Interactions of Antiviral Indolo[2,3-b]quinoxaline Derivatives with DNA
Artikel i vetenskaplig tidskrift, 2008

Here, we present the synthesis of five novel indoloquinoxaline derivatives and investigate the DNA binding properties of these monomeric as well as dimeric compounds using absorption, fluorescence, and linear dichroism. Several of the mono- and dicationic derivatives presented have previously demonstrated an excellent antiviral effect that is higher than already acknowledged agents against human cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV). We find that the DNA binding constants of the monomeric and dimeric derivatives are high (∼10 6 ) and very high (∼10 9 ), respectively. Results from the spectroscopic measurements show that the planar aromatic indoloquinoxaline moieties upon interaction with DNA intercalate between the nucleobases. Furthermore, we use poly(dAdT) 2 and calf thymus DNA in a competitive binding experiment to show that all our derivatives have an AT-region preference. The findings are important in the understanding of the antiviral effect of these derivatives and give invaluable information for the future optimization of the DNA binding properties of this kind of drugs. © 2008 American Chemical Society.

Författare

Marcus Wilhelmsson

Chalmers, Kemi- och bioteknik, Fysikalisk kemi

N. Kingi

Karolinska Institutet

Drug Development

J. Bergman

Karolinska Institutet

Journal of Medicinal Chemistry

0022-2623 (ISSN) 1520-4804 (eISSN)

Vol. 51 24 7744-7750

Ämneskategorier

Fysikalisk kemi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

Organisk kemi

DOI

10.1021/jm800787b