Old drug, new use: The thalidomide-based fluorescent probe for cysteine detection and imaging in living cells.

Thalidomide, as a high-profile cereblon (CRBN) ligand, has attracted much attention because of its ability to target protein degradation. In this study, we are committed to developing a new fluorescent probe THD-1 based on thalidomide, aiming at improving the performance of cysteine fluorescent probe in optical properties and biocompatibility. The experimental results showed that THD-1, as a cysteine fluorescent probe, owned the characteristics of obvious colorimetric change, fast response time, good selectivity and high sensitivity. The mechanism of THD-1 sensing cysteine was further verified to ensure its reliability and effectiveness. It was also worth mentioning that THD-1 was successfully applied to the biological imaging of cysteine in living A549 cells, which highlighted its value in practical application. Overall, thalidomide, as a clinically approved drug, not only enriches the fluorescent skeleton library, but also paves a new way for the further development of fluorescent probes.

Old drug, new use: The thalidomide-based fluorescent probe for hydrazine detection.

Thalidomide, a widely used ligand for cereblon (CRBN), has been gaining attention for its targeted protein degradation. In this study, we aimed to improve the optical and biocompatible features of hydrazine fluorescent probes by a novel probe called TH-1, based on the thalidomide moiety. Our results demonstrate that TH-1 exhibits remarkable properties including significant colorimetric changes, a fast response time, excellent selectivity, and high sensitivity as a hydrazine fluorescent probe. The mechanism by which TH-1 senses hydrazine has been convincingly verified. Notably, we have successfully applied TH-1 for bioimaging of hydrazine in living A549 cells, highlighting its practical significance. Moreover, the utilization of thalidomide, a clinically approved drug, as a fluorescent skeleton has expanded the repertoire of fluorescent skeleton libraries, paving the way for further on fluorescent probes.

The aptamer-based RNA-PROTAC.

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.

Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity.

The base excision repair (BER) pathway is essential for cancer cells to resist chemotherapeutic treatment, but its significance is underrated. The present study describes a novel Pt(IV) prodrug, AP1, targeting a critical BER protein, apurinic/apyrimidinic endonuclease 1 (APE1). AP1 induces intracellular accumulation of platinum and activates DNA damage response and apoptosis signals. AP1 can strongly inhibit the growth of malignant cells, including cisplatin-resistant cancer cells, with up to 18.11 times inhibition compared with cisplatin. Moreover, it is as toxic to normal cells as cisplatin. In a xenograft model, AP1 is 3.86-fold more potent than cisplatin without adverse effects. Intriguingly, AP1 can directly inhibit the AP endonuclease activity of APE1, leading to an interruption of miRNA processing and upregulation of the tumor suppressor PTEN. Our findings shed light on a mode of Pt(IV) interaction with a target protein and highlight the critical role of BER in platinum-based cancer treatment.

Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs.

The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.

Catalytic asymmetric synthesis of N-substituted tetrahydroquinoxalines via regioselective Heyns rearrangement and stereoselective transfer hydrogenation in one pot.

N-Substituted tetrahydroquinoxalines (37 examples) were step-economically obtained in good yield (<97%) and ee (<99%) with readily available substrates. The reaction proceeds through an interesting regioselective Heyns rearrangement/enantioselective transfer hydrogenation in one pot. The substrate scope and the reaction mechanism were systematically investigated.

Regioselective, Diastereoselective, and Enantioselective One-Pot Tandem Reaction Based on an in Situ Formed Reductant: Preparation of 2,3-Disubstituted 1,5-Benzodiazepine.

The 1,5-benzodiazepines are important skeletons frequently contained in medicinal chemistry. Herein, we described an unexpected tandem cyclization/transfer hydrogenation reaction for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The enolizable aryl aldehydes were chosen as substrates to react with symmetric and unsymmetric o-phenylenediamines. The unforeseen tandem reaction occurred among many possible latent side reactions under chiral phosphoric acid catalysis and affords the corresponding products in moderate yields and regioselectivities, good diastereoselectivities, and enantiomeric ratio (up to 99:1).