DNA Binding by Analogues of the Bifunctional Intercalator TANDEM

Hampshire, Andrew J.; Rusling, David A.; Bryan, Stephanie; Paumier, David; Dawson, Simon J.; Malkinson, John P.; Searcey, Mark; Fox, Keith R.

doi:10.1021/bi800573p

Cited by 9 publications

(10 citation statements)

References 35 publications

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“…Symmetrical and pseudosymmetrical nucleobase‐functionalized triostin A analogs were recently generated by solution‐phase peptide chemistry and found to have the potential to recognize double‐stranded DNA by hydrogen bonding (see Figure 8). 81, 82 A series of novel TANDEM derivatives was also reported 83. Replacement of L ‐Val at positions 4 and 8 with L ‐Lys residues was found to have no effect on selectivity for AT‐rich sites whereas replacement of the QXCs by two naphthoyl chromophores completely abolished binding to DNA.…”

Section: Bisintercalator Analogsmentioning

confidence: 98%

Recent developments in bisintercalator natural products

2010

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The bisintercalator natural products are a family of nonribosomal peptides possessing a range of biological properties that include antiviral, antibiotic, and anticancer activities. The name bisintercalator is derived from the ability to directly bind to duplex DNA through two planar intercalating moieties. Although 19 members of this family of compounds have been identified over the past 50 years, the biosynthetic genes responsible for the formation of four of these molecules (thiocoraline, SW‐163, triostin A, and echinomycin) were identified only recently. This recent progress opens an avenue towards understanding how Nature produces these bisintercalating products and provides the potential to develop and identify novel potent analogous lead compounds for clinical applications. This review discusses the mode of action of bisintercalators and summarizes recent genetic and biochemical insights into their biosynthetic production, analog formation, and possible mechanisms by which resistance to these compounds is achieved by their producing organisms. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 777–790, 2010.

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Section: Bisintercalator Analogsmentioning

confidence: 98%

Recent developments in bisintercalator natural products

2010

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“…Quinoxaline antibiotics, containing two quinoxaline moieties attached to an octadepsipeptide ring (Figure A), are able to bis‐intercalate double‐stranded DNA (dsDNA) in a sequence‐specific manner . In addition to studies on synthetic derivatives, potent anticancer agents have been designed using the depsipeptide‐biquinoxaline scaffold . In contrast, known DNA‐binding monoquinoxaline scaffolds are either metal chelates or contain a fused quinoxaline moeity .…”

Section: Figurementioning

confidence: 99%

The Benzyl Moiety in a Quinoxaline‐Based Scaffold Acts as a DNA Intercalation Switch

et al. 2016

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Quinoxaline antibiotics intercalate dsDNAa nd exhibit antitumor properties.H owever,t hey are difficult to synthesize and their structural complexity impedes ac lear mechanistic understanding of DNAbinding.Therefore design and synthesis of minimal-intercalators,u sing only part of the antibiotic scaffold so as to retain the key DNA-binding property,isextremely important. Reported is aunique example of am onomeric quinoxaline derivative of a6 -nitroquinoxaline-2,3-diamine scaffold which binds dsDNAbytwo different modes.W hile benzyl derivatives bound DNAi nasequential fashion, with intercalation as the second event, nonbenzyl derivatives showed only the first binding event. The benzyl intercalation switch provides important insights about molecular architecture which control specific DNAb inding modes and would be useful in designing functionally important monomeric quinoxaline DNAb inders and benchmarking molecular simulations.

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“…The bis-6-chloro and bis-6-bromo derivatives showed similar DNA-binding properties, whereas the bis-7-derivative showed a new marked preference for 5′-AT rich DNA [128]. In the case of TANDEM, several derivatives of this synthetic compound also exist, as for example one harboring l -Lys instead of the canonical l -Val at amino acid at positions E. [Lys 4 ,Lys 8 ]-TANDEM still shows a marked preference for 5′-AT rich DNA, but with higher affinity [129]. …”

Section: Unnatural Derivativesmentioning

confidence: 99%

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

et al. 2014

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Diverse actinomycetes produce a family of structurally and biosynthetically related non-ribosomal peptide compounds which belong to the chromodepsipeptide family. These compounds act as bisintercalators into the DNA helix. They give rise to antitumor, antiparasitic, antibacterial and antiviral bioactivities. These compounds show a high degree of conserved modularity (chromophores, number and type of amino acids). This modularity and their high sequence similarities at the genetic level imply a common biosynthetic origin for these pathways. Here, we describe insights about rules governing this modular biosynthesis, taking advantage of the fact that nowadays five of these gene clusters have been made public (thiocoraline, triostin, SW-163 and echinomycin/quinomycin). This modularity has potential application for designing and producing novel genetic engineered derivatives, as well as for developing new chemical synthesis strategies. These would facilitate their clinical development.

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DNA Binding by Analogues of the Bifunctional Intercalator TANDEM

Cited by 9 publications

References 35 publications

Recent developments in bisintercalator natural products

Recent developments in bisintercalator natural products

The Benzyl Moiety in a Quinoxaline‐Based Scaffold Acts as a DNA Intercalation Switch

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

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