Ren-Wang Jiang

Activating NRAS mutations occur in approximately 20% of melanomas but remain largely undruggable due to the lack of effective targeted therapies. We previously identified casein kinase 1δ (CK1δ) as a critical upstream regulator that stabilizes oncogenic NRAS mutants. However, no selective CK1δ inhibitors have advanced to clinical evaluation. Here, we report the discovery of 8u, a selective CK1δ degrader derived from PF-670462. Compound 8u potently degrades CK1δ in NRASQ61R melanoma cells (DC50 = 1.25 μM, Dmax = 74%) via the ubiquitin-proteasome system, sparing against the closely related isoform CK1α and CK1ε. CK1δ degradation induced by 8u leads to destabilization of NRASQ61R and attenuation of downstream signaling pathways. Furthermore, 8u elicited significant tumor regression (TGI = 58.9%) in an NRASQ61R xenograft model in vivo at 30 mg/kg. The studies establish targeted degradation of CK1δ as a promising therapeutic strategy for NRAS-mutant melanoma.

Single‐crystal X‐ray diffraction (SCXRD) is a key technique for the structural determination of organic molecules. However, natural flavonoid glycosides are difficult to crystallize due to their large volume, flexible glycosidic bonds, and limited solubility. Herein, a novel methylthio‐modified palladium(II)‐based metal‐organic macrocycle ( PdS‐MOM ) was designed and synthesized as a crystalline mate that exhibits an excellent structural match for flavonoid glycosides. PdS‐MOM can efficiently accommodate flavonoid glycosides with different sugar chains and substituents in its open cavity and stably anchor their aglycone and sugar moieties through a synergistic strategy of π–π stacking and C–H···O interactions, respectively. Such stabilization not only promotes co‐crystallization and enables high‐precision structural elucidation by subsequent SCXRD analysis, but also provides conclusive evidence of the important roles of weak interactions in supramolecular assembly. Furthermore, besides the successful application to the structural analysis of thirteen different complex flavonoid glycosides, including monoglycosides, diglycosides, and triglycosides via three binding modes, PdS‐MOM facilitates direct structural elucidation of isoflavone glycosides from crude plant extracts by offline LC‐SCXRD. These synergistic noncovalent interactions demonstrate that PdS‐MOM exhibits broad substrate compatibility and excellent potential for structural elucidation of complex flavonoid glycosides.

Perfluorooctanoic acid (PFOA), an emerging contaminant of growing concern in recent years, is widely distributed in aquatic environments. Characterized by its robust chemical structure and persistence against natural degradation, PFOA poses significant threats to human health due to its bioaccumulation and carcinogenicity. Therefore, there is an urgent need to develop efficient methods for its removal from aqueous solutions. In this work, we report a novel, highly stable zirconium-based metal–organic framework (Zr-705) featuring hexagonal cavities with a pore size of 2.5 nm. The cavity is functionalized with additional phenyl groups that provide additional adsorption sites. Remarkably, Zr-705 exhibits outstanding PFOA adsorption performance, including a record adsorption capacity (2031 mg g⁻¹), rapid uptake rate (2.25 mg mg⁻¹ h⁻¹), and excellent selectivity and reusability. Furthermore, we developed a novel PFOA capture device based on a Zr-705 packed column, which demonstrates outstanding PFOA removal efficiency and water purification performance.

Lanosdracaenin A (1), an unprecedented triterpenoid, featuring a cleaved C ring and a lactonized D ring, and (±)-neodracaflavonoids A [(±)-2], a pair of rearranged flavonoids, were isolated from the resinous wood of Dracaena cochinchinensi. The absolute configurations of these compounds were determined by NMR spectroscopy, ECD calculations, and X-ray crystallography. All compounds exhibited significant anti-inflammatory effects in zebrafish model and LPS-stimulated RAW264.7 cells and suppressed the expression of the inflammation related genes IL-1β and IL-6.

Liquid water is essential for life, but many other substances that exist in the liquid state under standard conditions can have severe detrimental effects on living organisms and the environment. Isolation of these substances and determination of their three-dimensional structures are important to understand and, ultimately, to eliminate their harmful effects. Unfortunately, the mobility and disorder inherent in liquid molecules present major challenges for their structure elucidation. Consequently, very few structures of liquid molecules have been determined with certainty. Here, a hexazirconium-based MOF [ZrFMOF, Zr₆(μ₃-O)₈(COO)₈(H₂O)₈(DEF)₇] was synthesized and shown to act as a host framework to capture and facilitate the crystal structure determination of a series of liquid molecules. In this respect, the ZrFMOF serves as a robust pre-organized single crystalline coating (PSCC) material on the target guest. The ZrFMOF successfully encapsulated 12 toxic liquid molecules through weak interactions within two binding cavities (A and B), enabling accurate structural determination of individual guest molecules, two mixtures and an unknown liquid, all without the need for activation. Three distinct binding modes were identified, involving cavities A, B and A and B together. Furthermore, the ZrFMOF showed excellent adsorption capacities on iodine, various dyes and polyfluoroalkyl substances (PFAS), which was confirmed by solid-state NMR. In particular, the ZrFMOF has been so far the strongest absorbent on PFAS (absorption capacity: 1.23 mg mg⁻¹). In summary, it is demonstrated for the first time that the ZrFMOF is a versatile PSCC material that can be used to sequester and identify a range of toxic liquid molecules and remove three kinds of pollutants (iodine, dyes and PFAS) in water.

An efficient method for the remote heteroarylation of unactivated C(sp³)–H bonds has been developed involving a silyl radical-mediated relay reaction.

Crystalline sponges have made “crystallography without crystals” possible and have currently receive much attention, but it is difficult to apply them directly because of the tedious activation procedures. Therefore, it is important to prepare crystalline sponges that are highly stable and easy to operate. In this work, a new carbazole metal organic framework (CMOF) was synthesized and characterized via NMR, MS and X-ray diffraction analyses. The CMOF could directly capture liquids G1–G3, solids G4 and G5 in a THF solution, a mixture of G2 and G5, and monomers and mixed enantiomeric molecules G6–G9 without the need for activation. Furthermore, the CMOF could be used to identify the products from phytochemical isolation [cinnamaldehyde (G10)], organic synthesis [benzyl 2-hydroxybenzoate (G11)] and biosynthesis [veratryl alcohol (G12)] and monitor chemical reactions [acetylation of 4-allyl-2-methoxyphenol (G13) to 4-allyl-2-methoxyphenyl acetate (G14)]. The guests bound to the CMOF via five different modes (I–V). Thus, this work reports a new crystalline sponge that does not require activation and, most surprisingly, can capture guest molecules within one minute.

Bufadienolides, naturally occurring steroids primarily found in toads, have garnered attention for their pharmacological properties and ecological significance. In this study, we isolated and identified 21 bufadienolides from the gallbladders of Bufo gargarizans, comprising four new compounds and 17 known ones. Notably, the predominance of 15 bufadienolides with a 3α-OH configuration in toad bile differs significantly from the 3β-OH bufadienolides found in venom secreted by toad glands. Moreover, our investigation into the biotransformation of 3β-OH and 3α-OH bufadienolides in the liver and kidney tissues of toads revealed an irreversible conversion from 3β-OH to 3α-OH bufadienolides, suggesting a crucial role in toad self-detoxification. These findings provide valuable insights into the structural diversity of bufadienolides and advance our understanding of their medical and ecological significance. Graphical Abstract