海洋双吲哚脱氧托普辛的合成类似物：耐甲氧西林金黄色葡萄球菌丙酮酸激酶的强效选择性抑制剂。
Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase.
作者信息
Veale Clinton G L, Zoraghi Roya, Young Ryan M, Morrison James P, Pretheeban Manoja, Lobb Kevin A, Reiner Neil E, Andersen Raymond J, Davies-Coleman Michael T
机构信息
†Department of Chemistry, Rhodes University, Grahamstown, South Africa.
⊥Department of Chemistry, University of the Western Cape, Bellville, South Africa.
出版信息
J Nat Prod. 2015 Mar 27;78(3):355-62. doi: 10.1021/np500755v. Epub 2014 Nov 5.
As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity.
作为一项正在进行的阐明双吲哚生物碱抑制剂对进化保守的耐甲氧西林金黄色葡萄球菌丙酮酸激酶（PK）的构效关系研究的一部分，我们在此展示了天然海绵代谢产物脱氧托普辛的六种二卤代类似物的合成及生物活性，包括天然存在的二溴脱氧托普辛。最具活性的化合物对耐甲氧西林金黄色葡萄球菌丙酮酸激酶显示出强效的低纳摩尔抑制活性，同时对耐甲氧西林金黄色葡萄球菌丙酮酸激酶相对于人类丙酮酸激酶同源物具有显著的选择性。计算研究表明，这些强效的耐甲氧西林金黄色葡萄球菌丙酮酸激酶抑制剂占据了酶四聚体小界面的一个区域，其中与常见人类丙酮酸激酶同源物的氨基酸序列差异可能导致了观察到的选择性。
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