Synthesis and in vitro anticancer activity of novel thiazacridine derivatives
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Med Chem Res DOI 10.1007/s00044-012-0236-2
ORIGINAL RESEARCH
Synthesis and in vitro anticancer activity of novel thiazacridine derivatives Marina Galdino da Rocha Pitta • E´rika Silva Souza • Francisco Washington Arau´jo Barros Manoel Odorico Moraes Filho • Cla´udia O. Pessoa • Marcelo Zaldini Hernandes • Maria do Carmo Alves de Lima • Suely Lins Galdino • Ivan da Rocha Pitta
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Received: 27 February 2012 / Accepted: 13 September 2012 Ó Springer Science+Business Media New York 2012
Abstract Acridine derivatives represent a well-known class of anticancer agents that generally interfere with DNA synthesis and inhibit topoisomerase II. A series of eight new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione and 3-acridin-9-ylmethyl-5-arylidene-thiazolidine-2,4-dione derivatives were synthesized. All the compounds were evaluated for their cell antiproliferation activity with the 3-(4,5-dimethyl-2-thiozolyl)-2,5-diphenyl-2H-tetrazolium bromide, MTT assay. The antiproliferative effects of the synthesized compounds were tested against several tumoral cell lines, namely SF-295 (central nervous system), HCT-8 (colon carcinoma), and MDA-MB-435 (melanoma) cells using doxorubicin as a positive control. Among the synthesized compounds, 3-acridin-9-ylmethyl-5-acridin-9-ylm ethylene-thiazolidine-2,4-dione, 3-acridin-9-ylmethyl-5(4-methoxy-benzylidene)-thiazolidine-2,4-dione, and 3-acridin-9-ylmethyl-5-(4-bromo-benzylidene)-thiazolidine-2, 4-dione exhibited the most potent anticancer activity against the HCT-8 and MDA-MB-435 cell lines. After a
M. G. da Rocha Pitta M. Z. Hernandes M. do Carmo Alves de Lima S. L. Galdino I. da Rocha Pitta (&) Nu´cleo de Pesquisa em Inovac¸a˜o Terapeˆutica, Centro de Cieˆncias Biolo´gicas, Universidade Federal de Pernambuco, CEP 50670-901 Recife, Brazil e-mail: [email protected] E´. S. Souza Universidade Tiradentes, CEP 49032-490 Aracaju´, Brazil F. W. A. Barros M. O. Moraes Filho C. O. Pessoa Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceara´, CEP 60430-270 Fortaleza, Brazil
detailed analysis of the structure of the thiazacridine molecules, we revealed the main possible interactions using the compound 3-acridin-9-ylmethyl-5-acridin-9-ylmethylenethiazolidine-2,4-dione as an example. The benefits of these compounds, regardless of the pharmacological target are the presence of two aromatic rings (pi systems), significant planarity (intercalating ability) and the presence of three hydrogen-bond acceptors, two of which are stronger (oxygen atoms) than the other (sulfur atom). Keywords Thiazacridine MTT assay anticancer Molecular modeling
Introduction Until the early 1980s, intense research of drug discovery programs for cancer resulted in efficient medicinals, but with high toxicity due to the lack of selectivity (Brana et al., 2001; Demeunynck et al., 2001; Martinez and Chacon-Garcia, 2005; Cummings and Smyth, 1993; Georghiou, 1977). The design and synthesis of small molecules that bind selectively to and cleave nucleic acids are still major c
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