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

International Journal of Molecular Sciences

Sinara Mônica Vitalino de Almeida³  Elizabeth Almeida Lafayette¹  Lྫྷia Patrໜia Bezerra Gomes da Silva³  Cézar Augusto da Cruz Amorim¹  Tiago Bento de Oliveira¹  Ana Lucia Tasca Gois Ruiz²  João Ernesto de Carvalho²  Ricardo Olímpio de Moura⁴  Eduardo Isidoro Carneiro Beltrão³  Maria do Carmo Alves de Lima¹  Luiz Bezerra de Carvalho Júnior³ 

[1]Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil

[2] E-Mails:

[3]Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (DFT/CPQBA), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-970, SP, Brazil

[4] E-Mails:

[5]Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil

[6] E-Mails:

[7]Departamento de Farmácia, Laboratório de Síntese e Vetorização de Moléculas, Universidade Estadual da Paraíba (UEPB), Campus Campina Grande 58429-500, PB, Brazil

[8] E-Mail:

关键词: acridine;    thiosemicarbazone;    DNA binding;    antiproliferative;   

DOI  :  10.3390/ijms160613023

来源: mdpi

【 摘 要 】

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 × 10⁴ to 1.0 × 10⁶ M⁻¹ and quenching constants from −0.2 × 10⁴ to 2.18 × 10⁴ 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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.