Synthesis, DNA binding, fluorescence measurements and antiparasitic activity of DAPI related diamidines

Farahat, Abdelbasset A.; Kumar, Arvind; Say, Martial; Barghash, Alaa El-Din M.; Goda, Fatma E.; Eisa, Hassan M.; Wenzler, Tanja; Brun, Reto; Liu, Yang; Mickelson, Leah; Wilson, W. David; Boykin, David W.

doi:10.1016/j.bmc.2009.12.011

Cited by 33 publications

(30 citation statements)

References 46 publications

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“…These three compounds have the amidine group at the 6-position of indole, while their isomers with the amidine group at 5-position ( 5a , 5c, 5f ) of indole exhibit lower Δ Tm values. We hypothize that this decrease in DNA affinity is likely due to the fact that in the complex 6- amidino indole can form a strong hydrogen bond involving the indole NH to a thymine carbonyl as has been previously reported [7]. While in the analogous complex for the 5-amidino indole such is not possible as the 3-position C—H is pointed into the groove.…”

Section: Resultsmentioning

confidence: 50%

“…We previously have reported some phenyl acetylene derivatives of DAPI (compound I, Fig. 1), that showed strong DNA binding and exhibited potent in vitro activity superior to that of DAPI [7]. In a related investigation, we extended the overall length of DAPI by adding one phenyl group at the 5 or 6 position of indole and replacing the phenyl group of DAPI with different aryl and heteroaryls (compound II, Fig.…”

Section: Introductionmentioning

confidence: 99%

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Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties

Farahat

Kumar

Say

et al. 2017

European Journal of Medicinal Chemistry

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The DAPI structure has been modified by replacing the phenyl group with substituted phenyl or heteroaryl rings. Twelve amidines were synthesized and their DNA binding, fluorescence properties, in vitro and in vivo activities were evaluated. These compounds are shown to bind in the DNA minor groove with high affinity, and exhibit superior in vitro antitrypanosomal activity to that of DAPI. Six new diamidines (5b, 5c, 5d, 5e, 5f and 5j) exhibit superior in vivo activity to that of DAPI and four of these compounds provide 100% animal cure at a low dose of 4 × 5 mg/kg i.p. in T. b. rhodesiense infected mice. Generally, the fluorescence properties of the new analogues are inferior to that of DAPI with the exception of compound 5i which shows a moderate increase in efficacy while compound 5k is comparable to DAPI.

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Section: Resultsmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties

Farahat

Kumar

Say

et al. 2017

European Journal of Medicinal Chemistry

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“…A solution of ethynylmagnesium bromide in THF (0.5 M solution, 2.5 ml, 1.25 mmol) was added into a solution of 5-ethynylpicolinonitrile (38) (80 mg, 0.625 mmol) in THF (1.5 mL) at 0°C under an argon atmosphere. After stirring at room temperature for 1 h 10 min, 20% aqueous HI (13 mL) were added to the reaction mixture at 0°C, and then the mixture was stirred for an additional 10 min at the same temperature.…”

Section: Methodsmentioning

confidence: 99%

Remarkable acceleration of a DNA/RNA inter-strand functionality transfer reaction to modify a cytosine residue: the proximity effect via complexation with a metal cation

et al. 2014

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Modified nucleosides in natural RNA molecules are essential for their functions. Non-natural nucleoside analogues have been introduced into RNA to manipulate its structure and function. We have recently developed a new strategy for the in situ modification of RNA based on the functionality transfer reaction between an oligodeoxynucleotide probe and an RNA substrate. 2′-Deoxy-6-thioguanosine (6-thio-dG) was used as the platform to anchor the transfer group. In this study, a pyridinyl vinyl ketone moiety was newly designed as the transfer group with the expectation that a metal cation would form a chelate complex with the pyridinyl-2-keto group. It was demonstrated that the (E)-pyridinyl vinyl keto group was efficiently and specifically transferred to the 4-amino group of the opposing cytosine in RNA in the presence of NiCl2 with more than 200-fold accelerated rate compared with the previous system with the use of the diketo transfer group. Detailed mechanistic studies suggested that NiCl2 forms a bridging complex between the pyridinyl keto moiety and the N7 of the purine residue neighboring the cytosine residue of the RNA substrate to bring the groups in close proximity.

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“…Upon addition of Et 3 N to the reaction mixture, a very distinct colour change, as reported, from bright yellow to black was observed to indicate the necessary reduction of Pd(II) to Pd(0). [260] Application of the same conditions to aryl bromide 200 gave no distinct colour change. Analysis of the crude reaction mixture by 1 H NMR indictated the TMS-acetylene dimer, but no starting material and no product with olefinic protons.…”

Section: Figure 116mentioning

confidence: 95%

“…[260] A flame dried 2-neck flask was charged with 4-bromo-2-fluorobenzonitrile (110.0 mg, 0.55 mmol, 1.0 eq. ), PdCl 2 (PPh 3 ) 2 (20 mg, 0.03 mmol, 5 mol %) and CuI (13 mg, 0.07 mmol, 12.5 mol %) and subjected to 10 sucessive vacuum-argon cycles.…”

Section: -Fluoro-4-[(trimethylsilyl)ethynyl]benzonitrile 205mentioning

confidence: 99%

Kinetic Template‐Guided Tethering of Fragments

2012

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This thesis is composed of two separate projects: Kinetic Template-Guided Tethering of Fragments and Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1 Degradation after DNA Damage. Kinetic Template-Guided Tethering of FragmentsThe development of a novel methodology for the site-directed discovery of small molecule, protein-binding ligands is described. The protein of interest, with a cysteine thiol (either native or engineered) adjacent to the desired binding pocket, is incubated with mixtures of low molecular weight compounds (fragments) modified with either an acrylamide or a vinyl sulfonamide capture group. Any ligand within the mixture that binds within the pocket brings the capture group into close proximity with the cysteine thiol, promoting a conjugate addition reaction at an increased rate over the background reaction. The capture reaction is designed to be slow, such that during the time course of an experiment, no adduct formation is observed unless the reaction is templated by the protein. By this method, binding ligands are rapidly identified by mass spectrometry analysis of the crude reaction mixtures. The methodology has been termed 'kinetic template-guided tethering'. Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1Degradation after DNA Damage An inhibitor described within the literature was found to attenuate the reduction of cyclin D1 after DNA damage to cells. In order to implement a two-step chemical proteomics strategy to find the molecular target of this inhibitor, a synthesis of the compound with an alkyne appendage was required. The alkyne acts as a functional handle for attachment of a reporter molecule in cells via the Huisgen cycloaddition ('Click') reaction. The design and synthesis of this inhibitor with the alkyne appendage is described.

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Synthesis, DNA binding, fluorescence measurements and antiparasitic activity of DAPI related diamidines

Cited by 33 publications

References 46 publications

Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties

Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties

Remarkable acceleration of a DNA/RNA inter-strand functionality transfer reaction to modify a cytosine residue: the proximity effect via complexation with a metal cation

Kinetic Template‐Guided Tethering of Fragments

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