Article
Biochemistry & Molecular Biology
Wojciech Bocian, Beata Naumczuk, Magdalena Urbanowicz, Jerzy Sitkowski, Anna Bierczynska-Krzysik, Elzbieta Bednarek, Katarzyna Wiktorska, Malgorzata Milczarek, Lech Kozerski
Summary: The study revealed that compounds 2 and 3, along with their decomposition products, form molecular complexes or alkylate DNA nitrogen bases inside the nick of DNA. Through a series of experiments, it was confirmed that these compounds effectively inhibit the activity of topoisomerase I.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Sabrina X. Van Ravenstein, Kavi P. Mehta, Tamar Kavlashvili, Jo Ann W. Byl, Runxiang Zhao, Neil Osheroff, David Cortez, James M. Dewar
Summary: Using Xenopus egg extracts, this study demonstrates that the TOP2 poisons etoposide and doxorubicin inhibit DNA replication through different mechanisms. Etoposide induces TOP2-dependent DNA breaks and TOP2-dependent fork stalling, while doxorubicin stalls replication forks independently of TOP2 by intercalating into parental DNA.
Article
Biochemistry & Molecular Biology
Amy Flor, Donald Wolfgeher, Jing Li, Leslyn A. Hanakahi, Stephen J. Kron
Summary: Camptothecins induce Top1 poisoning through covalent modification and oxidative stress-induced lipid peroxidation. This mechanism leverages a physiological cysteine-based redox switch in Top1 to selectively target rapidly proliferating cancer cells.
CELL CHEMICAL BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Endika Martin-Encinas, Asier Selas, Francisco Palacios, Concepcion Alonso
Summary: This review article provides an overview of the development of selective topoisomerase I inhibitors for cancer therapy, focusing on approved compounds, combination therapies, drawbacks, and future research directions. Studies on improving bioavailability and pharmacokinetics of potent synthetic derivatives are important for addressing the limitations of current clinically approved inhibitors.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Multidisciplinary Sciences
Diane T. Takahashi, Daniele Gadelle, Keli Agama, Evgeny Kiselev, Hongliang Zhang, Emilie Yab, Stephanie Petrella, Patrick Forterre, Yves Pommier, Claudine Mayer
Summary: In this study, the structure of archaeal CsTOP1 in the absence of DNA was solved, revealing an open conformation resulting from a rotation between the CAP and CAT modules. The flexibility of the hinge, a five-residue loop connecting these modules, allows the opening/closing of the enzyme and the entry of DNA. A conserved tyrosine near the hinge was identified as mediating the transition from the open to closed conformation upon DNA binding.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Eman M. Ahmed, Nadia A. Khalil, Ashraf F. Zaher, Shimaa M. Alhamaky, Mona S. El-Zoghbi
Summary: A series of newly synthesized compounds showed potent cytotoxic effects against tumor cell lines, with compounds 3a, 3d, 3e, and 3f exhibiting strong inhibition across various cancer cell lines and 4d and 4e demonstrating selective cytotoxic activity against melanoma cancer cells.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Xiaohong Yang, Zhi-Peng Wang, Sichuan Xiang, Daoqiang Wang, Yi Zhao, Dong Luo, Yanfei Qiu, Chao Huang, Jian Guo, Yuanwei Dai, Shao-Lin Zhang, Yun He
Summary: A library of novel CAA analogues was synthesized, among which compound F16 exhibited superior water solubility and antiproliferative activities compared to CAA. Mechanism studies confirmed that F16 acted as a dual Topo I and II poison and displayed potent antiproliferative activities against high Topo I and II expression cell lines. In xenograft models, F16 reduced tumor growth without apparent effect on mouse weight, making it a promising lead for the development of novel dual Topo I and II antitumor agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ryad M. Noha, Mohammed K. Abdelhameid, M. Mohsen Ismail, Manal R. Mohammed, Elmeligie Salwa
Summary: A series of benzimidazole derivatives with methoxylated aryl groups were designed and synthesized as potential cytotoxic agents. Some compounds showed strong inhibitory activity on tumor cells in vitro and had effects on key processes such as cell cycle and apoptosis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Somenath Roy Chowdhury, Subhendu K. Das, Bijoylaxmi Banerjee, Srijita Paul Chowdhuri, Hemanta K. Majumder, Benu Brata Das
Summary: This study reveals the important role of Tyrosyl DNA-phosphodiesterase 1 (TDP1) in protecting Leishmania donovani parasites from oxidative stress-induced DNA damage and resistance to certain antileishmanial drugs.
Article
Biochemistry & Molecular Biology
Bini Chhetri Soren, Jagadish Babu Dasari, Alessio Ottaviani, Beatrice Messina, Giada Andreotti, Alice Romeo, Federico Iacovelli, Mattia Falconi, Alessandro Desideri, Paola Fiorani
Summary: A drug obtained from an open-access drug bank was found to strongly and irreversibly inhibit the cleavage step of human DNA topoisomerase IB, reducing cell viability in three different cancer cell lines. Molecular docking and dynamics simulations suggested that the drug binds inside the enzyme's catalytic site, potentially offering a lead compound for developing an efficient anti-tumor molecule targeting human DNA topoisomerase IB.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Praffulla Kumar Arya, Pranabesh Mandal, Krishnendu Barik, Durg Vijay Singh, Anil Kumar
Summary: DNA topoisomerase I (Topo I) is an essential enzyme involved in various cellular activities and has been found to play a crucial role in the nucleic acid metabolism of Leishmania donovani. Inhibition of this enzyme has shown promise as a therapy for visceral leishmaniasis, but current treatment options have limitations. In this study, computational methods were used to investigate the inhibition of LdTopo I by phytochemicals derived from Indian medicinal plants. Three compounds exhibited the highest inhibitory potential and hold promise for the development of novel inhibitors.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Francesco Madeddu, Jessica Di Martino, Michele Pieroni, Davide Del Buono, Paolo Bottoni, Lorenzo Botta, Tiziana Castrignano, Raffaele Saladino
Summary: This study used computational methods to analyze the interaction between two new antitumor drug molecules and hTop1p enzyme. The results showed that these two compounds have a similar inhibitory mechanism to CPT and may have potential antitumor activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Kyung-Hwa Jeon, Seojeong Park, Hae Jin Jang, Soo-Yeon Hwang, Aarajana Shrestha, Eung-Seok Lee, Youngjoo Kwon
Summary: The study revealed that AK-I-190, a novel topoisomerase II inhibitor, exerts potent inhibitory activity by intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in less DNA toxicity compared to etoposide. AK-I-190 induces G1 arrest and effectively inhibits cell proliferation and colony formation in an androgen receptor-negative CRPC cell line, indicating the potential clinical relevance of topoisomerase II catalytic inhibitors in treating this type of prostate cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
J. Lapoirie, L. Tran, L. Piazza, C. Contin-Bordes, M. E. Truchetet, F. Bonnet
Summary: Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by microangiopathy and fibrosis. This study suggests that subcytotoxic doses of irinotecan and its active metabolite SN38 can effectively reduce collagen production in SSc fibroblasts by regulating the levels of gene expression, potentially limiting fibrosis.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Ahmed Seddek, Christian Madeira, Thirunavukkarasu Annamalai, Christopher Mederos, Purushottam B. Tiwari, Aaron Z. Welch, Yuk-Ching Tse-Dinh
Summary: This study establishes a yeast-based screening system that can identify human TOP1 poisons with anticancer efficacy and TOP1 suppressors that inhibit TOP1 DNA binding or cleavage activity.
FRONTIERS IN BIOSCIENCE-LANDMARK
(2022)