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13 pages, 2151 KiB

Open AccessArticle

In Silico and In Vitro Investigation of Cytotoxicity and Apoptosis of Acridine/Sulfonamide Hybrids Targeting Topoisomerases I and II

by Mohamed Badr, Elshaymaa I. Elmongy, Doaa Elkhateeb, Yasmine S. Moemen, Ashraf Khalil, Hadeer Ali, Reem Binsuwaidan, Feby Awadallah and Ibrahim El Tantawy El Sayed

Pharmaceuticals 2024, 17(11), 1487; https://doi.org/10.3390/ph17111487 - 6 Nov 2024

Cited by 2 | Viewed by 1807

Abstract

Background: Sulfonamide acridine derivatives have garnered significant attention from medicinal chemists due to their diverse range of biological activities. Methods: In this study, eleven compounds were synthesized according to the literature, and their impact on cell growth inhibition, induction of apoptosis, and cell [...] Read more.

Background: Sulfonamide acridine derivatives have garnered significant attention from medicinal chemists due to their diverse range of biological activities. Methods: In this study, eleven compounds were synthesized according to the literature, and their impact on cell growth inhibition, induction of apoptosis, and cell cycle distribution were assessed in three different cell lines. Their inhibitory effects on the topoisomerase (Topo) I and II were investigated in vitro. Molecular docking studies were conducted to predict the binding affinities of these compounds for crystallized downloaded topoisomerases. Results: The compounds were examined in vitro for their anticancer activity against human hepatic (HepG2) colon (HCT-8) and breast (MCF-7) carcinoma cell lines. Compound 8b was the most active against HepG2, HCT-116, and MCF-7 with IC₅₀ 14.51, 9.39, and 8.83 µM, respectively, compared to Doxorubicin as reference. In addition, it demonstrated the highest potency among the tested compounds against Topo-I, with an IC₅₀ value of 3.41 µg/mL compared to the control camptothecin (IC₅₀ of 1.46 μM). Compound 7c displayed a significant inhibitory effect on Topo-II, with an IC₅₀ of 7.33 μM, compared to an IC₅₀ value of 6.49 μM via Doxorubicin, the control. Compounds 7c and 8b were assessed against topoisomerases showing induction of apoptosis and a reduction in the S phase of the cell cycle. Molecular docking demonstrated interaction with the active site as with those exhibited by the co-crystallized ligands of the crystallized proteins in both topoisomerases. Conclusion: Compounds 7c and 8b hold promise as potential anticancer drugs due to their anti-proliferative and proapoptotic effects, which are mediated by their action on the topoisomerase enzyme, particularly Topo II. Full article

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

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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

Cited by 3 | Viewed by 2365

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 [...] Read more.

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 4 | Viewed by 2184

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 [...] Read more.

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 6 | Viewed by 2492

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 [...] Read more.

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 7 | Viewed by 3224

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 [...] Read more.

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

Jump to: Research

32 pages, 2602 KiB

Open AccessReview

Managing Irinotecan-Induced Diarrhea: A Comprehensive Review of Therapeutic Interventions in Cancer Treatment

by Xiaoqin Yang, Jiamei Chen, Yitao Wang, Yihan Wu and Jinming Zhang

Pharmaceuticals 2025, 18(3), 359; https://doi.org/10.3390/ph18030359 - 2 Mar 2025

Cited by 1 | Viewed by 2751

Abstract

Irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, stands as a pivotal therapeutic agent in oncology. However, its use is primarily constrained by side effects such as neutropenia and the onset of delayed diarrhea. Despite the effective management of neutropenia, CPT-11-induced diarrhea (CID) [...] Read more.

Irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, stands as a pivotal therapeutic agent in oncology. However, its use is primarily constrained by side effects such as neutropenia and the onset of delayed diarrhea. Despite the effective management of neutropenia, CPT-11-induced diarrhea (CID) is often severe, leading to hospitalization, dosage adjustments, and in some cases, treatment discontinuation, which can significantly impact therapeutic outcomes. A multitude of pharmacological agents have been investigated in preclinical and clinical studies with the aim of reducing or preventing the onset of delayed diarrhea associated with CPT-11. This comprehensive review examines the underlying mechanisms of CPT-11-triggered delayed diarrhea and discusses the experimental medications and strategies that have been utilized to combat this adverse effect. This review encompasses an exploration of chemical formulations, the application of traditional Chinese medicine, and the advent of innovative drug delivery systems. It is anticipated that this article will serve as a valuable resource for both novice researchers in the realm of irinotecan chemotherapy and for those who are well-versed in the field, including experts and practicing clinicians. Full article

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

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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 56 | Viewed by 8311

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 [...] Read more.

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 8 | Viewed by 4845

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 [...] Read more.

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 14 | Viewed by 7617

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 [...] Read more.

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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