Recognition in the Minor Groove of Double-Stranded DNA by Microgonotropens

Satz, Alexander L.; Bruice, Thomas C.

doi:10.1021/ar0101032

Cited by 36 publications

(17 citation statements)

References 41 publications

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“…Firstly, the formation of cross-link by 118 required two steps whereas cross-link by 119 probably in bisquinone methide intermediate or nonspontaneous quinone methide formation. Secondly, on comparison with planar 118, compound 119 like many DNA specific binders [76][77][78][79][80] apparently had good shape orientation to adopt helical conformation (twist ca. 35 o ) [81].…”

Section: Dna Alkylating and Dna Cross-linkingmentioning

confidence: 99%

Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions

Wang

Song²,

Zhang³

et al. 2005

CMC

113

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Induced DNA interstrand cross-links by chemical agents or photoactivation play very important roles for cancer therapy. Several important clinical drugs (e.g. cisplatin, psoralens, and mitomycin C) are known to induce DNA ISC formation, which can disrupt cell maintenance and replication. Among these anti-tumor agents, one mechanism was involved in quinone methide intermediate. Quinone methide derivative has played important roles in organic syntheses as well as in chemical and biological processes. This review is concerned with current efforts of quinone methide derivatives to DNA alkylation and DNA cross-links. The latest advances in this field will be reviewed in this article. The chemical and physical properties of quinone methide derivatives, the interactions between nucleobases and quinone methide derivatives, the reactions with phosphodiester, DNA alkylation and cross-link via quinone methide intermediate action will be discussed.

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Section: Dna Alkylating and Dna Cross-linkingmentioning

confidence: 99%

Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions

Wang

Song²,

Zhang³

et al. 2005

CMC

113

View full text Add to dashboard Cite

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“…This approach to polyamide functionalization was driven by the higher binding affinity and more effective inhibition of transcription factor-DNA interactions by polyamides integrating pyrrole N1-alkyl spermine/spermidine groups [44], [45]. The results of Δ T M and CD studies confirm that the presence of the N1-alkyl amino group increases binding affinity of the diamino Hx-polyamides 2 and 3 to the cognate sequence, because of electrostatic interactions between the additional positively charged amino group and the negatively charged phosphodiester groups of the DNA backbone.…”

Section: Discussionmentioning

confidence: 99%

Modulation of topoisomerase IIα expression and chemosensitivity through targeted inhibition of NF-Y:DNA binding by a diamino p-anisyl-benzimidazole (Hx) polyamide

Pett

Kiakos

Satam

et al. 2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Background Sequence specific polyamide HxIP 1, targeted to the inverted CCAAT Box 2 (ICB2) on the topoisomerase IIα (topo IIα) promoter can inhibit NF-Y binding, re-induce gene expression and increase sensitivity to etoposide. To enhance biological activity, diamino-containing derivatives (HxI*P 2 and HxIP* 3) were synthesised incorporating an alkyl amino group at the N1-heterocyclic position of the imidazole/pyrrole. Methods DNase I footprinting was used to evaluate DNA binding of the diamino Hx-polyamides, and their ability to disrupt the NF-Y:ICB2 interaction assessed using EMSAs. Topo IIα mRNA (RT-PCR) and protein (Immunoblotting) levels were measured following 18h polyamide treatment of confluent A549 cells. γH2AX was used as a marker for etoposide-induced DNA damage after pre-treatment with HxIP* 3 and cell viability was measured using Cell-Titer Glo®. Results Introduction of the N1-alkyl amino group reduced selectivity for the target sequence 5′-TACGAT-3′ on the topo IIα promoter, but increased DNA binding affinity. Confocal microscopy revealed both fluorescent diamino polyamides localised in the nucleus, yet HxI*P 2 was unable to disrupt the NF-Y:ICB2 interaction and showed no effect against the downregulation of topo IIα. In contrast, inhibition of NF-Y binding by HxIP* 3 stimulated dose-dependent (0.1-2 μM) re-induction of topo IIα and potentiated cytotoxicity of topo II poisons by enhancing DNA damage. Conclusions Polyamide functionalisation at the N1-position offers a design strategy to improve drug-like properties. Dicationic HxIP* 3 increased topo IIα expression and chemosensitivity to topo II-targeting agents. General Significance Pharmacological modulation of topo IIα expression has the potential to enhance cellular sensitivity to clinically-used anticancer therapeutics.

