School of Chemistry, University of Nottingham, University Park, U.K.
ACS Chem Biol. 2011 Dec 16;6(12):1339-47. doi: 10.1021/cb200196e. Epub 2011 Oct 4.
A series of resorcylic acid macrolactams, nitrogen analogues of the naturally occurring macrolactone radicicol, have been prepared by chemical synthesis and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves, as key steps, ring opening of an isocoumarin intermediate, followed by a ring-closing metathesis reaction to form the macrocycle. Subsequent manipulation of the ester group into a range of amides allows access to a range of new macrolactams following deprotection of the two phenolic groups. These new resorcylic acid lactams exhibit metabolic stability greater than that of related lactone counterparts, while co-crystallization of three macrolactams with the N-terminal domain ATP site of Hsp90 confirms that they bind in a similar way to the natural product radicicol and to our previous synthetic lactone analogues. Interestingly, however, in the case of the N-benzylamide, additional binding to a hydrophobic pocket of the protein was observed. In biological assays, the new macrocyclic lactams exhibit a biological profile equivalent or superior to that of the related lactones and show the established molecular signature of Hsp90 inhibitors in human colon cancer cells.
一系列的雷杜辛酸大环内酯，是天然大环内酯雷杜霉素的氮类似物，已通过化学合成制备，并作为热休克蛋白 90（Hsp90）的抑制剂进行了评估，Hsp90 是新型癌症治疗药物的一个新兴有吸引力的靶点。该合成涉及作为关键步骤的异香豆素中间体的开环，然后是闭环复分解反应以形成大环。随后对酯基进行一系列酰胺化操作，可在除去两个酚基后获得一系列新的大环内酯。这些新的雷杜辛酸内酰胺表现出比相关内酯类似物更高的代谢稳定性，而三种大环内酯与 Hsp90 的 N 端结构域 ATP 结合位点的共结晶证实它们以与天然产物雷杜霉素和我们之前合成的内酯类似物相似的方式结合。然而，有趣的是，在 N-苄基酰胺的情况下，观察到与蛋白质的疏水口袋的额外结合。在生物学测定中，新的大环内酯表现出与相关内酯相当或更好的生物学特征，并在人结肠癌细胞中显示出 Hsp90 抑制剂的既定分子特征。
