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. 2015 Jun 9;16(6):13023-42.
doi: 10.3390/ijms160613023.

Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives

Sinara Mônica Vitalino de Almeida  1   2 , Elizabeth Almeida Lafayette  3 , Lúcia Patrícia Bezerra Gomes da Silva  4 , Cézar Augusto da Cruz Amorim  5 , Tiago Bento de Oliveira  6 , Ana Lucia Tasca Gois Ruiz  7 , João Ernesto de Carvalho  8   9 , Ricardo Olímpio de Moura  10 , Eduardo Isidoro Carneiro Beltrão  11 , Maria do Carmo Alves de Lima  12 , Luiz Bezerra de Carvalho Júnior  13
Affiliations

Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives

Sinara Mônica Vitalino de Almeida et al. Int J Mol Sci. .

Abstract

In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.

Keywords: DNA binding; acridine; antiproliferative; thiosemicarbazone.

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Figures

Scheme 1
Scheme 1
Synthesis of acridine-thiosemicarbazone derivatives. Reagents and conditions: (i) pyridinium chlorochromate (PCC); (ii) EtOH, CH3COOH, reflux, 70 °C.
Figure 1
Figure 1
Absorption spectra of derivative 3a (50 µM) with increasing concentrations of calf thymus DNA (ctDNA). [DNA] = 0, 10, 20, 40, 60, 80, 100 and 120 µM. Arrows (↑) and (→) refer to hyperchromic, and bathchromic effects, respectively. Inset: Plot of [DNA]/(εa − εf) as function of DNA concentration as determined from the absorption spectral data.
Figure 2
Figure 2
Fluorescence spectra of derivative 3a (15 µM) with increasing concentrations of ctDNA. [DNA] = 0 (black), 10 (red), 20 (green), 40 (yellow), 60 (blue), 80 (pink), 100 (light blue) and 120 (gray) µM. Arrow (↓) refers to hypochromic effect.
Figure 3
Figure 3
Relative fluorescence intensities of acridine-thiosemicarbazone derivatives 3a (●), 3b (◊), 3c (▲), 3d (▽), 3e (♦), 3f (○), 3g (□) and 3h (▼), upon addition of ctDNA in Tris buffer (0.01 M, pH = 7.6).
Figure 4
Figure 4
Antiproliferative activity of 3a (concentrations of 0.7, 7.0, 70 and 702 µM) and amsacrine (m-AMSA)(concentrations of 0.6, 6.35, 63.5 and 635 µM) against nine cancerous cell lines: U251 (glioma, SNC); MCF-7 (breast adenocarcinoma); NCI-ADR/RES (ovary, multidrug resistance phenotype); 786-O (kidney); NCI-H460 (lung non-small cell adenocarcinoma); PC-3 (prostate); OVCAR-3 (ovary); HT-29 (colon); K-562 (Chronic myeloid leukemia) and human keratinocytes (HaCaT).
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