A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity.

The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and the amine-functionalised tetrazine Tz7.

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics.

Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI-286), a similarly potent synthetic analogue.

Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides.

Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53-MDM2 protein-protein interaction (PPI). The peptide developed showed complete and selective covalent binding resulting in potent inhibition of p53-MDM2 PPI.