Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand.
Bioorg Med Chem. 2009 Oct 15;17(20):7131-7. doi: 10.1016/j.bmc.2009.08.064. Epub 2009 Sep 4.
A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors.
已证明一系列与已知拓扑异构酶 II 抑制剂 eleutherin 1 相关的吡喃并萘醌衍生物可作为特定的拓扑异构酶 II 催化抑制剂，其中几种类似物的活性比天然产物本身更强。在测试的化合物中，有天然产物 ventiloquinone L 4 和 thysanone 8，它们表现出多种拓扑异构酶 II 抑制特性。有趣的是，天然产物通常比其合成对应物弱抑制剂，这强调了天然产物基本分子结构的细微变化会导致抑制谱的显著变化。这也是首次证明与 nanaomycin A 和 cardinalin 型二聚吡喃并萘醌相关的类似物具有很强的拓扑异构酶 II 抑制特性。就结构特征而言，似乎吡喃环上 C1 位的取代基的性质和芳基环上的含氧取代基对于抗拓扑异构酶 II 活性至关重要。重要的是，拓扑异构酶 II 抑制强度与对酵母的测量细胞毒性相关性不好，这表明在设计和使用这种结构类别作为高度特异性拓扑异构酶 II 抑制剂时，必须考虑吡喃并萘醌家族中的其他分子特征。
