Vol 31, No 8 (2024)

The topoisomerases (TOPO) play indispensable roles in DNA metabolism, by regulating the topological state of DNA. Topoisomerase I and II are the well-established drug-targets for the development of anticancer agents and antibiotics. These drugs-targeting enzymes have been used to establish the relationship between drug-stimulated DNA cleavable complex formation and cytotoxicity. Some anticancer drugs (such as camptothecin, anthracyclines, mitoxantrone) are also widely used as Topo I and Topo II inhibitors, but the poor water solubility, myeloma suppression, dose-dependent cardiotoxicity, and multidrug resistance (MDR) limited their prolong use as therapeutics. Also, most of these agents displayed selective inhibition only against Topo I or II. In recent years, researchers focus on the design and synthesis of the dual Topo I and II inhibitors, or the discovery of the dual Topo I and II inhibitors from natural products. Shikonin (a natural compound with anthraquinone skeleton, isolated from the roots of Lithospermum erythrorhizon) has drawn much attention due to its wide spectrum of anticancer activities, especially due to its dual Topo inhibitive performance, and without the adverse side effects, and different kinds of shikonin derivatives have been synthesized as TOPO inhibitors for the development of anticancer agents. In this review, the progress of the shikonin and its derivatives together with their anticancer activities, anticancer mechanism, and their structure-activity relationship (SAR) was comprehensively summarized by searching the CNKI, PubMed, Web of Science, Scopus, and Google Scholar databases.

Epilepsy is a chronic neurological degenerative disease with a high incidence, affecting all age groups. Refractory Epilepsy (RE) occurs in approximately 30-40% of cases with a higher risk of sudden unexpected death in epilepsy (SUDEP). Recent studies have shown that spontaneous seizures developed in epilepsy can be related to an increase in oxidative stress and reactive oxygen derivatives (ROS) production. Increasing ROS concentration causes lipid peroxidation, protein oxidation, destruction of nuclear genetic material, enzyme inhibition, and cell death by a mechanism known as "ferroptosis" (Fts). Inactivation of glutathione peroxidase 4 (GPX4) induces Fts, while oxidative stress is linked with increased intracellular free iron (Fe+2) concentration. Fts is also a non-apoptotic programmed cell death mechanism, where a hypoxia-inducible factor 1 alpha (HIF-1α) dependent hypoxic stress-like condition appears to occur with accumulation of iron and cytotoxic ROS in affected cells. Assuming convulsive crises as hypoxic stress, repetitive convulsive/hypoxic stress can be an effective inducer of the "epileptic heart" (EH), which is characterized by altered autonomic function and a high risk of malignant or fatal bradycardia. We previously reported that experimental recurrent seizures induce cardiomyocyte Fts associated with SUDEP. Furthermore, several genes related to Fts and hypoxia have recently been identified in acute myocardial infarction. An emerging theme from recent studies indicates that inhibition of GPX4 through modulating expression or activities of the xCT antiporter system (SLC7A11) governs cell sensitivity to oxidative stress from ferroptosis. Furthermore, during hypoxia, an increased expression of stress transcriptional factor ATF3 can promote Fts induced by erastin in a HIF-1α-dependent manner. We propose that inhibition of Fts with ROS scavengers, iron chelators, antioxidants, and transaminase inhibitors could provide a therapeutic effect in epilepsy and improve the prognosis of SUDEP risk by protecting the heart from ferroptosis.

Vitiligo is a disease characterized by skin discoloration, and no safe and effective drugs have been developed until now. New drug research and development are imminent. This article reviews the research on small-molecule drugs for vitiligo from 1990 to 2021 at home and abroad. They are classified according to their structures and mechanisms of action, including natural products and derivatives, anti-oxidative stress drugs, immunosuppressants, prostaglandins, etc. The research on their anti-vitiligo activity, structural modification, new dosage forms, clinical trials, and the development trend in new anti-vitiligo drugs are reviewed, which provides important references for the development of new drugs.

The application describes the synthesis of 1H-pyrazolo[4,3-H]quinazoline compounds for treating cell proliferation dysfunction and is a broad-spectrum and strongly- active inhibitor for a cell cyclin-dependent kinase (CDK).