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.
In order to harness the functionality of metals, nature has evolved over billions of years to utilize metalloproteins as key components in numerous cellular processes. Despite this, transition metals ...such as ruthenium, palladium, iridium, and gold are largely absent from naturally occurring metalloproteins, likely due to their scarcity as precious metals. To mimic the evolutionary process of nature, the field of artificial metalloenzymes (ArMs) was born as a way to benefit from the unique chemoselectivity and orthogonality of transition metals in a biological setting. In its current state, numerous examples have successfully incorporated transition metals into a variety of protein scaffolds. Using these ArMs, many examples of new-to-nature reactions have been carried out, some of which have shown substantial biocompatibility. Given the rapid rate at which this field is growing, this review aims to highlight some important studies that have begun to take the next step within this field; namely the development of ArM-centered drug therapies or biotechnological tools.
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The metal-catalyzed reactions have given ...various chemical modifications that could not be achieved through basic organic chemistry reactions. In the past decade, many metal-mediated catalytic systems have carried out different transformations in cellulo, such as decaging of fluorophores, drug release, and protein conjugation. However, translating abiotic metal catalysts for organic synthesis in vivo, including bacteria, zebrafish, or mice, could encounter numerous challenges regarding their biocompatibility, stability, and reactivity in the complicated biological environment. In this review, we categorize and summarize the relevant advances in this research field by emphasizing the system’s framework, the design of each transformation, and the mode of action. These studies disclose the massive potential of the emerging field and the significant applications in synthetic biology.
Akin to a cellular “fingerprint,” the glycocalyx is a glycan‐enriched cellular coating that plays a crucial role in mediating cell‐to‐cell interactions. To gain a better understanding of the factors ...that govern in vivo recognition, artificial glycoproteins were initially created to probe changes made to the accumulation and biodistribution of specific glycan assemblies through biomimicry. As a result, the organ‐specific accumulation for a variety of glycoproteins decorated with simple and/or complex glycans was identified. Additionally, binding trends with regard to cancer cell selectivity were also investigated. To exploit the knowledge gained from these studies, numerous groups thus became engaged in developing targeted drug methodologies based on the use of artificial glycoproteins. This has either been done through adopting the glycoprotein scaffold as a drug carrier, or to directly glycosylate therapeutic proteins/enzymes to localize their biological activity. The principle aim of this Review is to present the foundational research that has driven artificial glycoprotein‐based targeting and subsequent adaptations with potential therapeutic applications.
To gain a better understanding of the factors that govern in vivo cellular recognition, artificial glycoproteins are created as biomimetic probes to study the influence of specific glycan assemblies to biodistribution. The principle aim of this Review is to present pioneering research that has driven artificial glycoprotein‐based targeting and subsequent adaptations with potential therapeutic applications.
An emerging approach in the field of targeted drug delivery is the establishment of abiotic metal‐triggered prodrug mechanisms that can control the release of bioactive drugs. Currently, the design ...of prodrugs that use abiotic metals as a trigger relies heavily on uncaging strategies. Here, we introduce a strategy based on the gold‐catalyzed activation of a phenanthridinium‐based prodrug via hydroamination under physiological conditions. To make the prodrug strategy biocompatible, a gold artificial metalloenzyme (ArM) based on human serum albumin, rather than the free gold metal complex, was used as a trigger for prodrug activation. The albumin‐based gold ArM protected the catalytic activity of the bound gold metal even in the presence of up to 1 mM glutathione in vitro. The drug synthesized via the gold ArM exerted a therapeutic effect in cell‐based assays, highlighting the potential usefulness of the gold ArM in anticancer applications.
A gold artificial metalloenzyme catalyzes the conversion of a prodrug into a phenanthridinium‐based anticancer drug with a good turnover number (>100) via hydroamination under mild conditions. The gold artificial metalloenzyme successfully triggers drug synthesis to achieve cancer therapy in cell‐based assays.
The first known report on the fluoride catalytic reactivity of potassium aryltrifluoroborate is described. The fluoride reactivity of phenyltrifluoroborate was controlled by substituents on the ...trifluoroborate‐attached benzene, such as the methoxy group at the para‐position and the methyl group at the ortho‐position. In addition, the selective aryltrifluoroborate‐catalyzed cleavage of the diphenylmethylsilyl group was achieved.
The unique fluoride reactivity of phenyltrifluoroborate in the desilylation of diphenylmethylsilyl groups is controlled by substituents on the benzene ring. The fluorine on trifluoroborate interacts with silicon and activates the Si–O bond to enable selective desilylation of the diphenylmethylsilyl group. Selective desilylation of a primary silyl ether in the presence of a secondary silyl ether by the trifluoroborate was also successful.
Posttranslational modifications (PTMs) to proteins are regulatory mechanisms that play a critical role in regulating growth and development. The SUMO system is a rapid and dynamic PTM system employed ...by eukaryotic cells. Plant SUMOs are involved in many physiological processes, such as stress responses, regulation of flowering time and defense reactions to pathogen attack. In Arabidopsis thaliana and rice (Oryza sativa), eight and seven SUMO genes, respectively, were predicted by sequence analysis. Phylogenetic tree analysis of these SUMOs shows that they are divided into two groups. One consists of SUMOs that contain no SUMO acceptor site and are involved in monoSUMOylation of their target proteins. Rice OsSUMO1 and OsSUMO2 are in this group, and are structurally similar to each other and to Arabidopsis AtSUMO1. The other group is composed of SUMOs in which an acceptor site (ΨKXE/D) occurs inside the SUMO molecule, suggesting their involvement in polySUMOylation. Several studies on the rice SUMOs have been performed independently and reported. Individual names of rice SUMOs are confusing, because a unified nomenclature has not been proposed. This review clarifies the attribution of seven rice SUMOs and unifies the individual SUMO names.
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