The Synthesis of Some Head to Head Linked DNA Minor Groove Binders

Khalaf, Abedawn I.; Pitt, Andrew R.; Scobie, Martin; Suckling, Colin J.; Urwin, John; Waigh, Roger D.; Fishleigh, Robert V.; Young, Steven C.; Wylie, William A.

doi:10.1016/s0040-4020(00)00432-4

Cited by 34 publications

(38 citation statements)

References 12 publications

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“…The MGBs were prepared as described previously. [47] Millipore-filtered water was used in the preparation of all solutions. PIPES, ACES, ethylenediaminetetraacetic acid (EDTA), and NaCl (all from Sigma-Aldrich) were used to prepare buffers.…”

Section: Molecular Modellingmentioning

confidence: 99%

Recognition of the DNA Minor Groove by Thiazotropsin Analogues

et al. 2014

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Solution-phase self-association characteristics and DNA molecular-recognition properties are reported for three close analogues of minor-groove-binding ligands from the thiazotropsin class of lexitropsin molecules; they incorporate isopropyl thiazole as a lipophilic building block. Thiazotropsin B (AcImPy(iPr) ThDp) shows similar self-assembly characteristics to thiazotropsin A (FoPyPy(iPr) ThDp), although it is engineered, by incorporation of imidazole in place of N-methyl pyrrole, to swap its DNA recognition target from 5'-ACTAGT-3' to 5'-ACGCGT-3'. Replacement of the formamide head group in thiazotropsin A by nicotinamide in AIK-18/51 results in a measureable difference in solution-phase self-assembly character and substantially enhanced DNA association characteristics. The structures and associated thermodynamic parameters of self-assembled ligand aggregates and their complexes with their respective DNA targets are considered in the context of cluster targeting of DNA by minor-groove complexes.

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Section: Molecular Modellingmentioning

confidence: 99%

Recognition of the DNA Minor Groove by Thiazotropsin Analogues

et al. 2014

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“…They have used deoxyribonuclease I and hydroxyl radical footprinting and fluorescence melting to explore the sequence specificity of this compound. Thiazotropsin A was prepared as previously described, 4,7,12,15 while Thiazotropsin B was synthesized as described below (Schemes 4a, 4b). Fig.…”

Section: Mgbs Containing Isopropylthiazole and N-methylimidazolementioning

confidence: 99%

DNA Minor Groove Binders-Inspired by Nature

Khalaf¹,

Al-kadhimi²,

Ali³

2016

ACSi

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The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of authors. These compounds were subject to a large array of assays. Some of these compounds showed high activity against a range of Gram-positive, Gram-negative bacteria as well as fungi. To explore the anti-parasitic activity of this class of compounds, specific modifications had to be made. A number of these compounds proved to be active against Trypanosoma brucei. The binding of a number of these compounds to short sequences of DNA were also examined using footprinting assays as well as NMR spectroscopy. Computer modelling was employed on selected compounds to understand the way these compounds bind to specific DNA sequences. A large number of variations were made to the standard structure of Distamycin. These changes involved the replacement of the pyrrole moieties as well as the head and tail groups with a number of heterocyclic compounds. Some of these minor groove binders (MGBs) were also investigated for their capability for the treatment of cancer and in particular lung cancer.

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“…[15,17] Building blocks 9a and 9b were obtained upon condensation of pentafluorophenyl diester 8 with one equivalent of the appropriate 2-(trimethylsilyl)ethoxycarbonyl (Teoc)-monoprotected diamine. [16b] In order to minimize cross-linking of the 2-chlorotrityl chloride resin, it was loaded with the appropriate Teocmonoprotected diamine (Scheme 2).…”

