Asymmetric intercalation of N1-(acridin-9-ylcarbonyl)spermine at homopurine sites of duplex DNA

Blagbrough, Ian S.; Taylor, Steven W.; Carpenter, Mark L.; Novoselskiy, Vyacheslav; Shamma, Tatyana; Haworth, Ian S.

doi:10.1039/a709193a

Cited by 23 publications

(23 citation statements)

References 12 publications

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“…5 Within the prerequisites for delivery of DNA across an intact cytoplasmic membrane are condensation and masking the negative charge of the phosphate backbone; polyammonium ions are therefore suitable for use as gene delivery systems. 6,7 Covalent attachment of a lipid moiety, 8 such as an aliphatic chain 2,7,9 or a steroid, 6,10,11 further enhances polyaminemediated DNA condensation. 12 The mechanism by which these compounds cause lipofection is poorly understood.…”

mentioning

confidence: 99%

Synthesis of cholesterol-polyamine carbamates: pKa studies and condensation of calf thymus DNA

Geall¹,

Blagbrough²,

Taylor³

et al. 1998

Chem. Commun.

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confidence: 99%

Synthesis of cholesterol-polyamine carbamates: pKa studies and condensation of calf thymus DNA

Geall¹,

Blagbrough²,

Taylor³

et al. 1998

Chem. Commun.

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“…Alkyl diamines with 3 and 5 methylene groups show a significant effect on the compaction of individual single DNA molecules, but diamines with 2, 4 and 6 methylene groups are not effective in the compaction of DNA. They infer from such a drastic difference in the action of simple diamines that not only the number of positive charges, but also the length between the amino groups in the diamines plays an essential role in their interactions with DNA [87], a conclusion with which all our chemical biology studies are in agreement [14,[56][57][58][59][60][61][62][63]70,71,[88][89][90][91].…”

Section: Dna Binding and Bendingmentioning

confidence: 55%

“…the tertiary 5-dimethylaminonaphthalene-1-sulphonyl chloride, dansyl 32 ( Figure 7). As well as incorporating dansyl 32, we have also covalently bound DNA-intercalating 9-acridinyl fluorophores in our novel polyamine conjugates [89][90][91].…”

Section: Discussionmentioning

confidence: 99%

Polyamines and novel polyamine conjugates interact with DNA in ways that can be exploited in non-viral gene therapy

Blagbrough

Geall

Neal

2003

Biochemical Society Transactions

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As a part of our continuing studies on 'Polyamines and their role in human disease' we are investigating how polyamines, and especially how novel polyamine conjugates, interact with DNA. We are studying how these conjugates interact with circular plasmids in order to produce nanometre-sized particles suitable for transfecting cells. Our considerations of structure--activity relationships (SAR) within naturally occurring and synthetic polyamines have shown the significance of the inter-atomic distances between the basic nitrogen atoms. As these atoms are typically fully protonated under physiological conditions, they exist in equilibrium as polyammonium ions. The covalent addition of a lipid moiety, typically one or two alkyl or alkenyl chains, or a steroid, allows much greater efficiency in DNA condensation and in the cellular transfection achieved. Thus efficient DNA condensation and subsequently drug delivery (i.e. with DNA as the drug) can be brought about using novel polyamine conjugates. Taking further advantage of the functionalization of specific steroids (e.g. cholesterol and certain bile acids), we have designed and prepared novel fluorescent molecular probes as tools to throw light on the problematic steps in non-viral gene delivery which still impede efficient gene therapy. Thus, the current aims of our research are to understand, design and prepare small-molecule lipopolyamines for non-viral gene therapy (NVGT). The rational design and practical preparation of non-symmetrical polyamine carbamates and amides, based on steroid templates of cholesterol and the bile acid lithocholic acid as the lipid moiety, provides fluorescent molecular probes that condense DNA. These novel lipopolyamine conjugates mimic the positive charge distribution found in the triamine spermidine and the tetra-amine spermine alkaloids. After optimizing their SAR, these fluorescent probes will be useful in monitoring gene delivery in NVGT.

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“…like acridine. Three important features have been recently proven for a series of acridinepolyamine covalent conjugates [17][18][19][20][21]: i) they present higher affinities for DNA than acridine; ii) they preserve the topoisomerase II inhibitory activity of acridine and, iii) they are recognized by the polyamine transport system. Acridine-polyamine conjugates are, therefore, promising chemical systems for the development of more efficient anti-tumour drugs.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Study by optical spectroscopy and molecular dynamics of the interaction of acridine–spermine conjugate with DNA

Sánchez-Carrasco

Delcros

Moya‐García

et al. 2008

Biophysical Chemistry

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We report a spectroscopic and theoretical study of the interaction between double-stranded oligonucleotides containing either adenine-thymine or guanine-cytosine alternating sequences and N1-(Acridin-9-ylcarbonyl)-1,5,9,14,18-pentazaoctadecane, or ASC, which is formed by the covalent bonding of spermine and 9-amidoacridine moieties via a trimethylene chain. Solutions containing the oligonucleotides and the conjugate at different molar ratios were studied using complementary spectroscopic techniques, including electronic absorption, fluorescence emission, circular dichroism, and Raman spectroscopy. The spectroscopical properties of ASC at both the vibrational and the electronic levels were described by means of ab initio quantum-chemical calculations on 9-amidoacridine, used as a model compound. Molecular dynamics calculations, based on the QM/MM methodology, were also performed using previously docked structures of two oligonucleotide-ASC complexes containing the A-T and the G-C sequence. Our data, taken all together, allowed us to demonstrate that conjugation of spermine to acridine modulates and gives additional properties to the interaction of the latter with DNA. As the ASC molecule has a high affinity by the polyamine transport system, these results are promising for their application in the development of new anti-tumour drugs.

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Asymmetric intercalation of N1-(acridin-9-ylcarbonyl)spermine at homopurine sites of duplex DNA

Cited by 23 publications

References 12 publications

Synthesis of cholesterol-polyamine carbamates: pKa studies and condensation of calf thymus DNA

Synthesis of cholesterol-polyamine carbamates: pKa studies and condensation of calf thymus DNA

Polyamines and novel polyamine conjugates interact with DNA in ways that can be exploited in non-viral gene therapy

Study by optical spectroscopy and molecular dynamics of the interaction of acridine–spermine conjugate with DNA

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