Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics

Clark, Rachel L.; Deane, Fiona M.; Anthony, Nahoum G.; Johnston, Blair F.; McCarthy, Florence O.; Mackay, Simon P.

doi:10.1016/j.bmc.2007.05.002

Cited by 14 publications

(5 citation statements)

References 40 publications

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“…Topotecan, ethoxidine, fagaronine and BCP related compounds indicated the selectivity on TOP-I than TOP-II. These novel compounds acted as DNA intercalators and have two mechanisms including (i) TOP-I poison activity like fagaronine; and (ii) TOP-I suppressor activity like ethoxidine [24,25]. Our preliminary results from in silico modeling indicated that BCP compounds may inhibit the TOP-I activity via suppression mechanism.…”

Section: Resultsmentioning

confidence: 97%

“…From this QSAR study, the important role of natural functional groups related to biological activity is indicated in Figure 4. Hence, the combination of our QSAR models with other classification on TOP-I and cytotoxicity predictive models and molecular docking studies [12,25,26] could provide insight into the molecular basis of BCPs derivatives on antitumor and TOP-I inhibitory activity.…”

Section: Resultsmentioning

confidence: 99%

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QSAR Modeling on Benzo[c]phenanthridine Analogues as Topoisomerase I Inhibitors and Anti-cancer Agents

et al. 2012

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Benzo[c]phenanthridine (BCP) derivatives were identified as topoisomerase I (TOP-I) targeting agents with pronounced antitumor activity. In this study, hologram-QSAR, 2D-QSAR and 3D-QSAR models were developed for BCPs on topoisomerase I inbibitory activity and cytotoxicity against seven tumor cell lines including RPMI8402, CPT-K5, P388, CPT45, KB3-1, KBV-1and KBH5.0. The hologram, 2D, and 3D-QSAR models were obtained with the square of correlation coefficient R 2 = 0.58 − 0.77, the square of the crossvalidation coefficient q 2 = 0.41 − 0.60 as well as the external set's square of predictive correlation coefficient r 2 = 0.51 − 0.80. Moreover, the assessment method based on reliability test with confidence level of 95% was used to validate the predictive power of QSAR models and to prevent over-fitting phenomenon of classical QSAR models. Our QSAR model could be applied to design new analogues of BCPs with higher antitumor and topoisomerase I inhibitory activity.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

QSAR Modeling on Benzo[c]phenanthridine Analogues as Topoisomerase I Inhibitors and Anti-cancer Agents

et al. 2012

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“…However, one limitation of all machine learning approaches is their inability to indicate the important role of functional groups related to biological activity. Hence, the combination of this SVM classification model with molecular docking studies [ 27 , 28 ] and also related 2D- and 3D-QSAR model on cytotoxicity of BCPs [ 5 ] could provide insight into the molecular basis of TOP-I inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Topotecan, ethoxidine, fagaronine and BCP related compounds indicated the selectivity on TOP-I than TOP-II. These novels acted as DNA intercalators and having two mechanisms including (i) TOP-I poison as fagaronine; and (ii) TOP-I suppressor as ethoxidine [ 27 , 28 ]. Our preliminary results from in silico modeling indicated that BCP compounds may inhibit the TOP-I activity via suppression mechanism.…”

Section: Resultsmentioning

confidence: 99%

A Support Vector Machine Classification Model for Benzo[c]phenathridine Analogues with Topoisomerase-I Inhibitory Activity

Thai

Nguyen²,

Ngo³

et al. 2012

Molecules

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Benzo[c]phenanthridine (BCP) derivatives were identified as topoisomerase I (TOP-I) targeting agents with pronounced antitumor activity. In this study, a support vector machine model was performed on a series of 73 analogues to classify BCP derivatives according to TOP-I inhibitory activity. The best SVM model with total accuracy of 93% for training set was achieved using a set of 7 descriptors identified from a large set via a random forest algorithm. Overall accuracy of up to 87% and a Matthews coefficient correlation (MCC) of 0.71 were obtained after this SVM classifier was validated internally by a test set of 15 compounds. For two external test sets, 89% and 80% BCP compounds, respectively, were correctly predicted. The results indicated that our SVM model could be used as the filter for designing new BCP compounds with higher TOP-I inhibitory activity.

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“…DNA topoisomerases I are essential enzymes that control DNA supercoiling and torsional strain during processes such as replication, transcription and DNA repair [ 1 ] whose inhibition is involved in the treatment of many cancers. Ethoxidine, a benzo[ c ]phenanthridine, is a molecule that was synthesized in the late 90s to inhibit DNA topoisomerase I activity ( Figure 1 ) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway

Clere

Legeay

et al. 2017

Molecules

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Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10−9 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10–9 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression.

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Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics

Cited by 14 publications

References 40 publications

QSAR Modeling on Benzo[c]phenanthridine Analogues as Topoisomerase I Inhibitors and Anti-cancer Agents

QSAR Modeling on Benzo[c]phenanthridine Analogues as Topoisomerase I Inhibitors and Anti-cancer Agents

A Support Vector Machine Classification Model for Benzo[c]phenathridine Analogues with Topoisomerase-I Inhibitory Activity

Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway

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