Molecular editing around privileged scaffolds, also known as periphery editing, is a commonly used strategy in contemporary drug discovery and development. Tranylcypromine (TCP) is a widely acknowledged scaffold with diverse pharmacological activities. TCP-derived compounds target different enzymes and cellular receptors such as amine oxidase, platelet P2Y₁₂ receptor, and cytochrome P450 superfamily. These compounds have demonstrated various effects including antidepressant, anticancer, antiviral properties, involvement in prostaglandin synthesis, and mediation of drug metabolism. Notably, the first reversible oral P2Y₁₂ receptor antagonist, ticagrelor, is currently used to prevent future myocardial infarction, stroke, and cardiovascular death. Several TCP-based lysine demethylase 1 (LSD1) inhibitors are currently undergoing clinical assessment. MIV-150, a third-generation non-nucleoside reverse transcriptase inhibitor, has progressed to the clinical stage for treating human immunodeficiency virus type 1 (HIV-1) seronegative patients suffering from acute coronary syndrome. This review aims to explore the target landscape of TCPs, highlight key structure-activity relationships (SARs), and emphasize the therapeutic potential of TCPs for treating various diseases. Finally, the lessons learned from our medicinal chemistry practice, challenges and future directions of TCP-based drug discovery are briefly discussed.

The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8⁺ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.

Tepoxalin is a potent inhibitor of both the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade, as well as a potent anti-inflammatory and control-pain (postoperation, arthritis et. al.) agent. The new method about the use of novel synthesis reagents and the first using ionic liquid as reactive solvent to synthesize tepoxalin were presented in this paper. The ionic liquid can be easily recycled and reused for several runs efficiently. The analgesic activity of tepoxalin was detected by acetic acid test on mice. The analysis of variance showed that oral administration of tepoxalin could significantly inhibit the number of writhing response within 1 hour and prolong the latent time in a dose dependent manner as compared with CMC control group (P < 0.05). At the same time, tepoxalin had the same analgesic activity as diclofenac sodium.