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“…This inhibition mechanism is based on an increased energy barrier of DNA conformational changes, and it is complementary to changing DNA groove geometry by PAs as found, for example, by Chenoweth and Dervan (, ). Bruice and coworkers (reviewed in Satz and Bruice ) synthesized and studied positively charged tripyrrole PAs with several different cationic groups on the central Py. Their compounds are all similar to f‐Im‐Py(C 3 NH 3 ) + ‐Im‐Am + but have only Py rings.…”

Section: Discussionmentioning

confidence: 99%

“…From naturally occurring polyamides (PAs), such as distamycin and netropsin, to synthetic pyrrole (Py) and imidazole (Im) containing PAs, remarkable effort has been put into developing PAs for new applications as DNA complexes (Bando and Sugiyama ; Chavda et al ., ; Dervan ; Lacy et al ., ; Satz and Bruice ). Starting with the original studies on the distamycin stacked dimer complex (Pelton and Wemmer ; Pelton and Wemmer ; Pelton and Wemmer ), minor groove binding PAs have been designed to recognize a variety of DNA sequences with high affinity (Bando et al ., ; Buchmueller et al ., ; Wemmer ).…”

Section: Introductionmentioning

confidence: 98%

Conformational modulation of DNA by polyamide binding: structural effects of f‐Im‐Py‐Im based derivatives on 5′‐ACGCGT‐3′

Wang

Chai

Babu

et al. 2013

J of Molecular Recognition

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The DNA sequence 5’-ACGCGT-3’ is in the core site of the Mlu1 cell-cycle box, a transcriptional element in the promoter region of human Dbf4 gene which is highly correlated with a large number of aggressive solid cancers. The polyamide formamido-Imidazole-Pyrrole-Imidazole-Amine+ (f-Im-Py-Im-Am+) can target the minor groove of 5’-ACGCGT-3’ as an antiparallel stacked dimer and has shown good activity in inhibiting transcription factor (TF) binding. Recently, f-Im-Py-Im-Am+ derivatives that involve different orthogonally positioned substituents were synthesized to target the same binding site, and some of them have displayed improved binding and pharmacological properties. In this study, the gel electrophoresis-ligation ladders assay was used to evaluate the conformational effects of f-Im-Py-Im-Am+ and derivatives on the target DNA, an essential factor for establishing the molecular basis of polyamide-DNA complexes and their TF inhibition. The results show that the ACGCGT site in DNA has a relatively wide minor groove and a B-form like overall structure. After binding with f-Im-Py-Im-Am+ derivatives, the DNA conformation is changed as indicated by the different mobilities in the gel. These conformational effects on DNA will at least help to point to the mechanism for the observed Mlu 1 inhibition activity of these polyamides. Therefore, modulating DNA transcription by locking the DNA shape or altering the minor groove geometry to affect the binding affinity of certain TFs is an attractive possible therapeutic mechanism for polyamides. Some of the substituents are charged with electrostatic interactions with DNA phosphate groups and their charge effects on DNA gel mobility have been observed.

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Recognition in the Minor Groove of Double-Stranded DNA by Microgonotropens

Cited by 36 publications

References 41 publications

Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions

Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions

Modulation of topoisomerase IIα expression and chemosensitivity through targeted inhibition of NF-Y:DNA binding by a diamino p-anisyl-benzimidazole (Hx) polyamide

Conformational modulation of DNA by polyamide binding: structural effects of f‐Im‐Py‐Im based derivatives on 5′‐ACGCGT‐3′

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