The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure–activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure–activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.

We evaluated the cytotoxicity and underlying mechanisms of cardiac glycosides, including digoxin, ouabain and proscillaridin A, on the proliferation of breast cancer MCF-7 cells. In terms of inhibition of cell proliferation of MCF-7 cells, the compounds rank in the order proscillaridin A>digoxin>ouabain. While both digoxin and ouabain inhibited topoisomerase II catalytic activity at nanomolar concentrations (100 nM), neither agent inhibited topoisomerase I catalytic activity even at concentrations as high as 100 μM. On the other hand, proscillaridin A was a potent poison of topoisomerase I and II activity at nanomolar drug concentrations (30 nM, 100 nM, respectively), suggesting that this agent may produce its cytotoxic activity by targeting both enzymes simultaneously. These studies suggest that the stabilization of DNA-topoisomerase II complexes is closely linked to the mechanism of digoxin, ouabain and proscillaridin A cytotoxicity. The potential DNA-binding properties of the cardiac glycosides have been assessed by measuring the displacement of ethidium bromide from calf thymus DNA. These results indicate that digoxin, ouabain and proscillaridin A neither intercalate nor interact with the minor groove of DNA.

Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017–2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.

Endocytosis is one of the major ways cells communicate with their environment. This process is frequently hijacked by pathogens. Endocytosis also participates in the oncogenic transformation. Here, we review the approaches to inhibit endocytosis, discuss chemical inhibitors of this process, and discuss potential clinical applications of the endocytosis inhibitors.

We designed and synthesized the 1,3,4-thiadiazole derivatives differing in the structure of the substituents in C2 and C5 positions. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and normal cell line (fibroblasts). The results showed that in both breast cancer cell lines, the strongest anti-proliferative activity was exerted by 2-(2-trifluorometylophenylamino)-5-(3-methoxyphenyl)-1,3,4-thiadiazole. The IC₅₀ values of this compound against MCF-7 and MDA-MB-231 breast cancer cells were 49.6 µM and 53.4 µM, respectively. Importantly, all new compounds had weaker cytotoxic activity on normal cell line than on breast cancer cell lines. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds. The most likely mechanism of action for the new compounds is connected with the activities of Caspase 3 and Caspase 8 and activation of BAX proteins.

Three derivatives of ouabain, digoxin and proscillaridin A containing the carboxylic group instead of the lactone moiety were synthesized and examined for cytotoxicity in human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing an MTT assay and inhibition of [3H]thymidine incorporation into DNA in both MCF-7 and MDA-MB-231 breast cancer cells demonstrated that compound 3, the most active of the series, proved to be only slightly less potent than proscillaridin A. We evaluated the effects of these compounds 1—3 on change in intracellular Ca2+, appearance of apoptosis, inhibition of DNA topoisomerase I and II, and the activity of caspase-3 in breast cancer cells. These studies indicate that the increase in potency for 3 may be related, in part, to an activation of caspase-3, increasing free calcium concentration and topoisomerase II inhibition. All these data emphasize the potential usefulness of these derivatives of cardiac glycosides as anticancer agents.