Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Bioorg Med Chem. 2010 Aug 15;18(16):5950-64. doi: 10.1016/j.bmc.2010.06.081. Epub 2010 Jul 1.
Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.
小分子可以作用于多个生物靶点，被认为是克服癌症化疗中常见的耐药性的有效手段。本研究基于肉桂酸羟肟酸（CHA）骨架，设计并合成了同时抑制肌苷单磷酸脱氢酶（IMPDH）和组蛋白去乙酰化酶（HDAC）的双重抑制剂，将 IMPDH 和 HDAC 的抑制剂的结构特征进行融合。探讨了连接子长度、连接子功能、取代位置和相互作用基团等关键特征。评估了它们对人 IMPDH1 和 IMPDH2 以及 HDAC 的抑制活性的单独贡献。
