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Your search keyword '"Topoisomerase II Inhibitors metabolism"' showing total 3 results
Start Over Descriptor "Topoisomerase II Inhibitors metabolism" Journal bioorganic medicinal chemistry letters
3 results on '"Topoisomerase II Inhibitors metabolism"'

1. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.

Author

Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, Cheng RK, Felicetti B, Wood M, Hadfield AT, Scheich C, Moy TI, Yang Q, Shotwell J, Nguyen K, Lippa B, Dolle R, and Ryan MD

Subjects
Adenosine Triphosphatases metabolism, Anti-Bacterial Agents metabolism, Bacterial Proteins metabolism, Binding Sites, Crystallography, X-Ray, DNA Gyrase metabolism, DNA Topoisomerase IV antagonists & inhibitors, DNA Topoisomerase IV metabolism, Drug Design, Escherichia coli metabolism, Ligands, Magnetic Resonance Spectroscopy, Molecular Dynamics Simulation, Protein Binding, Protein Structure, Tertiary, Staphylococcus aureus enzymology, Topoisomerase II Inhibitors metabolism, Anti-Bacterial Agents chemistry, Bacterial Proteins antagonists & inhibitors, DNA Gyrase chemistry, Topoisomerase II Inhibitors chemistry
Abstract

Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 μM inhibitor is described herein., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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2. Design, synthesis, and DNA sequence selectivity of formaldehyde-mediated DNA-adducts of the novel N-(4-aminobutyl) acridine-4-carboxamide.

Author

Ankers EA, Evison BJ, Phillips DR, Brownlee RTC, and Cutts SM

Subjects
CpG Islands, Disinfectants pharmacology, Isoquinolines chemistry, Isoquinolines metabolism, Models, Molecular, Molecular Structure, Acridines chemistry, Acridines metabolism, DNA Adducts chemistry, DNA Adducts metabolism, Drug Design, Formaldehyde pharmacology, Topoisomerase II Inhibitors chemistry, Topoisomerase II Inhibitors metabolism
Abstract

A novel derivative of the anti-tumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) was prepared by reduction of 9-oxoacridan-4-carboxylic acid to acridine-4-carboxylic acid with subsequent conversion to N-(4-aminobutyl)acridine-4-carboxamide (C4-DACA). Molecular modeling studies suggested that a DACA analogue comprising a side chain length of four carbons was optimal to form formaldehyde-mediated drug-DNA adducts via the minor groove. An in vitro transcription assay revealed that formaldehyde-mediated C4-DACA-DNA adducts selectively formed at CpG and CpA dinucleotide sequences, which is strikingly similar to that of formaldehyde-activated anthracenediones such as pixantrone., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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3. Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy.

Author

Perola E, Stamos D, Grillot AL, Ronkin S, Wang T, LeTiran A, Tang Q, Deininger DD, Liao Y, Tian SK, Drumm JE, Nicolau DP, Tessier PR, Mani N, Grossman TH, and Charifson PS

Subjects
Animals, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Bacteria drug effects, Bacterial Infections drug therapy, Bacterial Infections enzymology, Bacterial Infections microbiology, Blood Proteins metabolism, DNA Topoisomerase IV metabolism, Humans, Rats, Topoisomerase II Inhibitors chemistry, Topoisomerase II Inhibitors metabolism, Topoisomerase II Inhibitors pharmacology, Anti-Bacterial Agents blood, Bacteria enzymology, DNA Gyrase metabolism, DNA Topoisomerase IV antagonists & inhibitors, Topoisomerase II Inhibitors blood
Abstract

A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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