RRC ID 71944
Author Nasibullin I, Smirnov I, Ahmadi P, Vong K, Kurbangalieva A, Tanaka K.
Title Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression.
Journal Nat Commun
Abstract 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.
Volume 13(1)
Pages 39
Published 2022-1-10
DOI 10.1038/s41467-021-27804-5
PII 10.1038/s41467-021-27804-5
PMID 35013295
PMC PMC8748823
MeSH Animals Antineoplastic Agents / chemistry* Antineoplastic Agents / pharmacology Biocatalysis* Biological Phenomena Cell Line, Tumor Drug Delivery Systems Drug Design Drug Development Drug Discovery Female Humans Infant, Newborn Infant, Newborn, Diseases Mice Mice, Inbred BALB C Mice, Nude Molecular Docking Simulation Neoplasms / drug therapy* Prodrugs / chemistry* Xenograft Model Antitumor Assays
IF 12.121
Human and Animal Cells HeLa S3 A549 PC-3