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Topoisomerases as Targets for Novel Drug Discovery

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 May 2024) | Viewed by 16909

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Special Issue Editor

Prof. Dr. Andrej Perdih

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Guest Editor

Theory Department, National Institute of Chemistry Ljubljana, Ljubljana, Slovenia
Interests: type II DNA topoisomerases; catalytic topo IIα inhibitors; medicinal chemistry; molecular simulations

Special Issue Information

Dear Colleagues,

A diverse family of efficient biological nanomachines, DNA topoisomerases monitor vital cellular processes such as replication and transcription. Because of their ability to efficiently modulate the topological changes of the DNA molecule, they are often referred to as the “magicians of the DNA world”. They are found in all prokaryotic and eukaryotic cells and even in some viruses and are involved in several processes that affect the DNA molecule. They are broadly classified as type I and type II topoisomerase and operate via complex catalytic cycles that allow DNA strands or duplexes to pass each other.

Molecules targeting DNA topoisomerases are well-established drugs that are widely used in therapy, either as antibacterial agents to treat numerous infections or in oncology as chemotherapeutic agents. However, current clinically used drugs targeting DNA topoisomerases face numerous challenges and limitations, such as the rapid emergence of bacterial resistance and the serious side effects of topoisomerase chemotherapeutics. Therefore, intensive research is currently underway to expand the understanding of these intriguing enzymes that modulate DNA topology and to develop new molecules that could overcome these challenges and lead to a new generation of drugs targeting topoisomerases.

In this special issue, Pharmaceuticals invites authors to submit research and review articles discussing new insights, perspectives, and challenges related to the study of topoisomerases and their use as drug targets. Topics may include a broad range of research, such as the study of bacterial or human topoisomerases by experimental or in silico methods, and the design, synthesis, and experimental characterization of new molecules targeting all members of the DNA topoisomerase family. The collection of manuscripts will be published as a Special Issue of the journal.

Prof. Dr. Andrej Perdih
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

topoisomerase
type I topoisomerase
type II topoisomerase
DNA Gyrase
DNA topology
catalytic inhibitors
topo II poisons
DNA gyrase inhibitors
Novel bacterial topoisomerase inhibitors (NBTI)
anticancer agents
antibacterial agents

Published Papers (7 papers)

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Research

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14 pages, 1833 KiB

Open AccessArticle

Gel-Free Tools for Quick and Simple Screening of Anti-Topoisomerase 1 Compounds

by Josephine Geertsen Keller, Kamilla Vandsø Petersen, Karol Mizielinski, Celine Thiesen, Lotte Bjergbæk, Rosa M. Reguera, Yolanda Pérez-Pertejo, Rafael Balaña-Fouce, Angela Trejo, Carme Masdeu, Concepcion Alonso, Birgitta R. Knudsen and Cinzia Tesauro

Pharmaceuticals 2023, 16(5), 657; https://doi.org/10.3390/ph16050657 - 27 Apr 2023

Viewed by 1584

Abstract

With the increasing need for effective compounds against cancer or pathogen-borne diseases, the development of new tools to investigate the enzymatic activity of biomarkers is necessary. Among these biomarkers are DNA topoisomerases, which are key enzymes that modify DNA and regulate DNA topology during cellular processes. Over the years, libraries of natural and synthetic small-molecule compounds have been extensively investigated as potential anti-cancer, anti-bacterial, or anti-parasitic drugs targeting topoisomerases. However, the current tools for measuring the potential inhibition of topoisomerase activity are time consuming and not easily adaptable outside specialized laboratories. Here, we present rolling circle amplification-based methods that provide fast and easy readouts for screening of compounds against type 1 topoisomerases. Specific assays for the investigation of the potential inhibition of eukaryotic, viral, or bacterial type 1 topoisomerase activity were developed, using human topoisomerase 1, Leishmania donovani topoisomerase 1, monkeypox virus topoisomerase 1, and Mycobacterium smegmatis topoisomerase 1 as model enzymes. The presented tools proved to be sensitive and directly quantitative, paving the way for new diagnostic and drug screening protocols in research and clinical settings. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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19 pages, 3626 KiB

Open AccessArticle

5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics

by Jessica Ceramella, Domenico Iacopetta, Anna Caruso, Annaluisa Mariconda, Anthi Petrou, Athina Geronikaki, Camillo Rosano, Carmela Saturnino, Alessia Catalano, Pasquale Longo and Maria Stefania Sinicropi

Pharmaceuticals 2023, 16(3), 353; https://doi.org/10.3390/ph16030353 - 25 Feb 2023

Cited by 2 | Viewed by 1371

Abstract

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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19 pages, 2739 KiB

Open AccessArticle

Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα

by Ilija N. Cvijetić, Barbara Herlah, Aleksandar Marinković, Andrej Perdih and Snežana K. Bjelogrlić

Pharmaceuticals 2023, 16(3), 341; https://doi.org/10.3390/ph16030341 - 23 Feb 2023