Section: Solid-phase Synthesis Of Philanthotoxin Analoguesmentioning

confidence: 99%

Section: Solid-phase Synthesis Of Philanthotoxin Analoguesmentioning

confidence: 99%

“…The commonly used solution-phase method for obtaining polyamines displaying a cyclopropane moiety is alkylation of mesitylenesulfonamides with mesitylenesulfonates of cyclopropane diols, but this is not readily transferred into an SPS protocol due to the harsh conditions required for deprotonation of the sulfonamide and the risk of cross-linking the resin due to the bifunctional building block. [14] Cyclopropane-trans-1,2-dicarboxylic acid [15] may be readily obtained from the corresponding ethyl diester and the cisanhydride 3-oxabicyclo[3.1.0]hexane-2,4-dione was commercially available, and therefore, we chose an approach involving on-resin reduction of the diamide corresponding to the desired 4,4'-dimethoxytrityl-protected polyamine. [16] In the present work we focus on incoporating unprecedented structural variations of the polyamine moiety present in both 1 and its well-studied close structural analogue, PhTX-343 (2), and examine how these influence the inhibitory effects of the resulting PhTX analogues on a specific subunit, GluA1flop, present in members of the AMPAR subdivision of the ionotropic glutamate receptor family.…”

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The Effects of Conformational Constraints in the Polyamine Moiety of Philanthotoxins on AMPAR Inhibition

et al. 2014

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[a] IntroductionPhilanthotoxin-433 (PhTX-433, 1; the numerals indicate the number of methylene groups spacing the nitrogens in the polyamine moiety; Figure 1) is a toxin found naturally in the venom of the solitary wasp, Philanthus triangulum. [1,2] PhTX-433 and many of its synthetic analogues have been shown to have non-competitive inhibitory effects at both ionotropic glutamate receptors and nicotinic acetylcholine receptors. [3][4][5][6] In that respect PhTXs are attractive molecules to investigate further given that both of these receptor types are accepted as valid drug targets for a variety of neurodegenerative and other disorders of the central nervous system. [7] The modular butyryl-tyrosylthermospermine composition of 1 has allowed for efficient generation of many synthetic analogues demonstrating the importance of all of these structure segments. [4,6,[8][9][10][11] PhTXs 1, 2 and an array of other analogues have been shown to produce powerful voltage-dependent inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) currents suggesting a binding mode with the polyamine inserted deeply within the pore region of the ion channel.[3] This hypothesis is supported by the observation that AMPARs containing the GluA2 subunit with arginine at the "Q/R" site in the selectivity filter of the pore exhibit drastically reduced inhibition by PhTX-343 and other polyamine-containing molecules. [12] In the last two decades advanced methodologies for solidphase synthesis (SPS) of polyamines have been developed, [13] however, no examples of SPS of cyclopropane-containing polyamine derivatives have been reported. The commonly used solution-phase method for obtaining polyamines displaying a cyclopropane moiety is alkylation of mesitylenesulfonamides with mesitylenesulfonates of cyclopropane diols, but this is not readily transferred into an SPS protocol due to the harsh conditions required for deprotonation of the sulfonamide and the risk of cross-linking the resin due to the bifunctional building block. [14] Cyclopropane-trans-1,2-dicarboxylic acid [15] may be readily obtained from the corresponding ethyl diester and the cisanhydride 3-oxabicyclo[3.1.0]hexane-2,4-dione was commercially available, and therefore, we chose an approach involving on-resin reduction of the diamide corresponding to the desired 4,4'-dimethoxytrityl-protected polyamine. [16] In the present work we focus on incoporating unprecedented structural variations of the polyamine moiety present in both 1 and its well-studied close structural analogue, PhTX-343 (2), and examine how these influence the inhibitory effects of the resulting PhTX analogues on a specific subunit, GluA1flop, present in members of the AMPAR subdivision of the ionotropic glutamate receptor family. This subunit is characteristic of a calcium-permeable and polyamine-sensitive subtype of AMPARs, with the flop splice variant (a 38 amino acid region upstream of the fourth transmembrane region) being upregulated in place of the flip splice variant during early...

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The Synthesis of Some Head to Head Linked DNA Minor Groove Binders

Cited by 34 publications

References 12 publications

Recognition of the DNA Minor Groove by Thiazotropsin Analogues

Recognition of the DNA Minor Groove by Thiazotropsin Analogues

DNA Minor Groove Binders-Inspired by Nature

The Effects of Conformational Constraints in the Polyamine Moiety of Philanthotoxins on AMPAR Inhibition

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