Hydrogen sulfide (H2S) is an endogenous gasotransmitter with therapeutic potential for stroke. Our previous work identified that ADT-OH, an H2S donor with mitochondrial uncoupling activity, protects against stroke by activating the SQR-UCP2-AMPK pathway. Here, we launched a medicinal chemistry campaign based on hit compound ADT-OH to design and synthesize 30 novel derivatives, among which compound 16 displayed more potent mitochondrial uncoupling activity than ADT-OH, effectively reducing the mitochondrial membrane potential at a low concentration of 1 μM. In mouse models of ischemic and hemorrhagic stroke, compound 16 significantly alleviated brain injury and improved functional outcomes. Notably, these therapeutic effects were completely abolished in microglia/macrophage-specific SQR deletion (Cx3cr1Cre: Sqrfl/fl) mice, confirming that the biological function of compound 16 is mediated by a strictly SQR-dependent mechanism. Proteomic analysis further validated these findings. Overall, compound 16 represents a promising lead compound for stroke therapy based on a novel mechanism, warranting further development.
Peng Song, Yuan Li, Xiaohan Song et al.· Journal of Medicinal Chemist...· 0 citations
Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains oxidative phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for cancer therapy.
Hairu Ren, Jie Liu, Dachi Wang et al.· Journal of Medicinal Chemist...· 0 citations
