Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression

Igor Nasibullin, Ivan Smirnov, Peni Ahmadi, Kenward Vong, Almira Kurbangalieva and Katsunori Tanaka ()
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Igor Nasibullin: RIKEN Cluster for Pioneering Research
Ivan Smirnov: Kazan Federal University
Peni Ahmadi: RIKEN Cluster for Pioneering Research
Kenward Vong: The Hong Kong University of Science and Technology
Almira Kurbangalieva: Kazan Federal University
Katsunori Tanaka: RIKEN Cluster for Pioneering Research

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27804-5

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DOI: 10.1038/s41467-021-27804-5

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