Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson's disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14-C15, and C17 positions. Systematic structure-activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC50 = 4.18 mu M), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP+-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD.

B(C6F5)(3)-promoted N-fluoroalkylthiolation reaction of amines with fluoroalkanesulfenic acids formed in situ from fluoroalkyl sulfoxides was successfully achieved, affording a series of fluoroalkanesulfenamides, while no N-fluoroalkylthiolation product was formed with sulfonamides under similar conditions. Notably, in the presence of Tf2O, the reaction of sulfonamides with fluoroalkyl sulfoxides proceeded smoothly at room temperature to give the corresponding N-fluoroalkylthiolation products. Two possible reaction pathways were proposed based on experimental results.

Halogenases offer valuable opportunities in synthetic chemistry and biocatalysis. Here, we identify two novel flavin-dependent phenolic multisite halogenases, FasVamrb99 and IdmB26, from distinct biosynthetic pathways that exhibit divergent polyhalogenation of naphthacemycin B2. Substrate screening revealed that both enzymes display robust polyhalogenation activity, enabling halogenation not only at ortho positions adjacent to nonphenolic hydroxyl groups but also across a range of drug molecules. These features highlight their versatility and potential as biocatalysts for synthetic applications.

Chiral amino-substituted piperidines are prevalent and privileged structural motifs in pharmaceuticals and bioactive compounds. Nevertheless, practical, atom-economical, and concise synthetic methods toward enantioenriched amino-substituted piperidines are still lacking. In this study, a highly efficient and enantioselective ruthenium-catalyzed asymmetric hydrogenation of readily available amino-substituted pyridinium salts is developed, providing a series of synthetically challenging chiral cis-3-amino-4-alkyl-substituted piperidines in good yields and enantioselectivities. The development of a sterically bulky Ad P -tBuO-BIBOP ligand is crucial for the success of this transformation. Mechanistic study revealed that the hydrogenation proceeds through initial formation of 4-methylene-1,4-dihydropyridine intermediate, followed by tautomerization to form acylimine species, asymmetric reduction of acylimine, and finally diastereoselective hydrogenation. The method has enabled concise and practical syntheses of JAK inhibitors tofacitinib and ASP3627, as well as the key chiral piperidine intermediate of ent-ritlecitinib.

Structure-based drug design (SBDD) has profoundly advanced the rational development of small molecule therapeutics by enabling the systematic optimization of drug-target interactions. A variety of molecular recognition models provide conceptual frameworks for understanding these interactions, thereby facilitating improvements in binding affinity, target selectivity, and pharmacokinetic profiles-key determinants of clinical success. To better emphasize the chemical nature of these interactions and to enhance the accessibility of rational drug design concepts for the synthetic chemistry community, we introduce chemical adaptation as a complementary framework to SBDD, offering an alternative, chemistry-oriented perspective for interpreting ligand-target interactions. This concept highlights deliberate, chemically driven strategies for optimizing ligand binding and improving drug-like characteristics. We classify chemical adaptation into four principal categories: ligand template adaptation (aligning the ligand's core structure with the topology of the target binding pocket), scaffold steric adaptation (refining the spatial orientation and steric complementarity of the molecular scaffold), functional group adaptation (modulating non-covalent interactions and physicochemical properties), and proximity-induced reactivity adaptation (leveraging covalent reactivity to strengthen target engagement). Collectively, these strategies underscore the necessity of precisely tailoring ligand structures to achieve optimal drug-like properties and offer a versatile, chemistry-centered framework applicable to the design of small molecule drugs across a broad spectrum of biological targets and therapeutic modalities.

