Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China.
School of Physical Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
Molecules. 2022 Dec 25;28(1):169. doi: 10.3390/molecules28010169.
NAMPT is an attractive target in cancer therapy and numerous NAMPT inhibitors have been developed. However, the clinical activities of NAMPT inhibitors have displayed disappointing results in clinical trials for their dose-limiting toxicities. In this study, reactive oxygen species (ROS)-responsive prodrugs of a NAMPT inhibitor FK866 were designed and synthesized. A short synthesis method was developed to shield the activity of FK866 through a quaternary ammonium connection. Two prodrugs, with boronic acid as a responsive group to ROS, were prepared and one of the prodrugs also contained a fluorescence carrier. Both of the prodrugs released the active compound by the treatment of HO, and the biological evaluation showed that they exhibited a higher potency in cells with high levels of ROS. Moreover, prodrug had the ability to release FK866 and simultaneously induce the fluorescence activation under the stimulation of HO. This method has the potential to improve the therapeutic window of NAMPT inhibitors.
NAMPT 是癌症治疗中有吸引力的靶点，已经开发出许多 NAMPT 抑制剂。然而，由于其剂量限制毒性，NAMPT 抑制剂在临床试验中的临床活性令人失望。在这项研究中，设计并合成了 NAMPT 抑制剂 FK866 的活性氧（ROS）响应前药。通过季铵连接开发了一种短的合成方法来屏蔽 FK866 的活性。制备了两个前药，其中一个前药含有硼酸作为 ROS 的响应基团，另一个前药还含有荧光载体。两种前药都通过 HO 的处理释放出活性化合物，生物学评价表明它们在 ROS 水平高的细胞中表现出更高的效力。此外，前药 能够在 HO 的刺激下释放 FK866 并同时诱导荧光激活。这种方法有可能提高 NAMPT 抑制剂的治疗窗口。
