An orally available non-nucleotide STING agonist with antitumor activity.

Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-ß secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.

Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.

Functionalised nanoparticles complexed with antibiotic efficiently kill MRSA and other bacteria.

Antibiotic-resistant bacterial infections are a vexing global health problem and have rendered ineffective many previously-used antibiotics. Here we demonstrate that antibiotic-linkage to surface-functionalized silica nanoparticles (sNP) significantly enhances their effectiveness against Escherichia coli, and Staphylococcus aureus, and even methicillin-resistant S. aureus (MRSA) strains that are resistant to most antibiotics. The commonly-used antibiotic penicillin-G (PenG) was complexed to dye-labeled sNPs (15 nm diameter) containing carboxyl groups located as either surface-functional groups, or on polymer-chains extending from surfaces. Both sNPs configurations efficiently killed bacteria, including MRSA strains. This suggests that activities of currently-ineffective antibiotics can be restored by nanoparticle-complexation and used to avert certain forms of antibiotic-resistance.

Studies toward the total synthesis of dihydrolycolucine. Preparation of AB and CEF ring fragments.

A strategy for the synthesis of the lycopodium alkaloid dihydrolycolucine (1) has been investigated. Synthetic routes were developed based on N-acylpyridinium salt chemistry to prepare target fragments 3 and 4 that could ultimately converge to the natural product. Key reactions include IMDA cycloadditions and retro-Mannich ring-openings to form both the AB and the EF ring fragments. The ring C precursor was prepared using pyridine substitution and directed lithiation chemistry. A Suzuki cross-coupling of rings C and EF led to the CEF ring fragment. Initial attempts at closure of the seven-membered D ring were unsuccessful.

Chemoselective derivatization of a bionanoparticle by click reaction and ATRP reaction.

Horse spleen apoferritin, the hollow protein shell derived from ferritin, a special biological nanoparticle, can be chemoselectively modified at the lysine residues, which affords a robust scaffold for further chemical reactions including Cu(i)-catalyzed azide-alkyne cycloaddition reaction and atom transfer radical polymerization reaction.

A fluorogenic 1,3-dipolar cycloaddition reaction of 3-azidocoumarins and acetylenes.

Copper(I)-catalyzed 1,3-dipolar cycloaddition reaction of nonfluorescent 3-azidocoumarins and terminal alkynes afforded intense fluorescent 1,2,3-triazole products. The mild condition of this reaction allowed us to construct a large library of pure fluorescent coumarin dyes. Since both azide and alkyne are quite inert to biological systems, this reaction has potential in bioconjugation and bioimaging applications. [reaction: see text]