The maleimide motif is widely used for the selective chemical modification of cysteine residues in proteins. Despite widespread utilization, there are some potential limitations, including irreversible nature reaction and, hence, and number attachment positions. We conceived a new class which would address these limitations provide opportunities protein modification. report herein use mono- dibromomaleimides reversible illustrate this on SH2 domain Grb2 adaptor (L111C). After initial with...

Although recent methods for the engineering of antibody-drug conjugates (ADCs) have gone some way to addressing challenging issues ADC construction, significant hurdles still remain. There is clear demand construction novel platforms that offer greater stability, homogeneity and flexibility. Here we describe a step towards platform next-generation antibody-based therapeutics by providing constructs combine site-specific modification, exceptional versatility high with retention antibody...

A general new method for the preparation of sulfonamides and activated sulfonate esters by direct coupling sulfonic acid salts with amines alcohols using reagent triphenylphosphine ditriflate is described. reusable polymer-supported these transformations under heterogeneous conditions also These methods provide a fundamentally approach to making small molecules containing sulfonamide functional group.

A series of dibromomaleimides have been shown to be very efficacious at insertion into peptidic disulfide bonds. This conjugation proceeds with a stoichiometric balance reagents in buffered solutions less than 15 min give discrete products while maintaining the bridge and thus peptide conformation. The is initiated by reduction using water-soluble phosphine, tris(2-carboxyethyl)phosphine (TCEP) which allows for subsequent substitution two maleimide bromides generated thiols. Reaction salmon...

The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody-drug conjugates (ADCs), in the clinic has had a major impact on treatment lymphoma breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages development, often due to shortcomings methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds allow efficient...

The introduction of non-natural entities into proteins by chemical modification has numerous applications in fundamental biological science and for the development manipulation peptide protein therapeutics. reduction native disulfide bonds provides a convenient method to access two nucleophilic cysteine residues that can serve as ideal attachment points such modification. optimum bioconjugation strategy utilizing these should include reconstruction bridge mimic role bond, maintaining...

An NHC/iron cooperative catalytic system mediates the aerobic oxidative esterification of aldehydes with phenols. The use equimolar amounts reactants led to good excellent isolated yields esters.

A next generation maleimide–ADC is shown to have excellent stability in blood serum, as well high potency and selectivity <italic>in vitro</italic>.

Reaction lubrication? The reaction between [Ni(1,5-cod)2] (cod=cyclooctadiene) and 1,3-bis-tert-butylimidazol-2-ylidene in the presence of silicone grease affords siloxane bridged dimer [{Ni[C(NtBuCH)2][O(Me2SiOSiMe2)-μ-O]}2]. In a greaseless apparatus, same yields 1 (see structure), via two structurally characterized intermediates.

Ligand exchange reactions reveal unexpected lability of the carbene ligands in two coordinate palladium(0) N-heterocyclic complexes; latter are found to be very effective catalysts for amination aryl chlorides.

The oxidative addition products trans-[Pd(NHC)(2)(Ar)Cl] (NHC = cyclo-C[N(t)BuCH](2); Ar Me-4-C(6)H(4), MeO-4-C(6)H(4), CO(2)Me-4-C(6)H(4)) have been isolated in good yields from the reactions of ArCl with amination precatalyst [Pd(NHC)(2)] and structurally characterized. former undergo reversible dissociation one NHC ligand at elevated temperatures, a value 25.57 kcal mol(-1) has determined for Pd-NHC enthalpy case where Me-4-C(6)H(4). Detailed kinetic studies established that proceed by...

Efficient dinuclear catalysts: A complex of {Rh2(OAc)4} with two N-heterocyclic carbenes (NHCs) at the axial positions catalyzes arylation aldehydes (see picture; R=alkyl, aryl). DFT calculations reveal subtle stereoelectronic effects resulting from NHC coordination to dirhodium(II) and suggest that complexes one ligand are catalytically active species.

Controlling maleimide hydrolysis allows the modular construction of bromomaleimide-mediated bioconjugates which are either stable or cleavable in an aqueous, thiol-mediated reducing environment.

An efficient new methodology for the arylation of aldehydes is disclosed which uses dirhodium(II) catalysts and N-heterocyclic carbene (NHC) ligands. Complexes Rh 2(OAc) 4 with one two NHCs attached on axial positions were successfully isolated, fully characterized, used as in reaction. The saturated monocomplex ((NHC 5)Rh 4) 31 was shown to be most active catalyst particularly alkyl aldehydes. DFT calculations support participation complexes NHC reaction species indicate that hydrogen bonds...

Bromopyridazinedione-mediated bioconjugation to a cysteine containing protein and disulfide peptide is described. The conjugates are cleavable in an excess of thiol, including cytoplasmically-relevant concentrations glutathione, show high level hydrolytic stability. constructs have the potential for four points chemical attachment.

Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened library isoxazolidine and isoxazole sulfonamides found four compounds that inhibited HIV‐1 infection in human CD4+ lymphocytic T cells with no toxicity at IC 90 concentrations. Structure‐activity relationship showed benzyl halo‐substituted aromatic ring on heterocycle scaffold were critical antiretroviral activity. The size position incorporated halogen had marked effect sulfonamide...

A next-generation disulfide stapling reagent, incorporating both reducing and re-bridging functions, is shown to be successful across various proteins.

In this communication we describe a novel acid-cleavable linker strategy for antibody–drug conjugation. Functional disulfide bridging of the single interchain bond trastuzumab Fab fragment yields homogeneous conjugate bearing thiomaleamic acid linker. This is stable at physiological pH and temperature, but quantitatively cleaves lysosomal to release drug payload.