Int. J. Mol. Sci. 2015, 16(6), 13023-13042; https://doi.org/10.3390/ijms160613023
Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives
1
Laboratório de Imunopatologia Keizo Asami (LIKA) and Departamento de Bioquímica, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
2
Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), Universidade de Pernambuco (UPE), Garanhuns 55290-000, PE, Brazil
3
Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
4
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
5
Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-859, SP, Brazil
6
Departamento de Farmácia, Laboratório de Síntese e Vetorização de Moléculas, Universidade Estadual da Paraíba (UEPB), Campus Campina Grande 58429-500, PB, Brazil
*
Author to whom correspondence should be addressed.
Academic Editor: Eric C. Long
Received: 27 March 2015 / Revised: 27 May 2015 / Accepted: 29 May 2015 / Published: 9 June 2015
(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)
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 × 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. View Full-TextKeywords:
acridine; thiosemicarbazone; DNA binding; antiproliferative
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de Almeida, S.M.V.; Lafayette, E.A.; da Silva, L.P.B.G.; Amorim, C.A.C.; de Oliveira, T.B.; Ruiz, A.L.T.G.; de Carvalho, J.E.; de Moura, R.O.; Beltrão, E.I.C.; de Lima, M.C.A.; Júnior, L.B.C. Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives. Int. J. Mol. Sci. 2015, 16, 13023-13042.
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