Synthesis of Dicationic 2,5-Diarylpyrroles

Arafa, Reem K.; Brun, Reto; Werbovetz, Karl A.; Tanious, Farial A.; Wilson, W. David; Boykin, David W.

doi:10.1515/hc.2004.10.6.423

Cited by 6 publications

(2 citation statements)

References 13 publications

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“…Preparation of Reversed Amidines: General Procedure. The new compounds in this report were prepared following the general method previously developed by us . The general procedure used follows along with characterization data for DB1215 (structure in Table ).…”

Section: Methodsmentioning

confidence: 99%

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

et al. 2007

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To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations, a series of "reversed amidine" substituted heterocycles has been prepared. Amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system while in the reverse orientation, an amidine nitrogen provides the link. The reverse system has a larger dihedral angle as well as a modified spatial relationship with the groove relative to amidines. Because of the large dihedral, the reversed amidines should have reduced binding to DNA relative to similar amidines. Such a reduction is observed in footprinting, circular dichroism (CD), biosensor-surface plasmon resonance (SPR) and isothermal titration calorimetric (ITC) experiments with DB613, which has a central phenyl-furan-phenyl heterocyclic system. The reduction is not seen when a pyrrole (DB884) is substituted for the furan. Analysis of a number of derivatives defines the pyrrole and a terminal phenyl substituent on the reversed amidine groups as critical components in the strong binding of DB884. ITC and SPR comparisons showed that the better binding of DB884 was due to a more favorable binding enthalpy and that it had exceptionally slow dissociation from DNA. Crystallographic analysis of DB884 bound to an AATT site show that the compound was bound in the minor groove in a 1:1 complex as suggested by CD solution studies. Surprisingly, unlike the amidine derivative, the pyrrole -NH of DB884 formed an H-bond with a central T of the AATT site and this accounts for the enthalpy driven strong binding. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for related amidine and reversed amidine analogs.

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Section: Methodsmentioning

confidence: 99%

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

et al. 2007

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“…2,5‐Bis(4‐nitrophenyl)‐1‐methylpyrrole 5 :15 From 4‐bromonitrobenzene (0.606 g, 3 mmol) and 1‐methylpyrrole (0.081 g, 1 mmol), 5 was obtained in 67 % (0.216 g) yield.…”

Section: Methodsmentioning

confidence: 99%

Palladium‐Catalysed Direct Polyarylation of Pyrrole Derivatives

Zhao¹,

Bruneau²,

Doucet³

2012

ChemCatChem

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International audienceThe palladium-catalysed direct polyarylation of 1-methylpyrrole and 1-phenylpyrrole was studied. As the C2 and C5 positions of pyrroles are more reactive for C-H bond functionalisation than the C3 and C4 positions, the formation of 2,5-diarylpyrroles was found to proceed selectively in the presence of 3 equiv. of a variety of aryl bromides. The sequential C2 arylation followed by C5 arylation to prepare non-symmetrically substituted 2,5-diarylpyrroles was also studied. For the synthesis of such pyrroles, higher yields were obtained for the couplings with electron-deficient aryl bromides. The tetraarylation of 1-methylpyrrole was also achieved. From 4 equiv. of 3,5-bis(trifluoromethyl) bromobenzene, the 2,3,4,5-tetraarylated pyrrole was obtained in good yield

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Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

Arafa

Ismail

Munde

et al. 2008

European Journal of Medicinal Chemistry

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A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bisguanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by T m values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.

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Synthesis of Dicationic 2,5-Diarylpyrroles

Cited by 6 publications

References 13 publications

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

Palladium‐Catalysed Direct Polyarylation of Pyrrole Derivatives

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

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