Mechanism of interaction of small transcription inhibitors with DNA in the context of chromatin and telomere

Ghosh, Saptaparni; Majumder, Pritha; Pradhan, Suman; Dasgupta, Dipak

doi:10.1016/j.bbagrm.2010.06.008

Cited by 11 publications

(8 citation statements)

References 195 publications

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“…ligands with chromatin at different levels and demonstration of the outcome of the association has not been reported till date. The broad objective of our study is to classify small DNA binding molecules in terms of their ability to bind chromosomal DNA alone and/or both histones and chromosomal DNA (dual binding mode) [5][6][7]42]. The results presented here show the core histone binding ability of a classical intercalator and its structural analogue.…”

Section: Introductionmentioning

confidence: 89%

“…Histone post‐translational modification as well as DNA methylation can be impacted by these small molecule modulators. In this context, we earlier proposed a classification of DNA‐binding ligands in two types: single binding mode and dual binding mode in the chromatin context [5,6]. The former class of ligands binds to chromosomal DNA only while the later has the ability to bind both histone(s) and chromosomal DNA.…”

Section: Introductionmentioning

confidence: 99%

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The DNA intercalators ethidium bromide and propidium iodide also bind to core histones

et al. 2014

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The DNA intercalators ethidium bromide and propidium iodide also bind to core histones

et al. 2014

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“…Significance of Studying DNA Alkylation. Duocarmycins exert cytotoxicity through DNA minor-groove binding and alkylation, interfering with transcriptional activities and causing DNA damage (Kiakos et al, 2007;Ghosh et al, 2010). Bis-CPI/CBIs are potential drug candidates because of their enhanced cytotoxicity from DNA crosslinking, but it is difficult to analyze them for structure-activity correlation because of their DNA reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, these compounds carry different types of side chains, with variable lengths serving as handles for the antibody linkage. The DNA alkylation by duocarmycins is not only a mechanism of pharmacological activity but also serves as a process for cells to eliminate these compounds (Kiakos et al, 2007;Ghosh et al, 2010). Since DNA adducts have not been systemically characterized before for bis-CBI compounds, to the best of our knowledge, the DNA alkylation of bis-seco-CBIs 4 and 5 were characterized in comparison with bis-seco-CBI 3 and two mono-seco-CPIs 1 and 2 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

Wang¹,

Chen²,

Dragovich³

et al. 2019

Drug Metab Dispos

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Duocarmycins [including cyclopropyl pyrroloindole (CPI) or cyclopropyl benzoindole (CBI)] are a class of DNA minor-groove alkylators and seco-CPI/CBIs are synthetic pro-forms that can spirocyclize to CPI/CBI. Bis-CPI/CBIs are potential drug candidates because of their enhanced cytotoxicity from DNA crosslinking, but it is difficult to analyze them for structure-activity correlation because of their DNA reactivity. To study their DNA alkylation, neutral thermal hydrolysis has been frequently applied to process depurination. However, unwanted side reactions under this condition have been reported, which could lead to poor correlation of DNA alkylation data with efficacy results, especially for bis-CPI/CBIs. In this study, an acidic depurination method was developed and applied for analysis of DNA alkylation and shown to be an easier and milder method than the traditional neutral thermal hydrolysis. DNA alkylation and stability of three bis-seco-CBIs were characterized in comparison with two mono-seco-CPIs. The results suggested that: 1) The acidic depurination method was capable of capturing a more representative population, sometimes a different population, of DNA adducts as they existed on DNA compared with the heat depurination method. 2) Di-adenine adducts were captured as expected for the CBI dimers, although the major type of adduct was still mono-adenine adducts.3) The rate of DNA alkylation, DNA adduct profile, and relative amounts of di-adduct versus mono-adduct were significantly affected by the size, and possibly lipophilicity, of the nonalkylating part of the molecules. 4) Spirocyclization and amide hydrolysis represented two major pathways of degradation. Overall, by applying acidic depurination analyses, this study has illustrated DNA adduct characteristics of novel bis-seco-CBIs with dominating monoalkylation and provides an alternative method for evaluating DNA minor-groove alkylators. These findings provide an effective analytical tool to evaluate DNA alkylators and to study the DNA alkylation that is a disposition mechanism of these compounds. Polakis, 2016). With this as an objective, duocarmycins were made and https://doi.org/10.1124/dmd.118.085209.s This article has supplemental material available at dmd.aspetjournals.org.

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“…It has the ability to rebalance epigenetic histone modifications. The binding properties of MTR with histone proteins have been examined from the perspective of the current proposition from our laboratory to classify small DNA binding molecules in terms of their ability to bind chromosomal DNA alone (single binding mode) or both histones and chromosomal DNA (dual binding mode) [2,3]. …”

Section: Introductionmentioning

confidence: 99%

Mithramycin interacts with core histones and modulates epigenetic modifications

Banerjee

Das

Dasgupta

2013

Epigenetics & Chromatin

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Mechanism of interaction of small transcription inhibitors with DNA in the context of chromatin and telomere

Cited by 11 publications

References 195 publications

The DNA intercalators ethidium bromide and propidium iodide also bind to core histones

The DNA intercalators ethidium bromide and propidium iodide also bind to core histones

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

Mithramycin interacts with core histones and modulates epigenetic modifications

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