Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan; School of Life Science and Technology, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Bioorg Med Chem. 2019 Jul 1;27(13):2832-2844. doi: 10.1016/j.bmc.2019.05.013. Epub 2019 May 10.
A series of carborane-containing NAMPT inhibitors were designed and synthesized based on the structure of compounds 1 and the NAMPT inhibitory activity was evaluated using NAMPT Colorimetric Assay. Among the compounds synthesized, compounds 2b and 2c showed significant NAMPT inhibitory activity with IC values of 0.098 ± 0.008 and 0.057 ± 0.001 µM, respectively. Docking simulation of compound 2 toward NAMPT using the crystal structure of the FK866-NAMPT complex (PDB code: 2GVJ) with replacing the boron atom type by the C3 atom type of carboranes predicted that the NAMPT inhibitory activity of 2c was improved by the hydrogen bond formation between the carborane amide and H191 of NAMPT. Although dicarborane compounds 38, 50, 51, and 55 were synthesize aiming to two hydrophobic pockets present in the binding pocket of NAMPT, their inhibitory activity was moderate.
基于化合物 1 的结构，设计并合成了一系列含碳硼烷的 NAMPT 抑制剂，并采用 NAMPT 比色法评估了它们的 NAMPT 抑制活性。在所合成的化合物中，化合物 2b 和 2c 表现出显著的 NAMPT 抑制活性，IC 值分别为 0.098 ± 0.008 和 0.057 ± 0.001 µM。用 FK866-NAMPT 复合物（PDB 代码：2GVJ）的晶体结构进行化合物 2 对 NAMPT 的对接模拟，用碳硼烷的 C3 原子类型取代硼原子类型，预测 2c 的 NAMPT 抑制活性得到提高，是因为碳硼烷酰胺与 NAMPT 的 H191 之间形成氢键。尽管为了与 NAMPT 结合口袋中的两个疏水性口袋结合，合成了二碳硼烷化合物 38、50、51 和 55，但它们的抑制活性中等。
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