Cited by 1 | Viewed by 1578

Abstract

Phenotypic screening of α-substituted thiocarbohydrazones revealed promising activity of 1,5-bis(salicylidene)thiocarbohydrazide against leukemia and breast cancer cells. Supplementary cell-based studies indicated an impairment of DNA replication via the ROS-independent pathway. The structural similarity of α-substituted thiocarbohydrazone to previously published thiosemicarbazone catalytic inhibitors targeting the ATP-binding site of human DNA topoisomerase IIα prompted us to investigate the inhibition activity on this target. Thiocarbohydrazone acted as a catalytic inhibitor and did not intercalate the DNA molecule, which validated their engagement with this cancer target. A comprehensive computational assessment of molecular recognition for a selected thiosemicarbazone and thiocarbohydrazone provided useful information for further optimization of this discovered lead compound for chemotherapeutic anticancer drug discovery. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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13 pages, 1721 KiB

Open AccessArticle

Synthesis, Characterization, and Biological Evaluation of Meldrum’s Acid Derivatives: Dual Activity and Molecular Docking Study

by Syed Nasir Abbas Bukhari, Mohamed Abdelwahab Abdelgawad, Naveed Ahmed, Muhammad Wahab Amjad, Muhammad Ajaz Hussain, Mervat A. Elsherif, Hasan Ejaz, Nasser H. Alotaibi, Ignjat Filipović and Nenad Janković

Pharmaceuticals 2023, 16(2), 281; https://doi.org/10.3390/ph16020281 - 13 Feb 2023

Cited by 2 | Viewed by 2067

Abstract

In the presented study, eight novel Meldrum’s acid derivatives containing various vanillic groups were synthesized. Vanillidene Meldrum’s acid compounds were tested against different cancer cell lines and microbes. Out of nine, three showed very good biological activity against E. coli, and HeLa and A549 cell lines. It is shown that the O-alkyl substituted derivatives possessed better antimicrobial and anticancer activities in comparison with the O-acyl ones. The decyl substituted molecule (3i) has the highest activity against E. coli (MIC = 12.4 μM) and cancer cell lines (HeLa, A549, and LS174 = 15.7, 21.8, and 30.5 μM, respectively). The selectivity index of 3i is 4.8 (HeLa). The molecular docking study indicates that compound 3i showed good binding affinity to DNA, E. coli Gyrase B, and topoisomerase II beta. The covalent docking showed that 3i was a Michael acceptor for the nucleophiles Lys and Ser. The best E_b was noted for the topoisomerase II beta-LYS482-3i cluster. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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Review

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24 pages, 6355 KiB

Open AccessReview

Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents

by Prasanna Anjaneyulu Yakkala, Naveen Reddy Penumallu, Syed Shafi and Ahmed Kamal

Pharmaceuticals 2023, 16(10), 1456; https://doi.org/10.3390/ph16101456 - 13 Oct 2023

Cited by 7 | Viewed by 2909

Abstract

Topoisomerases are very important enzymes that regulate DNA topology and are vital for biological actions like DNA replication, transcription, and repair. The emergence and spread of cancer has been intimately associated with topoisomerase dysregulation. Topoisomerase inhibitors have consequently become potential anti-cancer medications because of their ability to obstruct the normal function of these enzymes, which leads to DNA damage and subsequently causes cell death. This review emphasizes the importance of topoisomerase inhibitors as marketed, clinical and preclinical anti-cancer medications. In the present review, various types of topoisomerase inhibitors and their mechanisms of action have been discussed. Topoisomerase I inhibitors, which include irinotecan and topotecan, are agents that interact with the DNA-topoisomerase I complex and avert resealing of the DNA. The accretion of DNA breaks leads to the inhibition of DNA replication and cell death. On the other hand, topoisomerase II inhibitors like etoposide and teniposide, function by cleaving the DNA-topoisomerase II complex thereby effectively impeding the release of double-strand DNA breaks. Moreover, the recent advances in exploring the therapeutic efficacy, toxicity, and MDR (multidrug resistance) issues of new topoisomerase inhibitors have been reviewed in the present review. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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17 pages, 3123 KiB

Open AccessReview

Developments in Non-Intercalating Bacterial Topoisomerase Inhibitors: Allosteric and ATPase Inhibitors of DNA Gyrase and Topoisomerase IV

by Scott Grossman, Colin W. G. Fishwick and Martin J. McPhillie

Pharmaceuticals 2023, 16(2), 261; https://doi.org/10.3390/ph16020261 - 8 Feb 2023

Cited by 2 | Viewed by 2273

Abstract

Increases in antibiotic usage and antimicrobial resistance occurrence have caused a dramatic reduction in the effectiveness of many frontline antimicrobial treatments. Topoisomerase inhibitors including fluoroquinolones are broad-spectrum antibiotics used to treat a range of infections, which stabilise a topoisomerase-DNA cleavage complex via intercalation of the bound DNA. However, these are subject to bacterial resistance, predominantly in the form of single-nucleotide polymorphisms in the active site. Significant research has been undertaken searching for novel bioactive molecules capable of inhibiting bacterial topoisomerases at sites distal to the fluoroquinolone binding site. Notably, researchers have undertaken searches for anti-infective agents that can inhibit topoisomerases through alternate mechanisms. This review summarises work looking at the inhibition of topoisomerases predominantly through non-intercalating agents, including those acting at a novel allosteric site, ATPase domain inhibitors, and those offering unique binding modes and mechanisms of action. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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20 pages, 1552 KiB

Open AccessReview

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

by Victor M. Matias-Barrios and Xuesen Dong

Pharmaceuticals 2023, 16(1), 94; https://doi.org/10.3390/ph16010094 - 9 Jan 2023

Cited by 6 | Viewed by 4056

Abstract

DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

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