Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya street, Kazan, 420008, Russia.
Nat Commun. 2022 Jan 10;13(1):39. doi: 10.1038/s41467-021-27804-5.
Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. As a way to address this issue, this study investigates the design of synthetic prodrugs that are not only tuned to be harmless, but can be robustly transformed in vivo to reach therapeutically relevant levels. To accomplish this, retrosynthetic prodrug design highlights the potential of naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization. Structural adjustments will also be done to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. The developed prodrug therapy is found to possess excellent anticancer activities in cell-based assays. Furthermore, in vivo activation by intravenously administered glycosylated artificial metalloenzymes can also induce significant reduction of implanted tumor growth in mice.
考虑到过渡金属的固有毒性，它们在药物治疗中的应用必须控制在最小剂量，同时确保在复杂的生物系统中具有足够的催化活性。为了解决这个问题，本研究探讨了合成前药的设计，这些前药不仅经过精心设计使其无害，而且可以在体内进行稳健转化，达到治疗相关的水平。为了实现这一目标，回溯性前药设计突出了基于萘基 Combretastatin 的前药的潜力，这些前药通过连续的闭环复分解和芳构化形成高度活性的细胞抑制剂。还将进行结构调整，以改善与催化反应性、内在生物活性和水解稳定性相关的方面。所开发的前药疗法在基于细胞的测定中表现出优异的抗癌活性。此外，通过静脉内给予糖基化人工金属酶的体内激活也可以诱导小鼠植入肿瘤生长的显著减少。
