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.
Highlights
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
With the goal of developing a synthetic prodrug that can be activated in vivo, retrosynthetic prodrug design helped to identify the use of sequential ring closing metathesis (RCM)/aromatization as an attractive mechanism to construct the core backbone of known aromatic drugs (Fig. 1b)
Given the general difficulty in producing working examples of synthetic prodrugs, a train of thought described as retrosynthetic prodrug design was employed
Summary
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. One of the principal aims of this study was to develop a working example of synthetic prodrugs that can be activated in vivo using artificial metalloenzymes. To tackle this challenge, a concept referred to as retrosynthetic prodrug design was employed. To minimize variables during in vivo prodrug activation, intramolecular reactions were prioritized This led to the selection of ring closing metathesis (RCM) as a starting point. With the goal of developing a synthetic prodrug that can be activated in vivo, retrosynthetic prodrug design helped to identify the use of sequential RCM/aromatization as an attractive mechanism to construct the core backbone of known aromatic drugs (Fig. 1b)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
