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

de Almeida SM, Lafayette EA, da Silva LP, Amorim CA, de Oliveira TB, Ruiz AL, de Carvalho JE, de Moura RO, Beltrão EI, de Lima Mdo C, de Carvalho Júnior LB - Int J Mol Sci (2015)

Bottom Line: Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. sinara.monica@gmail.com.

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.

No MeSH data available.


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.
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ijms-16-13023-f002: 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.

Mentions: Spectrofluorimetric studies were also performed to analyze the binding properties between acridine-thiosemicarbazone derivatives and ctDNA. Table 1 summarizes the fluorescence emission from the derivatives under investigation (excitation and emission spectra can be seen in Figures S24–S31). Compounds 3a–h exhibited an emission band in the range of 400–500 nm. Excitation wavelengths were at 350–370 nm and spectra were monitored at a fixed concentration of 15 µM of each derivative and different ctDNA concentrations. The fluorescence of acridine-thiosemicarbazone derivatives was quenched upon addition of ctDNA, except for 3b and 3e derivatives that exhibited an increase in their fluorescence intensity upon DNA addition. In general, the enhancement of fluorescence intensity may be explained by a significant suppression of the conformational flexibility of the ligand within the DNA–ligand complex [38]. Figure 2 presents the emission spectra of 3a in the presence of different concentrations of ctDNA (for the other derivatives see Figures S32–S38).


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

de Almeida SM, Lafayette EA, da Silva LP, Amorim CA, de Oliveira TB, Ruiz AL, de Carvalho JE, de Moura RO, Beltrão EI, de Lima Mdo C, de Carvalho Júnior LB - Int J Mol Sci (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490484&req=5

ijms-16-13023-f002: 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.
Mentions: Spectrofluorimetric studies were also performed to analyze the binding properties between acridine-thiosemicarbazone derivatives and ctDNA. Table 1 summarizes the fluorescence emission from the derivatives under investigation (excitation and emission spectra can be seen in Figures S24–S31). Compounds 3a–h exhibited an emission band in the range of 400–500 nm. Excitation wavelengths were at 350–370 nm and spectra were monitored at a fixed concentration of 15 µM of each derivative and different ctDNA concentrations. The fluorescence of acridine-thiosemicarbazone derivatives was quenched upon addition of ctDNA, except for 3b and 3e derivatives that exhibited an increase in their fluorescence intensity upon DNA addition. In general, the enhancement of fluorescence intensity may be explained by a significant suppression of the conformational flexibility of the ligand within the DNA–ligand complex [38]. Figure 2 presents the emission spectra of 3a in the presence of different concentrations of ctDNA (for the other derivatives see Figures S32–S38).

Bottom Line: Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil. sinara.monica@gmail.com.

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.

No MeSH data available.