Organic & Biomolecular Chemistry最新文献

Copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) was employed to synthesize a new cavitand (1) having four cholate groups covalently connected to the cavitand core. CuAAC between a tetrapropargyl cavitand 2 and 3α-azido-cholic acid 3 led to the isolation of pure cavitand 1, which was fully characterized by the usual complement of spectroscopic techniques. While its solubility was limited in pure aqueous media, the complexation of three 4,4′-bipyridinum (viologen) guests could be investigated, using square wave voltammetric (SWV) techniques, in a mixture of H₂O/DMSO (5 : 2 v/v) also containing 40 mM sodium tetraborate as the supporting electrolyte and further experimental evidence supporting the formation of a complex between cavitand 1 and V²⁺ (viologen) with a 1 : 1 stoichiometry was obtained using ITC and electrospray ionization mass spectrometry (ESI-MS). Computational studies at the GFN2-xTB/ALPB(water) semiempirical level of theory revealed that the cavitand adopts a compact globular structure in solution, while docking effectively with methylviologen as a guest without forming an inclusion complex.

Chiral pyrrolidines are key motifs in natural products and pharmaceutically active intermediates. Herein, we report a metal-free enantioselective intramolecular hydroamination of alkenes catalyzed by a chiral borophosphate. This chiral frustrated Lewis pair (FLP)-type catalyst outperforms chiral phosphoric acid alone, furnishing chiral pyrrolidines in up to 96% yield and 95% ee. This work extends the utility of chiral FLP catalysis to non-reductive asymmetric cyclization reactions.

Microwave technology is a green synthesis method that uses microwave energy to efficiently and selectively heat reaction systems, thereby significantly accelerating chemical reactions and enhancing product selectivity. Compared with conventional conductive heating, microwave-assisted synthesis enables rapid and uniform heating of the reaction system via its distinct mechanisms of volumetric heating and selective molecular excitation. This approach can markedly shorten reaction times, increase target product yields and selectivity, lower energy consumption, and reduce by-product formation, making it a valuable tool for advancing green and efficient synthetic technologies. Consequently, its application has expanded rapidly in the field of pharmaceutical synthesis in recent years. This article summarizes recent research progress in the use of microwave technology for various aspects of drug synthesis.

Ene-reductases (ERs) catalyze the reduction of activated carbon–carbon double bonds, a key transformation in metabolism and biocatalysis. While microbial ERs are well characterized, higher-eukaryote ERs remain largely unexplored. Here, the mammalian NADPH-dependent ER PTGR2 was systematically characterized through whole-cell biotransformations, in vitro assays, and molecular docking, revealing a broad substrate scope and demonstrating that xenobiotics competitively inhibit the reduction of endogenous mediators. This work adds to the known diversity of ERs beyond microbial families and provides a chemical perspective on the crosstalk between xenobiotic metabolism and inflammatory regulation.

A palladium-catalyzed cascade double annulation reaction for the synthesis of unsymmetrical di(heteroaryl)methanes from non-heteroaryl substrates has been developed. This five-step cascade reaction integrates a furan ring and an indole/isoquinolinone scaffold into a methane molecule through η³-allylpalladium(II)-catalyzed cycloisomerization of β-chlorovinyl ketones followed by allylic heteroarylation, enabling the rapid construction of diverse heteroaryl units with a flexible methylene linker. Furthermore, initial screening indicated that compound 5fa exhibited potential antitumor activity in HeLa cells with the highest inhibition rate among the selected compounds.

