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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.


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.
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ijms-16-13023-f001: 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.

Mentions: The absorption spectra of the new acridine-thiosemicarbazone derivatives 3a–h show that all compounds displayed absorption bands in the region of 300–500 nm. The different donor or acceptor substituents present in compounds 3c–h induced red shifts on UV–Vis spectra relative to that of 3a, with exception of 3f. In order to examine the general affinity of the derivatives 3a–h to dsDNA, the binding interactions of these ligands with calf thymus DNA (ctDNA) were examined by spectrophotometric titrations. It is widely accepted that if the compounds can bind to DNA, their UV–Vis curves result in a characteristic shift of the absorption maximum wavelength (bathochromic or hypsochromic shift) and a decrease (hypochromicity) [35,36] or increase (hyperchromicity) of the absorbance [9]. The absorption spectra of 3a (50 µM) in both the absence and presence of ctDNA (0–120 µM) are given in Figure 1 (for the other derivatives see Figures S17–S23). The curve shows significant hyperchromicity (92.58% at 120 µM of ctDNA) and a slight bathochromic shift (Δλ 6 nm) with increasing ctDNA concentration, indicating a complex 3a-DNA formation. In the presence of ctDNA, all compounds (3a–h) produced hyperchromic or hypochromic effects, with the highest hypochromism being induced by the 3f derivative (Table 1). With the exception of compound 3g, all complexes with ctDNA showed bathochromic or hypsochromic effects with the most remarkable shifts for derivatives 3a and 3h, 6 and 12 nm, respectively.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-13023-f001: 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.
Mentions: The absorption spectra of the new acridine-thiosemicarbazone derivatives 3a–h show that all compounds displayed absorption bands in the region of 300–500 nm. The different donor or acceptor substituents present in compounds 3c–h induced red shifts on UV–Vis spectra relative to that of 3a, with exception of 3f. In order to examine the general affinity of the derivatives 3a–h to dsDNA, the binding interactions of these ligands with calf thymus DNA (ctDNA) were examined by spectrophotometric titrations. It is widely accepted that if the compounds can bind to DNA, their UV–Vis curves result in a characteristic shift of the absorption maximum wavelength (bathochromic or hypsochromic shift) and a decrease (hypochromicity) [35,36] or increase (hyperchromicity) of the absorbance [9]. The absorption spectra of 3a (50 µM) in both the absence and presence of ctDNA (0–120 µM) are given in Figure 1 (for the other derivatives see Figures S17–S23). The curve shows significant hyperchromicity (92.58% at 120 µM of ctDNA) and a slight bathochromic shift (Δλ 6 nm) with increasing ctDNA concentration, indicating a complex 3a-DNA formation. In the presence of ctDNA, all compounds (3a–h) produced hyperchromic or hypochromic effects, with the highest hypochromism being induced by the 3f derivative (Table 1). With the exception of compound 3g, all complexes with ctDNA showed bathochromic or hypsochromic effects with the most remarkable shifts for derivatives 3a and 3h, 6 and 12 nm, respectively.

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.