Novel DNA Topoisomerase IIα Inhibitors from Combined Ligand- and Structure-Based Virtual Screening (original) (raw)
Related papers
We previously reported a first set of hybrid topoisomerase II (topoII) poisons whose chemical core merges key pharmacophoric elements of etoposide and merbarone, which are two well-known topoII blockers. Here, we report on the expansion of this hybrid molecular scaffold and present 16 more hybrid derivatives that have been designed, synthesized, and characterized for their ability to block topoII and for their overall drug-like profile. Some of these compounds act as topoII poison and exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound 3f (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile in vivo. Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration and that 3f is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in in vivo tumor models.
ACS Medicinal Chemistry Letters, 2015
A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choicebased change" in target-specific mode of action for rapid drug discovery.
Synthesis and cytotoxic activity of a new series of topoisomerase I inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008
A series of structurally simple analogues of natural topopyrone C were synthesized and tested for cytotoxic and topoisomerase I inhibitory activities. The removal of the hydroxyl groups at the 5 and 9 positions resulted in an increased cytotoxic potency and ability to stabilize topoisomerase-mediated cleavage. In addition, the results suggest that some structural features, such as the pyrone ring and a polar group in position 11, are fundamental for topoisomerase I inhibitory effect. These structural requirements are also consistent with the cytotoxic activity.
Recent Developments of DNA Poisons - Human DNA Topoisomerase IIα Inhibitors - as Anticancer Agents
Current Pharmaceutical Design, 2013
DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule. Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel anticancer drugs especially supported by recent structural advances in the field.
Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents
PLOS One, 2011
DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1 -DNA covalent complex. This complex can be trapped by a group of anticancer agents interacting with the DNA bases and the enzyme at the cleavage site, preventing further topoisomerase activity. Here we have identified novel Top1 inhibitors as potential anticancer agents by using a combination of structureand ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristics of derivatives of the alkaloid camptothecin (CPT), which represent potent antitumour agents and the main group of Top1 inhibitors. The models generated were used for in silico screening of the National Cancer Institute (NCI, USA) compound database, leading to the identification of a set of structurally diverse molecules. The strategy is validated by the observation that amongst these molecules are several known Top1 inhibitors and agents cytotoxic against human tumour cell lines. The potential of the untested hits to inhibit Top1 activity was further evaluated by docking into the binding site of a Top1 -DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability, 7 compounds have been tested in vitro for their Top1 inhibitory activity, 5 of which display mild to moderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the identification of structurally novel Top1 inhibitors worthy of further investigation as potential anticancer agents.
Current Medicinal Chemistry, 2013
DNA topoisomerases comprise an important family of enzymes that catalyse the induction of topological changes (e.g. relaxation/supercoiling, catenation/decatenation and knotting/unknotting) in the DNA molecule. These enzymes perform their functions by creating transient either single-stranded or double-stranded breaks in the DNA molecule. Due to their ability to modulate the topology of the DNA molecule, DNA topoisomerases play vital roles in replication, transcription, chromosome separation and segregation, and thus represent an important collection of design targets for novel anticancer drugs. The aim of this review is to provide an overview of the development of catalytic inhibitors of the human topoisomerase II enzyme -an important member of the DNA topoisomerase family -as potential novel anticancer agents. The group of catalytic topoII inhibitors is classified into four types according to their molecular mechanism of action: inhibitors that bind to the ATP binding site, inhibitors that prevent the ATP hydrolysis step and trap the enzyme in a closed clamp, inhibitors that block the DNA cleavage and inhibitors that prevent the enzyme binding to the DNA. One of the important considerations highlighted throughout this review is the structure-based perspective of inhibitor design, giving the reader a medicinal chemist's perspective on this vibrant and active field of drug design research.
