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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.


Related in: MedlinePlus

Synthesis of acridine-thiosemicarbazone derivatives. Reagents and conditions: (i) pyridinium chlorochromate (PCC); (ii) EtOH, CH3COOH, reflux, 70 °C.
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ijms-16-13023-scheme1: Synthesis of acridine-thiosemicarbazone derivatives. Reagents and conditions: (i) pyridinium chlorochromate (PCC); (ii) EtOH, CH3COOH, reflux, 70 °C.

Mentions: The reaction sequence used for the synthesis of novel acridine-thiosemicarbazone compounds is shown in Scheme 1. The compound 9-methylacridine (1) was prepared from diphenylamine with zinc dichloride in acetic acid according to Tsuge et al. [32]. Subsequently, the oxidation of 1 with pyridinium chlorochromate (PCC) was accomplished according to Mosher and Natale [33] yielding 9-acridinaldehyde (2). Compound 2 was used as starting reagent in the synthesis of different types of acridine-thiosemicarbazone derivatives. Thiosemicarbazides were synthesized in good yields (>90%) by adding hydrazine hydrate to different aryl isothiocyanates as previously described [34]. Thus, condensation of different thiosemicarbazide derivatives with 9-acridinaldehyde afforded the corresponding acridine-thiosemicarbazone derivatives 3a–h (Scheme 1).


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)

Synthesis of acridine-thiosemicarbazone derivatives. Reagents and conditions: (i) pyridinium chlorochromate (PCC); (ii) EtOH, CH3COOH, reflux, 70 °C.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-13023-scheme1: Synthesis of acridine-thiosemicarbazone derivatives. Reagents and conditions: (i) pyridinium chlorochromate (PCC); (ii) EtOH, CH3COOH, reflux, 70 °C.
Mentions: The reaction sequence used for the synthesis of novel acridine-thiosemicarbazone compounds is shown in Scheme 1. The compound 9-methylacridine (1) was prepared from diphenylamine with zinc dichloride in acetic acid according to Tsuge et al. [32]. Subsequently, the oxidation of 1 with pyridinium chlorochromate (PCC) was accomplished according to Mosher and Natale [33] yielding 9-acridinaldehyde (2). Compound 2 was used as starting reagent in the synthesis of different types of acridine-thiosemicarbazone derivatives. Thiosemicarbazides were synthesized in good yields (>90%) by adding hydrazine hydrate to different aryl isothiocyanates as previously described [34]. Thus, condensation of different thiosemicarbazide derivatives with 9-acridinaldehyde afforded the corresponding acridine-thiosemicarbazone derivatives 3a–h (Scheme 1).

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.


Related in: MedlinePlus