DNA topoisomerases as molecular targets for anticancer drugs

Abstract

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.

The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative

“…Due to the known activity of acridine and acridone derivatives as human topoisomerase inhibitors widely analysed for cancer chemotherapy [14,17,31], we decided to analyse the influence of Compound 1 as well as its R8 conjugate on the fungal equivalent of that enzyme. The relaxation of supercoiled plasmid DNA by yeast topoisomerase II (yTOPO II) was studied in the presence of different concentrations of both compounds.…”

“…These enzymes are the targets of important anticancer and antibacterial drugs. Human type IIA topoisomerases are the targets of the widely used anticancer agents such as etoposide, anthracyclines and mitoxantrone [17]. Bacterial type II topoisomerases (gyrase and Topo IV) are the targets of quinolones and aminocoumarin antibiotics [18], whereas eukaryotic type IB topoisomerases (Top1) are targeted by camptothecin and its derivatives and novel noncamptothecins in clinical development (indenoisoquinolines and ARC-111) [19].…”

“…Hence, in this paper, we report the synthesis and biological properties of C-1311 and C-1305 analogues (Figure 1) and the ability of bioactive peptide octaarginine to smuggle C-1311 imidazoacridinone scaffold into fungal cells. As acridine and acridinone derivatives with anticancer activity are reported to be effective human topoisomerase I and II inhibitors (e.g., mitoxantrone [30], C-1311 and C-1305 [14,31], m-AMSA [17] or 9-aminoacridine derivatives [32]), we have also analysed the inhibitory effect of selected derivatives on yeast topoisomerase II activity (yTOPO II). 1 were prepared as monohydrochlorides according to the previously reported procedure [33].…”

Unboxing the molecular modalities of mutagens in cancer

“…For example, the first compounds as DNA damaging agents that entered the market were DNA intercalating alkylating agents such as Carmustine, Lomustine, and Semustine, which modify DNA bases by forming cross-linkages (Nikolova et al 2000 ). Similarly, other compounds inducing DNA damage effect are platinum compounds such as Carboplatin, Cisplatin, Oxaliplatin induce DNA damage by forming DNA crosslinks (Hato et al 2014 ); antimetabolite DNA antagonists like 5-Fluorouracil, Gemcitabine, Floxuridine, 6-mercaptopurine, Fludarabine, Cladribine induce DNA damage by generating replication interference (Tiwari 2012 ); and topoisomerase inhibitors such as Etoposide, Doxorubicin, Daunorubicin, interfere with DNA function by inhibiting the DNA-protein complex stability (Buzun et al 2020 ) (Cheung-Ong et al 2013 ). Although chemotherapeutic DNA damaging agents have been investigated for their anti-cancer properties in various cancers, several adverse outcomes are also reported.…”

Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

“…The enzyme tyrosil-DNA-phosphodiesterase 1 (TDP1) is one of the promising ones [ 4 ]. This enzyme is an important supplementary target for anticancer therapies based on topoisomerase inhibitors 1 (TOP1), since it plays a key role in the removal of TOP1-DNA adducts stabilized by TOP1 inhibitors such as camptothecine [ 5 ] and its clinical derivatives [ 6 ]. TDP1 is also capable of hydrolysing apurinic sites, and thus leading to their repair.…”