Qing-Long Xu

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays a pivotal role in host defense against pathogenic microbes and tumors. However, aberrant activation of this pathway is tightly associated with a wide spectrum of inflammatory and autoimmune disorders, positioning STING inhibition as a promising therapeutic strategy. In this study, we designed and synthesized a series of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine derivatives as STING inhibitors. Compound 37 displayed potent STING inhibitory activity and favorable in vivo pharmacokinetic properties and safety. Further studies revealed that 37 blocks STING palmitoylation, thereby suppressing downstream signaling pathway activation. Oral administration of 37 exhibited significant anti-inflammatory effects in 10-carboxymethyl-9-acridanone (CMA)-challenged mice, Trex1−/− mice and cisplatin-induced acute kidney injury (AKI) mice. Collectively, compound 37 represents a novel orally bioavailable STING inhibitor with therapeutic potential against STING-driven inflammatory and autoimmune diseases.

Peroxisome proliferator-activator receptor δ (PPARδ) is ubiquitously expressed in the kidney, and its agonists are increasingly being recognized as a potential therapeutic strategy for renal diseases. In this work, we developed a series of arylimidazole derivatives as potent PPARδ agonists. Among them, compound 16a exhibited potent PPARδ agonistic activity (EC₅₀ = 0.50 nM) and high selectivity over PPARα/γ and some other nuclear receptors. The X-ray cocrystal structure revealed the binding mode of 16a and PPARδ at 1.94 Å resolution. Remarkably, compound 16a exhibited acceptable pharmacokinetic properties and good safety profiles in vivo and showed antirenal fibrosis effects in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Mechanistically, 16a activated PPARδ to restore fatty acid oxidation to attenuate TGF-β1-induced renal fibroblast activation. Collectively, 16a warrants further investigation as a promising drug candidate for treating renal fibrosis.

We report a novel visible light-promoted cascade reaction for the efficient synthesis of substituted naphthalenes in good yields. Upon visible-light irradiation, 2-methylbenzophenones generate transient hydroxy-o-quinodimethanes, which act as nucleophiles to attack (trifluoromethyl)alkenes, forming key intermediates containing carbonyl and 1,1-difluoroalkene moieties. Subsequently, a visible light-driven intramolecular Paternò-Büchi reaction ([2 + 2] cycloaddition) occurs, followed by a retro-[2 + 2] process that yields substituted 1,2-dihydronaphthalenes with concomitant release of carbonyl fluoride. Finally, a dehydrogenative aromatization step affords the desired substituted naphthalenes.

The cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway plays a key role in triggering interferon and inflammatory responses against microbial invasion or tumor. However, aberrant activation of the cGAS-STING pathway is associated with a variety of inflammatory and autoimmune diseases, and thus inhibition of STING is regarded as a potential new approach to treating these diseases. Herein, we report a series of novel indolyl-urea derivatives as STING inhibitors. The representative compound 42 exhibited potent STING inhibitory activity, acceptable pharmacokinetic properties, and good in vivo safety profiles. Mechanistically, 42 could block the palmitoylation of the STING protein and STING downstream signaling. Importantly, oral administration of 42 could effectively suppress STING-mediated inflammation in 10-carboxymethyl-9-acridanone (CMA)-treated mouse and Trex1^-/- mouse. Together, compound 42 represents a promising STING inhibitor for treating STING-associated inflammatory and autoimmune diseases.

An efficient organophosphorus-catalyzed thiocarbonylation reaction of disulfides with carboxylic acids under air conditions was described. Various functional groups on carboxylic acids and disulfides can be tolerated under the present reaction conditions, affording thioesters in good to excellent yields. This method exhibited excellent chemoselectivity and can be applied for the late-stage functionalization of drug molecules containing a carboxylic acid group.

This work reports a method for the catalytic synthesis of C(3) SCF₃-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF₃ reagent. This method can drive the conversion of tryptamine to the C(3) SCF₃-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF₃ source by P^III/P^V redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF₃-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.

An organophosphorus catalytic method for the synthesis of substituted 2-amidopyridines is reported. The method employs a small-ring organophosphorus-based catalyst and a hydrosilane reductant to drive the conversion of ketoximes and pyridine-N-oxides into 2-amidopyridines through sequential Beckmann rearrangement followed by [2,3]-sigmatropic rearrangement. The readily available ketoximes could be activated to nitrilium ions in P^III/P^V redox catalysis and could efficiently participate in the domino reaction of pyridine-N-oxides, thus providing various substituted 2-amidopyridines in moderate to excellent yields. This presented strategy features excellent functional group tolerance and a broad substrate scope.

Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC₅₀ = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC₅₀ = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8⁺ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.

A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by P^III/P^V═O redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.