A series of novel 9-anilinoacridines was designed and their molecular docking studies into the active site were examined as topoisomerase I inhibitor. Several compounds showed significant high simulation docking score. The designed compounds were synthesized and biologically evaluated against mammary carcinoma cell line (MCF-7), where compounds 8,11e,11f,13b,14b,14e and 14f showed significant inhibitory activity at a concentration 10g/mL). It appears that the in vitro activity of compounds 8,11e,11f,13b,14b,14e and 14f were consistent with their molecular modeling results, and compound 14b showed the highest activity with IC 50 value of 7.8 µg. [Journal of American Science. 2010;6(11):148-158]. (ISSN: 1545-1003).
Zenodo (CERN European Organization for Nuclear Research), 2021
Topoisomerase II alpha catalyses and guides the unknotting of DNA by creating double transient breaks in the DNA using a conserved tyrosine as the catalytic residue. Topoisomerase II alpha has been shown to be overexpressed in numerous types of cancers and it is a target for multiple chemotherapeutic agents. Many DNA topoisomerase inhibitors have been identified from natural sources and have been reviewed in many reports as anticancer agents. In the present study, a total of 240 phytochemicals characterized from four reported anticancer plants (Anacardium occidentale, Andrographis paniculata, Cannabis sativa and Tinospora cordifolia) were obtained from literatures and screened against the binding pocket of topoisomerase II alpha. From the pool of phytochemicals only 7-o-methylcyanidin, 20betaecdysone, Andropanoside and Palmatoside-G qualified as Phyto-compounds with good oral bioactivity when subjected to the Lipinski's rule of five. Bioassay data containing the IC50 of compounds screened against topoisomerase II alpha was used to generate a regression model using the 3D-QSAR techniques. A very viable model with R 2 = 0.954, adjusted R 2 = 0.908, Pearson R = 0.977, cross validation Q 2 = 0.851, Standard Error of Estimate = 0.125, F = (20.803, p < 0.05) and Durbin-Watson constant = 1.613 was obtained. The 3D-QSAR result shows that Andropanoside and 20betaecdysone may be better inhibitors of topoisomerase II alpha catalytic site than the standard drug, Etoposide. To further confirm this, the molecular interactions of Andropanoside and 20-betaecdysone were compared to those of Etoposide using the ligand interaction interface of Maestro environment.
European journal of medicinal chemistry, 2016
Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA-enzyme complex because its function attributes to inhibition of the catalytic steps of the enzyme such as before generating DNA DSBs or in the last step of the catalytic cycle after religation. It has been reported that the stabilizing effect of etoposide on transient cleavable DNA-topoisomerase IIβ complex attributes to its secondary malignancy. Therefore, topoisomerase IIα has been considered as more attractive target than topoisomerase IIβ for the development of chemotherapeutic agents. In the previous work, we reported compounds I and II as novel topoisomerase IIα catalytic inhibitors targeting for ATP binding site of human topoisomerase IIα ATP-binding domain. As a continuous work, we have designed and synthesized 43 compounds of C1-O-alkyl and arylalk...
Journal of Cheminformatics, 2019
Molecular descriptor (2D) and three dimensional (3D) shape based similarity methods are widely used in ligand based virtual drug design. In the present study pairwise structure comparisons among a set of 4858 DTP compounds tested in the NCI60 tumor cell line anticancer drug screen were computed using chemical hashed fingerprints and 3D molecule shapes to calculate 2D and 3D similarities, respectively. Additionally, pairwise biological activity similarities were calculated by correlating the 60 element vectors of pGI50 values corresponding to the cytotoxicity of the compounds across the NCI60 panel. Subsequently, we compared the power of 2D and 3D structural similarity metrics to predict the toxicity pattern of compounds. We found that while the positive predictive value and sensitivity of 3D and molecular descriptor based approaches to predict biological activity are similar, a subset of molecule pairs yielded contradictory results. By simultaneously requiring similarity of biological activities and 3D shapes, and dissimilarity of molecular descriptor based comparisons, we identify pairs of scaffold hopping candidates displaying characteristic core structural changes such as heteroatom/heterocycle change and ring closure. Attempts to discover scaffold hopping candidates of mitoxantrone recovered known Topoisomerase II (Top2) inhibitors, and also predicted new, previously unknown chemotypes possessing in vitro Top2 inhibitory activity.