Atmospheric pressure Solids Analysis Probe (ASAP) mass spectrometry has facilitated the ionisation of oligomers from low molecular weight synthetic polymers, poly(ethylene glycol) (PEG: M(n) = 1430) and poly(styrene) (PS: M(n) = 1770), directly from solids, providing a fast and efficient method of identification. Ion source conditions were evaluated and it was found that the key instrument parameter was the ion source desolvation temperature which, when set to 600 °C was sufficient to vapourise the heavier oligomers for ionisation. PS, a non-polar polymer that is very challenging to analyse by MALDI or ESI without the aid of metal salts to promote cationisation, was ionised promptly by ASAP resulting in the production of radical cations. A small degree of in-source dissociation could be eliminated by control of the instrument ion source voltages. The fragmentation observed through in-source dissociation could be duplicated in a controlled manner through Collision-Induced Dissociation (CID) of the radical cations. PEG, which preferentially ionises through adduction with alkali metal cations in MALDI and ESI, was observed as a protonated molecular ion by ASAP. In-source dissociation could not be eliminated entirely and the fragmentation observed resulted from cleavage of the C-C and C-O backbone bonds, as opposed to only C-O bond cleavage observed from tandem mass spectrometry.

Collision-induced dissociation (CID) and electron-induced dissociation (EID) have been investigated for a selection of small, singly charged organic molecules of pharmaceutical interest. Comparison of these techniques has shown that EID carried out on an FTICR MS and CID performed on a linear ion trap MS produce complementary data. In a study of 33 molecule-cations, EID generated over 300 product ions compared to 190 product ions by CID with an average of only 3 product ions per precursor ion common to both tandem MS techniques. Even multiple stages of CID failed to generate many of the product ions observed following EID. The charge carrying species is also shown to have a very significant effect on the degree of fragmentation and types of product ion resulting from EID. Protonated species behave much like the ammonium adduct with suggestion of a hydrogen atom from the charge carrying species strongly affecting the fragmentation mechanism. Sodium and potassium are retained by nearly every product ion formed from [M + Na](+) or [M + K](+) and provide information to complement the EID of [M + H](+) or [M + NH(4)](+). In summary, EID is proven to be a fitting partner to CID in the structural elucidation of small singly charged ions and by studying EID of a molecule-ion holding different charge carrying species, an even greater depth of detail can be obtained for functional groups commonly used in synthetic chemistry.

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) was used to prepare glycosylated polyethylene (PE)-poly(ethylene glycol) (PEG) amphiphilic block copolymers. The synthetic approach involves preparation of alkyneterminated PE-b-PEG followed by CuAAC reaction with different azide functionalized sugars. The alkyne-terminated PE-b-PEG was prepared by etherification reaction between hydroxyl-terminated PE-b-PEG (M n $ 875 g mol 21 ) and propargyl bromide and azidoethyl glycosides were prepared by glycosylation of 2-azidoethanol. Atmospheric pressure solids analysis probe-mass spectrometry was used as a novel solid state characterization tool to determine the outcome of the CuAAC click reaction and end-capping of PE-b-PEG by the azidoethyl glycoside group. The aqueous solution selfassembly behavior of these amphiphilic glycosylated poly-V C 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 5184-5193

Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl 3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable "dual-base" palladiumcatalyzed C−N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.

Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody–drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens—but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin–drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads. Due to their small size (10 kDa), renal filtration eliminates Adnectins from the bloodstream within minutes to hours, ensuring low exposure to normal tissues. We used an engineered cysteine to conjugate an Adnectin that binds Glypican-3, a membrane protein overexpressed in hepatocellular carcinoma, to a cytotoxic derivative of tubulysin, with the drug-to-Adnectin ratio of 1. We demonstrate specific, nanomolar binding of this Adnectin–drug conjugate to human and murine Glypican-3; its high thermostability; its localization to target-expressing tumor cells in vitro and in vivo, its fast clearance from normal tissues and its efficacy against Glypican-3-positive mouse xenograft models.