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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

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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ijms-16-13023-f004: 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).

Mentions: The type of side chain influences the cytotoxic activities of acridine derivatives [50]. For acridine-thiosemicarbazone derivatives, the nature of the substituent on the phenyl ring significantly influenced the antiproliferative activity (Table 2). The most active derivative was 3a as demonstrated in Figure 4 (for the other derivatives see Figures S39–S45). Compound 3a inhibited the growth of all cell lines in a dose-dependent manner, with GI50 values lower than 10 µM for all tumor cell lines. Tumor cell selectivity was not observed in the growth inhibition, but the pattern was similar to the positive control m-AMSA, also presented in Figure 4. However, the GI50 concentrations of 3a ranged widely from 3- to 30-fold higher than those for m-AMSA.


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)

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).
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-13023-f004: 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).
Mentions: The type of side chain influences the cytotoxic activities of acridine derivatives [50]. For acridine-thiosemicarbazone derivatives, the nature of the substituent on the phenyl ring significantly influenced the antiproliferative activity (Table 2). The most active derivative was 3a as demonstrated in Figure 4 (for the other derivatives see Figures S39–S45). Compound 3a inhibited the growth of all cell lines in a dose-dependent manner, with GI50 values lower than 10 µM for all tumor cell lines. Tumor cell selectivity was not observed in the growth inhibition, but the pattern was similar to the positive control m-AMSA, also presented in Figure 4. However, the GI50 concentrations of 3a ranged widely from 3- to 30-fold higher than those for m-AMSA.

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