Campbell Jennifer, Blackwell Helen E
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706-1322, USA.
J Comb Chem. 2009 Nov-Dec;11(6):1094-9. doi: 10.1021/cc900115x.
Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as promising biologically active scaffolds. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of these privileged structures, expediting the synthesis and, often, the discovery of active compounds. We recently identified several DKPs that are capable of inhibiting the luminescence response of the bacterial symbiont Vibrio fischeri, and we sought to further test the scope of this biological activity. Herein, we report the synthesis of DKP macroarrays using a SPOT-synthesis approach based on an Ugi/DeBoc/Cyclize strategy. Neither a spacer nor a linker was required for macroarray construction on cellulose support, and the cyclative cleavage produced high purity DKPs in good yields. Using this protocol, we prepared a library of 400 DKPs on cellulose support and evaluated its members as luminescence inhibitors in V. fischeri. We found six DKPs capable of inhibiting luminescence by at least 80% at 500 muM. Collectively, this work serves to further highlight the utility of the small molecule macroarray platform for the synthesis and evaluation of focused libraries.
二酮哌嗪（DKPs）是一类著名的杂环化合物，已成为具有前景的生物活性骨架。固相有机合成已成为对这些优势结构进行组合探索的重要工具，加速了活性化合物的合成，并且常常有助于其发现。我们最近鉴定出几种能够抑制细菌共生体费氏弧菌发光反应的二酮哌嗪，并且我们试图进一步测试这种生物活性的范围。在此，我们报道了基于Ugi/脱Boc/环化策略，使用SPOT合成方法合成二酮哌嗪宏观阵列。在纤维素载体上构建宏观阵列时既不需要间隔臂也不需要连接子，并且环化裂解以良好的产率产生了高纯度的二酮哌嗪。使用该方案，我们在纤维素载体上制备了一个包含400种二酮哌嗪的文库，并评估了其成员作为费氏弧菌发光抑制剂的活性。我们发现有六种二酮哌嗪在500 μM时能够抑制发光至少80%。总的来说，这项工作进一步突出了小分子宏观阵列平台在合成和评估聚焦文库方面的实用性。
