Journal of Medicinal Chemistry最新文献

Botulinum neurotoxin (BoNT) is the most toxic protein known to man and a Tier 1 bioterrorism agent. Among its serotypes, BoNT/A possesses the greatest potency and persistence, as such strategies to counteract it are highly coveted. Bifunctional molecules incorporating both metal chelation and a covalent warhead have shown great potential for blunting BoNT/A LC’s toxicity/longevity. To further explore this idea, new warheads as well as zinc metal-chelating scaffolds were prepared and examined. The structure–activity relationship and kinetic analyses of these inhibitors challenged the standard protease assay leading to a new screening platform implemented and validated. Reconnaissance studies from this new screening platform delineated an unprecedented structural flexibility associated with BoNT/A’s enzyme pocket, which can be induced by a small molecule for enhanced allosteric target inhibition of the protease. The culmination of these findings offers previously unrealized opportunities for neutralizing the BoNT/A protease and thus future in vivo applications.

Gram-positive superbugs resistant to methicillin and vancomycin pose a severe threat to global public health, urgently demanding novel therapeutic strategies. Herein, we rationally designed and synthesized vancomycin derivatives modified with diverse aryl sulfonium moieties to reactivate its antibacterial potency. By optimizing the sulfonium-based SAR, we got derivatives 2–3 orders of magnitude more active in vitro than vancomycin. Subsequently, preliminary toxicity evaluations for the optimal derivative, 7e, indicated a favorable therapeutic index, while pharmacokinetic assays revealed its good properties, suggesting great drug-like potential. Notably, 7e showed extremely potent in vivo protection efficacy by only a single-dose treatment in the challenging methicillin-resistant Staphylococcus aureus and VRE lethal sepsis mice models. Moreover, two independent and synergistic mechanisms of action were uncovered: membrane perturbation and enhanced cell wall biosynthesis inhibition. These findings revealed the unknown role of sulfonium strategy in vitro and in vivo and positioned 7e as a promising candidate for future development.

Tumor-associated macrophages (TAMs) are highly plastic tumor-infiltrating immune cells. Their reprogramming has emerged as a pivotal strategy in antitumor immunotherapy. The TLR7/8 agonist, IMDQ, has significant potential for reprogramming macrophages but lacks target specificity. To address this challenge, we developed novel folate receptor beta (FR-β) targeting chimeric molecules using 6-substituted pyrrolo[2,3-d]pyrimidines as high-affinity ligands, which demonstrate superior FR-β targeting capability compared with classical folic acid. These molecules integrate the FR-β targeting moiety with IMDQ, marking the first application of this immunomodulator in targeted chimeric constructs. In vitro and in vivo studies demonstrated that our chimeric molecules selectively reprogrammed TAMs toward an immunostimulatory phenotype, reshaped the tumor microenvironment, and inhibited tumor progression without systemic toxicity. Given that TAM accumulation is prevalent across all solid tumors, our strategy of precisely targeting and reprogramming of TAMs is universally applicable to treating various types of cancers, a potent and effective strategy for antitumor immunotherapy.

Small molecules capable of degrading estrogen receptor α (ERα) are of significant interest in breast cancer treatment. Herein, we rationally designed a series of ERα degraders (MR1–MR3) by conjugating methylene blue, a bifunctional photosensitizer, with the raloxifene pharmacophore. The lead compound MR3 exhibited high affinity to ERα, and it can induce a complete depletion of ERα in MCF7 breast cancer cells after 660 nm irradiation (0.4 W/cm²) for 1 min. Owing to the ERα degradation merit, MR3 displayed a 45-fold boosted anticancer activity (IC₅₀ = 0.55 μM) after irradiation. In the breast cancer xenograft mouse model, MR3 induced an obvious tumor regression (tumor growth inhibition = 118%), which was superior to that of the FDA-approved ERα degrader Faslodex. These important features make MR3 extremely intriguing for breast cancer treatment.