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. 2013 Dec 6;18(12):15035-50.
doi: 10.3390/molecules181215035.

Synthesis, DNA binding and topoisomerase I inhibition activity of thiazacridine and imidazacridine derivatives

Elizabeth Almeida Lafayette  1 , Sinara Mônica Vitalino de Almeida, Marina Galdino da Rocha Pitta, Eduardo Isidoro Carneiro Beltrão, Teresinha Gonçalves da Silva, Ricardo Olímpio de Moura, Ivan da Rocha Pitta, Luiz Bezerra de Carvalho Jr, Maria do Carmo Alves de Lima
Affiliations

Synthesis, DNA binding and topoisomerase I inhibition activity of thiazacridine and imidazacridine derivatives

Elizabeth Almeida Lafayette et al. Molecules. .

Abstract

Thiazacridine and imidazacridine derivatives have shown promising results as tumors suppressors in some cancer cell lines. For a better understanding of the mechanism of action of these compounds, binding studies of 5-acridin-9-ylmethylidene-3-amino-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-imidazolidin-4-one and 3-acridin-9-ylmethyl-thiazolidin-2,4-dione with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopy and circular dichroism spectroscopy were performed. The binding constants ranged from 1.46 × 10(4) to 6.01 × 10(4) M(-1). UV-Vis, fluorescence and circular dichroism measurements indicated that the compounds interact effectively with ctDNA, both by intercalation or external binding. They demonstrated inhibitory activities to human topoisomerase I, except for 5-acridin-9-ylmethylidene-2-thioxo-1,3-thiazolidin-4-one. These results provide insight into the DNA binding mechanism of imidazacridines and thiazacridines.

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Figures

Scheme 1
Scheme 1
Synthesis of thiazacridine and imidazacridine derivatives.
Figure 1
Figure 1
Chemical structure of 3-acridin-9-ylmethylthiazolidine-2,4-dione (7).
Figure 2
Figure 2
Absorption spectra of derivative 6 (25 µM) with increasing concentrations of ctDNA. [DNA] = 0 (black), 10 (red), 20 (green), 40 (yellow), 60 (blue), 80 (pink) µM. Arrows (↓) and (→) refer to hypochromic and bathchromic effects, respectively. Inset: corresponding to the plot of [DNA]/(εa − εf) as function of DNA concentration as determined from the absorption spectral data.
Figure 3
Figure 3
Absorption spectra of derivative 5 (50 µM) with increasing concentrations of ctDNA. [DNA] = 0 (black), 10 (red), 20 (green), 40 (yellow), 60 (blue), 80 (pink) µM. Arrow (↑) refers to hyperchromic effect. Inset: corresponding to the plot of [DNA]/(εa − εf) as function of DNA concentration as determined from the absorption spectral data.
Figure 4
Figure 4
Fluorescence spectra of derivative 5 (10 µM) with increasing concentrations of ctDNA. [DNA] = 0 (black), 20 (red), 40 (green), 80 (yellow) e 120 (blue) µM. Insert: corresponding the fluorescence intensity of bound derivative to ctDNA (I)/fluorescence intensity of free derivative (I0).
Figure 5
Figure 5
Circular dichroism spectra of ctDNA (100 µM) in 10 mM Tris HCl buffer pH 7.6, in the presence of 4 (red), 5 (green), 6 (yellow) and 7 (blue) derivatives.
Figure 6
Figure 6
Quantitative analysis of the thiazacridine and imidazacridine derivatives effects on the relaxation of pUC19 DNA plasmid by human topoisomerase 1.
See this image and copyright information in PMC

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