| 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
|
| Resource |
| Human and Animal Cells |
HeLa S3
A549
PC-3 |
