Yunsheng Xue

The present study systematically evaluated the structure–antioxidant activity relationship and mechanism of pterocarpans at the molecular level using theoretical calculations.

A facile, mild, and scalable late-stage N-alkenylative modification strategy is introduced on 1H-indoles, 9H-carbazoles, and their structural derivatives and analogues, including alkaloids, bioactive agents, and tryptophan motifs, via chemo- and regioselective phosphine-mediated propiolate hydroamination. Saliently, through this protocol, bisconjugation and macrocyclization on (bis)indolic scaffolds can also be accomplished, with the installation of new α,β-unsaturated ester handles for potential further versatile synthetic manipulations.

Non-aryl substituted aza-BODIPYs exhibit extraordinary optical properties. 1-Phenylethyl-substituted aza-BODIPY PE-BDP was herein successfully prepared. Based on X-ray crystallographic analysis, 1-phenylethyl segments at 1,7-sites in PE-BDP as a stable mesomer were observed for the first time, and the plane of the phenyl group in the 1-phenylethyl segment is orthogonal to the core of PE-BDP. This orthogonal structure enhanced the spin–orbit charge transfer intersystem crossing (SOCT-ISC), and PE-BDP could induce type-I ROS generation. By the cyclic voltammetry test of PE-BDP, the reduction–oxidation processes remained electrochemically reversible. Under alkaline conditions, the new dianion species generated from PE-BDP can be monitored by spectroscopic redshift, and theoretical calculations also supported this result. Self-assembled PE-BDP nanoparticles under irradiation exhibited a good tumor-inhibition capability by inhibiting proliferation and migration, and promoting the apoptosis of glioma cells by type-I ROS and photothermal effects.

A carbazole-stabilized boron-centered monoradical has been isolated and characterized. Interestingly, the B–N bond was elongated and activated in 1˙⁻[Na(15-crown-5)₂]⁺, which provides a new idea for the subsequent activation of the B–N bond.

A pair of aza-BODIPY isomers, 1,7-di-tert-butyl-3,5-dinaphthyl (Nap-BDP) and 1,7-dinaphthyl-3,5-di-tert-butyl (revNap-BDP), were prepared in this study.

C-Src is involved in multiple signaling pathways and serves as a critical target in various cancers. Growing evidence suggests that prolonging a drug’s residence time (RT) can enhance its efficacy and selectivity. Thus, the development of c-Src antagonists with longer residence time could potentially improve therapeutic outcomes. In this study, we employed molecular dynamics simulations to explore the binding modes and dissociation processes of c-Src with antagonists characterized by either long or short RTs. Our results reveal that the long RT compound DAS-DFGO-I (DFGO) occupies an allosteric site, forming hydrogen bonds with residues E310 and D404 and engaging in hydrophobic interactions with residues such as L322 and V377. These interactions significantly contribute to the long RT of DFGO. However, the hydrogen bonds between the amide group of DFGO and residues E310 and D404 are unstable. Substituting the amide group with a sulfonamide yielded a new compound, DFOGS, which exhibited more stable hydrogen bonds with E310 and D404, thereby increasing its binding stability with c-Src. These results provide theoretical guidance for the rational design of long residence time c-Src inhibitors to improve selectivity and efficacy.

Orthogonal therapy that combines CRISPR-based gene editing and prodrug-based chemotherapy is a promising approach to combat multidrug-resistant cancer. However, its potency to precisely regulate different therapeutic modalities in vivo is limited due to the lack of an integrated platform with high spatiotemporal resolution. Taking advantage of CRISPR technology, a Pt(IV)-based prodrug and orthogonal emissive upconversion nanoparticles (UCNPs), we herein rationally designed the first logic-gated CRISPR-Cas13d-based nanoprodrug for orthogonal photomodulation of gene editing and prodrug release for enhanced cancer therapy. The nanoprodrug (URL) was constructed by encapsulating a green light-activatable Pt(IV) prodrug and UV light-activatable Cas13d gene editing tool into UCNPs. We demonstrated that URL maintained excellent orthogonal emission behaviors under 808 and 980 nm excitations, allowing wavelength-selective photoactivation of Cas13d and the prodrug for downregulation of the resistance-related gene and induction of chemo-photodynamic therapy, respectively. Moreover, the photomodulation superiority of URL for overcoming drug resistance was highlighted by integrating it with a Boolean logic gate for programmable modulation of multiple cell behaviors. Importantly, in vivo studies demonstrated that URL can promote Pt(IV) prodrug activation and ROS generation and massively induce on-target drug accumulation by Cas13d-mediated drug resistance attenuation, delivering an ultimate chemo-photodynamic therapeutic performance in efficiently eradicating primary tumors and preventing further liver metastasis. Collectively, our results suggest that URL expands the Cas13d-based genome editing toolbox into prodrug nanomedicine and accelerates the discovery of new orthogonal therapeutic approaches.