The relative configuration and the substitution pattern control the interaction of 2-(2-phenyl1,3-dioxan-4-yl)ethan-1-amines with σ₁ receptors or the PCP binding site of NMDA receptors. In order to investigate the influence of the orientation of the phenyl moiety in 2-position on the receptor interaction, the 2-phenyl-1,3-dioxane system was embedded in a tricyclic benzomorphan scaffold (3) fixing the phenyl moiety in an axial orientation relative to the 1,3-dioxane ring. The key step of the synthesis of tricyclic amines 3 was the addition of lithiated 2-methylbenzamide 7 at pentanone 6 to afford the tertiary alcohol 8. Lactone formation (9), DIBAH reduction (10) and intramolecular transacetalization led to the tricyclic alcohol 11, which was converted into a series of twelve primary, secondary and tertiary amines 3a–m. Although the primary amine 3a is structurally related to the potent PCP antagonist 2a, it did not interact with the PCP binding site of the NMDA receptor. The missing ethyl moiety and/or an unfavorable orientation of the phenyl moiety might be responsible for the lost PCP affinity of 3a. As observed for the flexible 1,3-dioxanes 1b and 2b, introduction of a benzyl moiety at the amino group resulted in high σ₁ receptor affinity of 3b. In accordance with σ₁ pharmacophore models, two small or two large substituents at the amino moiety were less tolerated by the σ₁ receptor, whereas an additional small methyl moiety increased the σ₁ affinity of 3h and 3j. With respect to σ₁ receptor affinity and selectivity over the σ₂ subtype, the methylated cyclohexylmethylamine 3j (K_i(σ₁) = 6.4 nM, 9-fold selectivity) represents the most promising ligand. The highest ligand-lipophilicity efficiency (LLE) was obtained for the secondary cyclohexylmethylamine 3d (LLE = 6.7). However, the highest metabolic stability (phase I metabolism) was determined for the benzylamine 3b (89% intact after incubation for 90 min).

Cell-penetrating peptides (CPPs) are short amino acid sequences capable of traversing biological membranes and enabling intracellular delivery of diverse therapeutic cargos, thereby addressing core barriers in drug development, including poor cellular uptake, rapid systemic clearance, nonspecific distribution, and enzymatic instability. This review dissects the physicochemical design principles governing CPP–membrane interactions—charge density and distribution, amphipathicity, secondary structure, and environmental responsiveness—and explains how these features influence internalization pathways and cytosolic access. Therapeutic applications are organized by cargo class, including nucleic acids, proteins and antibodies, and small molecules and imaging agents. For each category, we analyze how cargo size, charge, and structural complexity constrain delivery efficiency and how strategies such as conjugation, nanocarrier functionalization, and chemical modification have been applied to circumvent these limitations. Effective CPP-mediated delivery is therefore determined not by peptide sequence alone but by deliberate alignment of peptide properties with cargo characteristics, biological context, and therapeutic objectives. By integrating mechanistic understanding with practical constraints in therapeutic development, we aim to provide practical guidance for the deliberate design of CPP systems with improved delivery efficiency and translational relevance.

We here report a novel acetohydroxamic acid-assisted peptide hydrazide ligation (APHL) strategy for chemical protein synthesis. With acetohydroxamic acid serving as a non-thiol additive, sodium nitrite-activated peptide hydrazides are in situ converted to reactive peptide O-acyl hydroxamates, which undergo efficient and direct ligation with N-terminal cysteine-containing peptides. This thiol-additive-free approach is compatible with one-pot ligation–desulfurization and ligation–oxidative folding. The utility of this strategy is demonstrated by the expedient synthesis of site-specifically lactylated histone H3 (H3K18la) and the disulfide-rich neurotoxin Calciseptine. Our study expands the repertoire of hydrazide-based ligation and provides a practical, operationally straightforward tool to accelerate chemical protein synthesis.

Bisaspochalasin F (1), a new cytochalasan homodimer featuring a fused tetrahydrofuran ring, was isolated from the endophytic fungus Aspergillus flavipes KIB-636, derived from Asarum heterotropoides Fr. Schmidt. Its structure, including the absolute configuration, was unambiguously established by single-crystal X-ray diffraction analysis and comprehensive spectroscopic data. A biomimetic semisynthesis of 1 was successfully achieved from the natural precursor aspochalasin D via LiOH-mediated dimerization. Notably, this dimerization significantly potentiated the inhibitory effect on Ca_v3.2 calcium channels: compound 1 exhibited an IC₅₀ value of 6.99 ± 0.23 μM, whereas the monomer aspochalasin D was inactive. Consistent with this in vitro finding, 1 demonstrated analgesic efficacy in a mouse acetic acid-induced writhing model at a dosage of 10 mg kg⁻¹, significantly reducing the total number of writhes and prolonging the latency to the first writhe in mice.

House–Meinwald rearrangement of oxindole substrates facilitating a one-pot synthesis of 3-substituted 4-hydroxyquinolin-2-ones and quinoline-2,4-diones under EBHP and base-mediated conditions is reported. This transformation proceeds through a well-defined sequence involving epoxidation, formation of a quinone methide-type intermediate, and subsequent ring expansion. The crucial carbonyl migration step was further substantiated by DFT studies. Moreover, the synthetic utility of the resulting 3-substituted 4-hydroxyquinolin-2-ones was demonstrated through late-stage diversification, highlighting the versatility of this protocol.