Mini Reviews in Medicinal Chemistry - Volume 25, Issue 12, 2025

DNA topoisomerases, particularly type II, are crucial for DNA processes, such as replication, transcription, and chromosome segregation, making them prime targets for cancer therapy. This review delves into the multifaceted mechanisms of action of type II topoisomerases, highlighting their essential roles beyond cancer progression. It explores recent advancements in screening and designing metallic complexes as inhibitors of topoisomerase II activity. Emphasizing the structural and functional diversity between alpha and beta isoforms, it elucidates their significance in DNA metabolism and genome integrity. Additionally, this review discusses the interplay of topoisomerase II with cellular components, underscoring its regulatory roles in gene expression. Insights into screening and design strategies for metallic complex inhibitors are provided, showcasing their therapeutic potential against cancer. Overall, this review highlights the importance of understanding topoisomerase II inhibition mechanisms and the versatility of metallic complexes in biomedical research, paving the way for novel therapeutic strategies and broader applications beyond cancer therapy.

This mini-review summarizes the structure-property relationships of seven small-molecule drugs approved in 2024, providing insights into effective lead-to-candidate optimization strategies. The analysis focused on aprocitentan, flurpiridaz F-18, inavolisib, vorasidenib, ensitrelvir, golidocitinib, and zorifertinib, highlighting the key structural modifications that enhanced their drug-like properties. Notable optimization strategies included the strategic use of five- and six-membered nitrogen-containing heterocycles as cyclic bioisosteres and solubilizing groups. For the kinase inhibitor golidocitinib, the unique position of a solubilizing group within the binding pocket achieved dual benefits, i.e., enhanced target selectivity and physicochemical properties. When developing central nervous system-penetrant drugs such as zorifertinib, careful control of rotatable bonds, hydrogen bond donors, and molecular lipophilicity was critical for optimizing blood-brain barrier penetration while remaining suitable for oral administration. These findings on structure-property relationships offer valuable guidance for future drug development, particularly in addressing challenges related to solubility, bioavailability, and tissue-specific drug distribution.

This review delves into the potential of nanotechnology for improved lung cancer diagnosis and treatment. A critical focus is placed on various overexpressed biomarkers within lung tumors. These biomarkers serve as potential targets for nanoparticle-based drug delivery strategies. The review explores two main targeting approaches: passive and active (receptor-based) targeting. Active targeting mechanisms like EGFR, folic acid, and CD44 receptor targeting are specifically discussed. Additionally, the review examines stimuli-responsive systems for targeted drug delivery, including pH, temperature, ligand-attached, and multi-stimuli-responsive systems. Moreover, the role of nanotechnology in theranostics, which combines therapeutic and diagnostic capabilities, is explored and different types of nanocarriers, including lipid-based, polymer-based, metal-based, and magnetic nanoparticles, are examined for their potential applications. The review also highlights advancements in lung cancer diagnostic techniques beyond nanotechnology. This includes emerging tools like biomarkers, biosensors, and artificial intelligence, alongside improvements to established methods. Finally, the review provides a glimpse into ongoing clinical trials and concludes by emphasizing the transformative potential of nanotechnology in improving lung cancer patient outcomes.

Sigma receptors (σRs), comprising σ1 and σ2 subtypes, are versatile pharmacological targets with significant roles in cancer, neurodegeneration, and psychiatric disorders. The tetrahydroisoquinoline (THIQ) scaffold, a core structure in many biologically active compounds, has garnered attention as a versatile platform for designing σRs ligands. THIQ-based compounds exhibit potent σRs binding affinity, leading to therapeutic effects ranging from neuroprotection to antitumor activity. This mini-review explores the structural features of THIQ ligands, their interaction with σRs, and their therapeutic implications. Challenges and future prospects for THIQ derivatives in σRs research are also discussed.