Asymmetric living crystallization-driven self-assembly (CDSA) has recently emerged as a robust strategy toward the precision creation of pi-conjugated chiroptical nanostructures by taking advantage of the intrinsic optoelectronic properties and crystallinity of pi-conjugated blocks and the aggregation-induced chirality amplification effect. However, the field of asymmetric living CDSA remains in its infancy with a limited understanding of the relationship between the structure of pi-conjugated building blocks and asymmetric living CDSA behavior. In this contribution, we prepared a series of block copolymers consisting of core-forming oligo(p-phenylene ethynylene) pentamers and heptamers with linear pentyloxy, branched racemic 2-methylbutyloxy, and chiral (S)-2-methylbutyloxy side chains (denoted L-OPE n , rac-OPEn, and (S)-OPE n , n = 5 and 7, respectively) and corona-forming poly(N-isopropylacrylamide) (PNIPAM n , n = 36 and 40). We then investigated their CDSA behavior in detail. It was found that the increase of the OPE chain length and the decrease of the PNIPAM chain length could promote the crystallization of block copolymers. More importantly, the structure of the side chain significantly affected asymmetric CDSA behavior. In comparison with the linear side chains, branched racemic and chiral side chains can not only significantly enhance pi-pi stacking strength but also induce regularly twisted stacking of OPE units to give helical nanofibers with a preferred handedness. (S)-OPE5/7 and rac-OPE5/7 units of block copolymers adopted a single-layer face-to-face twisted stacking mode to form helical nanofibers with comparable circular dichroism (CD) signals in methanol. On the contrary, L-OPE5/7 units of counterparts followed a face-to-face/side-by-side packing mode to form CD-silent nanofibers and nanoribbons. By one-step heating/cooling and self-seeding approaches, both (S)-OPE7-b-PNIPAM36 and rac-OPE7-b-PNIPAM36 gave uniform helical nanofibers of controlled lengths, showing typical living/controlled characteristics in micellar elongation. In stark contrast, the L-OPE7-containing counterpart only formed CD-silent and ill-defined nanofibers and nanoribbons. The results manifested that it was the subtle interplay of pi-pi stacking of the OPE backbone and the conformation effect of branched racemic and chiral side chains that rendered the regularly twisted stacking of rac-OPE5/7 and (S)-OPE5/7 units to give helical nanofibers with a preferred handedness. This work provides additional insights into the correlation between the structure of pi-conjugated segments, especially the side chains, and the asymmetric CDSA behavior. More appealingly, this work illustrates a more economical and efficient "racemic"-side-chain-directed asymmetric living CDSA approach toward precision creation of chiroptical nanostructures from diverse pi-conjugated entities.

The development of catalytic asymmetric strategies for directly constructing axially chiral diaryl ethers presents a substantial challenge owing to the inherent flexibility of the C-O bond and sterically congested substitution patterns that typically suppress both reactivity and enantioselectivity. Here we report an organocatalytic C-O bond-forming reaction that enables the facile synthesis of these chiral scaffolds. Employing a peptide-mimic phosphonium salt catalyst, this method exhibits broad substrate scope and achieves exceptional performance (up to 99% yield, 99% e.e.) under mild conditions. The efficacy of this methodology is further demonstrated through the late-stage diversification of complex molecular architectures, including derivatives of commercially available drugs. Mechanistic investigations delineate a peptide-mimic phosphonium salt-promoted stepwise nucleophilic aromatic substitution (SNAr) pathway, where the initial nucleophilic attack plays a pivotal role, serving as the determinant step for both rate and stereochemistry. Collectively, this work provides an efficient and enantioselective route to axially chiral diaryl ethers, opening practical avenues for integrating simple motifs into value-added, complex molecular architectures.

We report two model compounds, TTPY and BTPY, which feature resonance-assisted hydrogen bonds (RAHBs) formed between carbamate-functionalized thieno[3,2-b]thiophene or 2,2 '-bithiophene cores and flanking pyridine units. Single-crystal structure analysis reveals that moderate RAHBs run along the long axis, whereas weaker noncovalent interactions (e.g., S & centerdot;& centerdot;& centerdot;O and O & centerdot;& centerdot;& centerdot;H) are present along the short axis. The synergetic effect of these interactions imparts a rigid, coplanar structure to both TTPY and BTPY. Both computational and experimental studies indicate that RAHBs stabilize the planar molecular conformation through an enthalpic effect, with stabilization energies exceeding 10 kcal mol-1. The formation of these RAHBs is also entropically favorable, which ensures the stability of the planar conformation at elevated temperatures. Both single crystals adopt a one-dimensional layered stacking mode, and TTPY exhibits closer pi-pi stacking compared to BTPY. Consequently, TTPY-based organic field-effect transistors (OFETs) show optimal charge transport performance, achieving a maximum hole mobility of 0.035 cm2 V-1 s-1, which is slightly higher than that of BTPY-based devices (0.026 cm2 V-1 s-1). Thin film microstructural characterization confirms that TTPY possesses higher crystallinity and greater structural order, accounting for its superior device performance.