Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer

2021 ◽  
Author(s):  
De-Xuan Hu ◽  
Wen-Lin Tang ◽  
Yu Zhang ◽  
Hao Yang ◽  
Wenjie Wang ◽  
...  
Keyword(s):  
Biological Activity ◽  
Drug Resistant ◽  
Dna Topoisomerase ◽  
Topoisomerase Ib

scholarly journals In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB

2021 ◽  
Vol 22 (14) ◽  
pp. 7455
Author(s):  
Bini Chhetri Soren ◽  
Jagadish Babu Dasari ◽  
Alessio Ottaviani ◽  
Beatrice Messina ◽  
Giada Andreotti ◽  
...  
Keyword(s):  
Enzyme Reaction ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib ◽  
Topological State ◽  
Cleavage Step ◽  
Dynamics Simulations ◽  
In Silico Characterization ◽  
Dna Complex

Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.

scholarly journals First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme

2012 ◽  
Vol 84 (9) ◽  
pp. 1867-1875 ◽  
Author(s):  
Néstor M. Carballeira ◽  
Michelle Cartagena ◽  
Fengyu Li ◽  
Zhongfang Chen ◽  
Christopher F. Prada ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Total Synthesis ◽  
Leishmania Donovani ◽  
Dna Topoisomerase ◽  
Triple Bonds ◽  
Weak Intermolecular Interactions ◽  
Topoisomerase Ib ◽  
Effective Inhibition ◽  
Acetylenic Fatty Acid

The fatty acids (±)-2-methoxy-6Z-heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme (LdTopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited LdTopIB, with the acetylenic acid displaying an EC50 = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit LdTopIB. The (±)-2-methoxy-6Z-heptadecenoic acid preferentially inhibited LdTopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of LdTopIB and either the double or triple bonds of the fatty acids. Toxicity toward Leishmania donovani promastigotes was also investigated, resulting in the order acetylenic > olefinic > saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC50 = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C17:1 fatty acids toward L. donovani promastigotes, but improves their selectivity index.

scholarly journals Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect

2013 ◽  
Vol 85 (10) ◽  
pp. 1433-1440 ◽  
Author(s):  
Christopher F. Prada ◽  
Raquel Álvarez-Velilla ◽  
Rafael Balaña-Fouce ◽  
Carlos Prieto ◽  
Estefania Calvo-Álvarez ◽  
...  
Keyword(s):  
Dna Topoisomerase ◽  
Topoisomerase Ib

Comparative studies of oxindolimine-metal complexes as inhibitors of human DNA topoisomerase IB

2018 ◽  
Vol 186 ◽  
pp. 85-94 ◽  
Author(s):  
Silvia Castelli ◽  
Marcos Brown Gonçalves ◽  
Prafulla Katkar ◽  
Gabriela Cristina Stuchi ◽  
Ricardo Alexandre Alves Couto ◽  
...  
Keyword(s):  
Metal Complexes ◽  
Comparative Studies ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib

A new bisbenzylisoquinoline alkaloid isolated from Thalictrum foliolosum, as a potent inhibitor of DNA topoisomerase IB of Leishmania donovani

Fitoterapia ◽  
2016 ◽  
Vol 109 ◽  
pp. 25-30 ◽  
Author(s):  
Ashish Kumar ◽  
Somenath Roy Chowdhury ◽  
Tapas Sarkar ◽  
Tulika Chakrabarti ◽  
Hemanta K. Majumder ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Potent Inhibitor ◽  
Dna Topoisomerase ◽  
Topoisomerase Ib ◽  
Bisbenzylisoquinoline Alkaloid

scholarly journals Characterization of DNA Binding by the Isolated N-Terminal Domain of Vaccinia Virus DNA Topoisomerase IB

