘤阿司他汀A类似物的综合方法：化学合成以及生物学，理化和中枢神经系统药代动力学分析
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An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

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