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Bifunctional ligands possessing both μOR agonism and σ1R antagonism have shown promise in producing strong analgesic effects with reduced opioid-related side effects. However, the μOR agonism activity of most dual ligands diminishes compared with classical opioids, raising concern about their effectiveness in managing nociceptive pain. In this study, a new class of dual μOR agonist/σ1R antagonist was reported. Through structure–activity relationship analyses, we identified the optimal compound, 4x, which displayed picomolar μOR agonism activity (EC50: 0.6 ± 0.2 nM) and good σ1R inhibitory activity (Ki: 363.7 ± 5.6 nM) with excellent selectivity. Compound 4xexhibited robust analgesic effects in various pain models, with significantly reduced side effects. Importantly, compound 4xalso possessed good safety profiles and no abnormalities were observed in biological parameters even under a high dosage. Our findings suggest that 4xmay be a promising lead compound for developing safer opioids and warrants further in-depth studies.

Cancer still has elevated morbidity and mortality, which undoubtedly impacts the life quality of affected individuals. Remarkable advances have been made in cancer therapy, although the toxicities of traditional therapies remain an obvious challenge. Dahuang Zhechong Pill (DHZCP), developed by Zhongjing Zhang in the Synopsis of the Golden Chamber, represents an effective anticancer traditional Chinese medicine (TCM). In this review, it was found that DHZCP is therapeutically utilized in liver, lung, gastric, pancreatic and other cancers in clinic. Pharmacological evidence showed that its anti-tumor mechanisms mainly involve induced cell cycle arrest, apoptosis and autophagy, as well as suppressed tumor cell proliferation, obstructed angiogenesis and metastasis, enhanced immunity, and reversal of multidrug resistance. The present review provides a solid basis for the clinical application of DHZCP and may promote the wide use of TCM in clinical antitumor application.

Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3swith a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11kand 11l, which inhibited hDHODH activity with IC50values of 9 and 4.5 nM, respectively. Protein–ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11kand 11lwith hDHODH. Compounds 11kand 11lsignificantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11ldisplayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11lwith hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.

As a neurotransmitter, norepinephrine (NE) is critical for psychiatric conditions, neurodegenerative diseases, and pheochromocytoma. A real-time and noninvasive method for the detection of NE as a tracer to investigate the NE-relevant disease treatment process is urgently desirable. Herein, we successfully developed a turn-on NE bioluminescent probe (NBP), which was grounded on p-toluenethiol deprotectrf by nucleophilic substitution. Compared with other analytes, the NBP exhibited high sensitivity and selectivity in vitro. More importantly, the NBP provides a promising strategy for in vivoimaging of NE in living animals with noninvasive visualization and real-time features.