Biochemistry ◽  
2017 ◽  
Vol 56 (26) ◽  
pp. 3307-3317 ◽  
Author(s):  
Benjamin Reed ◽  
Lyudmila Yakovleva ◽  
Stewart Shuman ◽  
Ranajeet Ghose
Keyword(s):  
Dna Binding ◽  
Vaccinia Virus ◽  
Dna Topoisomerase ◽  
Terminal Domain ◽  
Topoisomerase Ib

Molecular Beacon Enables Combination of Highly Processive and Highly Sensitive Rolling Circle Amplification Readouts for Detection of DNA-Modifying Enzymes

Nano LIFE ◽  
2015 ◽  
Vol 05 (02) ◽  
pp. 1541002 ◽  
Author(s):  
Emil L. Kristoffersen ◽  
Maria Gonzalez ◽  
Magnus Stougaard ◽  
Cinzia Tesauro
Keyword(s):  
Real Time ◽  
Dna Cleavage ◽  
Topoisomerase I ◽  
Drug Response ◽  
Molecular Beacon ◽  
Rolling Circle Amplification ◽  
Dna Topoisomerase ◽  
Rolling Circle ◽  
Topoisomerase Ib ◽  
Highly Sensitive

Here we present an optimized readout format for detection of the circularized products from a DNA-based sensor for measurement of DNA-modifying enzymes including DNA Topoisomerase I. The basic design of the DNA-sensor relies on the use of a substrate that can be circularized by the activity of DNA-modifying enzymes like type IB Topoisomerases and subsequently amplified by a rolling circle amplification (RCA) mechanism. The RCA process can be followed in real-time by the addition of a molecular beacon with a fluorophore/quencher pair. Upon hybridization to the amplified product, the fluorophore/quencher pair is separated, giving rise to a fluorescent signal, measurable in pseudo real-time using a qPCR machine or in a fluorimeter. The RCA products in complex with the molecular beacon can subsequently be moved to microscopic slides and analyzed in a fluorescence microscope. We describe the proof of the principle of this molecular beacon-based method combining the qPCR readout format with the standard Rolling circle Enhanced Enzymatic Assay previously reported. Although the qPCR setup is less sensitive, it allows easy, fast, and high-throughput measurement of enzyme activities. Human Topoisomerase IB (TopIB) is a well-known target for the clinically used anticancer drugs of the camptothecin family. The cytotoxic effect of camptothecins correlates directly with the intracellular TopIB activity affecting reversibly the Topoisomerase/DNA cleavage complexes. Therefore, we envisioned that the presented method may find use for the prediction of cellular drug response and for drug screening to discover novel molecules that specifically inhibit TopIB or other DNA-modifying enzymes.

Design, Synthesis, and Cytotoxicity of Indolizinoquinoxaline-5,12-dione Derivatives, Novel DNA Topoisomerase IB Inhibitors

2010 ◽  
Vol 63 (7) ◽  
pp. 1116 ◽  
Author(s):  
De-Qing Shen ◽  
Ning Wu ◽  
Yan-Ping Li ◽  
Zu-Ping Wu ◽  
Hong-Bin Zhang ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Carcinoma Cell ◽  
Large Cell ◽  
Cancer Drug ◽  
Significant Activity ◽  
Dna Topoisomerase ◽  
Design Synthesis ◽  
Cell Lung Carcinoma ◽  
Heterocyclization Reaction ◽  
Topoisomerase Ib

A series of new indolizinoquinoxaline-5,12-dione derivatives were designed and synthesized via a heterocyclization reaction of 6,7-dichloroquinoxaline-5,8-dione with active methylene reagents and pyridine derivatives. The synthesized compounds exhibited significant activity to inhibit the growth of four human tumour cell lines, including lung adenocarcinoma cell, large-cell lung carcinoma cell, breast carcinoma cell, and ardriamycin-resistant breast carcinoma cell at micromolar range. These compounds were also investigated for their inhibition to DNA topoisomerase IB activity. The results indicated that the indolizinoquinoxaline-5,12-dione structure might be a potential pharmacophore in anti-cancer drug design.

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