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

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.

Oncolytic Hairpin DNA Pair: Selective Cytotoxic Inducer through MicroRNA-Triggered DNA Self-Assembly

“…In particular, biomedical applications have been limited to secondary roles such as imaging systems, drug delivery carriers, and enzyme reaction sites. , Our hairpin DNA self-assembly system makes it possible to use the products as therapeutic agents and would bring about a breakthrough in DNA nanotechnology-based drug discovery methods. The recent introduction of a synthetic prodrug design strongly supports the strategic advancement of in situ construction of therapeutic molecules . In the field of nucleic acid therapeutics, build-up approaches for RNA interference using linear siRNA fragments or circular siRNA precursors have been reported .…”

Transition Metal Scaffolds Used To Bring New‐to‐Nature Reactions into Biological Systems

“…Serum albumin, which can be easily extracted from a number of sources (i. e. human, bovine, etc), has been another protein scaffold of interest. Different from many of the scaffolds discussed so far, albumin is known to have multiple binding pockets that can be exploited for various transformations [203–214] . For instance, binding of a manganese‐porphyrin complex into drug site 3 allowed researchers to demonstrate the asymmetric sulfoxidation of thioanisole and its derivatives [207] .…”

“…Different from many of the scaffolds discussed so far, albumin is known to have multiple binding pockets that can be exploited for various transformations. [203][204][205][206][207][208][209][210][211][212][213][214] For instance, binding of a manganese-porphyrin complex into drug site 3 allowed researchers to demonstrate the asymmetric sulfoxidation of thioanisole and its derivatives. [207] On the other hand, researchers can also target the deep hydrophobic binding pocket of albumin (drug site 1).…”

Direct Organocatalytic Reductive Alkylation of Syncarpic Acid: Scope and Applications

“…The same result was observed in case of various basic reaction conditions (Scheme ). Because the Michael adduct 8a releases 4-benzylsyncarpic acid 5a under amino acid catalysis, we can use 8a as a prodrug in the cellular systems for further investigations. We have also performed a chemoselective mono-carbonyl reduction of the carbonyl rich adduct 8a (0.3 mmol, 1.0 equiv) with sodium borohydride (0.36 mmol, 1.2 equiv) in methanol at 25 °C for 12 h, which afforded the chemo-selectively mono-carbonyl reduced compound 9a in 62% yield (Scheme ).…”