Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target.

Discovery of GSK3527497: A Candidate for the Inhibition of Transient Receptor Potential Vanilloid-4 (TRPV4).

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors and . Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CL, Vdss, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdss and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdss in addition to bulk physicochemical properties.

Calcium-Catalyzed Formal [5 + 2] Cycloadditions of Alkylidene β-Ketoesters with Olefins: Chemodivergent Synthesis of Highly Functionalized Cyclohepta[]indole Derivatives.

The calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl alkylidene β-ketoesters with mono- and disubstituted aryl olefins to form cyclohepta[]indole derivatives has been established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged cyclohepta[]indoles. Overall, the method's highlights include: (1) use of a green, calcium-based catalyst (2.

Catalytic, Interrupted Formal Homo-Nazarov Cyclization with (Hetero)arenes: Access to α-(Hetero)aryl Cyclohexanones.

The first examples of a Lewis-acid catalyzed (hetero)arene interrupted, formal homo-Nazarov cyclization have been disclosed. Using SnCl4 as the catalyst, alkenyl cyclopropyl ketones undergo ring-opening cyclization to form six-membered cyclic oxyallyl cations. Subsequent intermolecular Friedel-Crafts-type arylation with various electron-rich arenes and heteroarenes provides functionalized α-(hetero)arylated cyclohexanones, a scaffold present in many natural products and bioactive compounds, in yields up to 88% and diastereomeric ratios up to 12:1.

Catalysis and chemodivergence in the interrupted, formal homo-Nazarov cyclization using allylsilanes.

A chemodivergent, Lewis acid catalyzed allylsilane interrupted formal homo-Nazarov cyclization is disclosed. With catalytic amounts of SnCl4 and in the presence of allyltrimethylsilane, a formal Hosomi-Sakurai-type allylation of the oxyallyl cation intermediate is observed. A variety of functionalized donor-acceptor cyclopropanes and allylsilanes were shown to be amenable to the reaction transformation and the allyl products were formed in up to 92% yield.

A catalytic diastereoselective formal [5+2] cycloaddition approach to azepino[1,2-a]indoles: putative donor-acceptor cyclobutanes as reactive intermediates.

A catalytic formal [5+2] cycloaddition approach to the diastereoselective synthesis of azepino[1,2-a]indoles is reported. The reaction presumably proceeds through a Lewis acid catalyzed formal [2+2] cycloaddition of an alkene with an N-indolyl alkylidene β-amide ester to form a donor-acceptor cyclobutane intermediate, which subsequently undergoes an intramolecular ring-opening cyclization. Azepine products are formed in up to 92% yield with high degrees of diastereoselectivity (up to 34:1 d.