Search

Antibody-enzyme conjugates have shown potential as tissue-specific prodrug activators by antibody-directed enzyme prodrug therapy (ADEPT), but the approach met challenges clinically due to systemic drug release. Here, we report a novel dual-targeting ADEPT system (DuADEPT) which is based on active cancer receptor targeting of both a trastuzumab-sialidase conjugate (Tz-Sia) and a highly potent sialidase-activated monomethyl auristatin E (MMAE) prodrug scaffold. The scaffold is based on a four-way junction of the artificial nucleic acid analog acyclic (L)-threoninol nucleic acid ((L)-aTNA) which at the ends of its four arms carries one nanobody targeting HER2 and three copies of the prodrug. Dual-targeting of the constructs to two proximal epitopes of HER2 was shown by flow cytometry, and a dual-targeted enzymatic drug release assay revealed cytotoxicity upon prodrug activation specifically for HER2-positive cancer cells. The specific delivery and activation of prodrugs in this way could potentially be used to decrease systemic side effects and increase drug efficacy, and utilization of Tz-Sia provides an opportunity to combine the local chemotherapeutic effect of the DuADEPT with an anticancer immune response., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Herein we report on the decarboxylative alkenylation between alkyl carboxylic acids and enol triflates. The reaction is mediated by a dual catalytic nickel and iridium system, operating under visible light irradiation. Two competing catalytic pathways, from the excited state iridium photocatalyst, are identified. One is energy transfer from the excited state, resulting in formation of an undesired enol ester. The desired pathway involves electron transfer, resulting in decarboxylation to ultimately give the target product. The use of a highly oxidizing iridium photocatalyst is essential to control the reactivity. A diverse array of enol triflates and alkyl carboxylic acids are investigated, providing both scope and limitations of the presented methodology., (© 2023 Wiley-VCH GmbH.)

A method for automated solid-phase synthesis of oligo(disulfide)s was developed. It is based on a synthetic cycle comprising removal of a protecting group from a resin-bound thiol followed by treatment with monomers containing a thiosulfonate as an activated precursor. For ease of purification and characterization, the disulfide oligomers were synthesized as extensions of oligonucleotides on an automated oligonucleotide synthesizer. Six different dithiol monomer building blocks were synthesized. Sequence-defined oligomers of up to seven disulfide units were synthesized and purified. The sequence of the oligomer was confirmed by tandem MS/MS analysis. One of the monomers contains a coumarin cargo that can be released by a thiol-mediated release mechanism. When the monomer was incorporated into an oligo(disulfide) and subjected to reducing conditions, the cargo was released under near-physiological conditions, which underlines the potential use of these molecules in drug delivery systems., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We describe here the development of a visible light driven nickel carbonylation catalyst. The combination of the large bite-angle Xantphos ligand with nickel(0) generates a catalyst capable of activating alkyl halides toward carbonylation at ambient temperature in the presence of blue light irradiation, and the reductive elimination of high energy acid chloride products. Unlike classical carbonylations, where the coordination of carbon monoxide inhibits the reactivity of earth abundant nickel catalysts, a CO-associated nickel is found to be the active catalyst in the reaction. Coupling the build-up of acid chlorides with nucleophile addition can be used to access various amides, esters and thioesters, including those of sterically encumbered substrates or with metal-reactive functionalities., (© 2022 Wiley-VCH GmbH.)

Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)