Original article 2-Acetylpyridine- and 2-benzoylpyridine-derived hydrazones and their gallium(III) complexes are highly cytotoxic to glioma cells Angel A.R. Despaigne a , Gabrieli L. Parrilha a , Jans B. Izidoro b , Pryscila R. da Costa b , Raquel G. dos Santos b , Oscar E. Piro c , Eduardo E. Castellano d , Willian R. Rocha a , Heloisa Beraldo a, * a Departamento de Química, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil b Centro de Desenvolvimento da Tecnologia Nuclear, CDTN, 31270-901, Belo Horizonte, MG, Brazil c Departamento de Física, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and Instituto IFLP (CONICET e CCT La Plata), C.C. 67, 1900 La Plata, Argentina d Instituto de Física de São Carlos, Universidade de São Paulo, 13560-970, São Carlos, SP, Brazil article info Article history: Received 3 October 2011 Received in revised form 20 January 2012 Accepted 24 January 2012 Available online 2 February 2012 Keywords: Hydrazones Gallium(III) complexes Crystal structures Glioma cells Cytotoxic activity SAR studies abstract 2-Acetylpyridine-phenylhydrazone (H2AcPh), its para-chlorophenylhydrazone (H2AcpClPh) and para- nitrophenylhydrazone (H2AcpNO 2 Ph) analogues, the corresponding 2-benzoylpyridine-derived hydra- zones (H2BzPh, H2BzpClPh and H2BzpNO 2 Ph) and their gallium(III) complexes were assayed for their cytotoxic activity against U87 (expressing wild-type p53 protein) and T98 (expressing mutant p53 protein) glioma cells. IC 50 values against both glioma cells and against the MRC5 (human fetal lung fibroblast) lineage were obtained for the hydrazones, but not for their gallium(III) complexes, due to their low solubility. Hydrazones were highly cytotoxic at nanomolar doses against U87 and T98 cells. The therapeutic indexes (TI ¼ IC 50MRC5 /IC 50glioma ) were 2-660 for T98 cells and 28-5000 for U87 cells, indi- cating that the studied hydrazones could be good antitumor drug candidates to treat brain tumors. Ó 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]. Although brain tumors constitute only 1e2% of the tumors in adults, they have a poor prognosis and the patients’ chance of survival is generally very low. Moreover, brain tumors represent one of the most common solid tumors in children, being responsible for 20% of childhood neoplasms [2,3]. Gliomas, especially glioblastomas (GBMs), represent the most malignant primary brain tumors. GBMs have a high rate of cellular proliferation and a marked propensity to infiltrate diffusely into normal brain regions rendering impossible total surgical extirpa- tion and difficult effective local radiotherapy. Such aggressive and invasive growth is the main characteristic which results in their high morbidity and mortality, the median survival of a patient with GBMs being 15 months [4,5]. Hydrazones and their metal complexes are an important class of compounds which present innumerous pharmacological applications as antimicrobial [6,7], anticonvulsant [8,9], analgesic and anti-inflammatory [10e12], and anticancer [13e15] agents. Gallium, as Ga(NO 3 ) 3 , is the second metal ion, after platinum, to be used in cancer treatment, but its unfavorable pharmacokinetics has prevented its widespread use in systemic chemotherapy of cancer [16]. Hence, coordination of gallium with organic ligands has been recognized as a promising strategy for the design of new antitumor agents with higher bioavailability and hydrolytic stability, and better membrane penetration ability [17,18]. Gallium’s activity against tumors is thought to be due to its anti- proliferative and antimitotic effects. Once gallium gets into the cell it exerts its anti-proliferative effects by inhibiting the catalytic activity of ribonucleoside diphosphate reductase (RDR), a key enzyme in DNA biosyntheses, which is involved in the conversion of ribonucleotides into deoxyribonucleotides. Due to competitive binding of gallium(III) and iron(III), gallium affects intracellular iron availability, but it also interacts directly with RDR, displacing iron from the enzyme [19e21]. In a previous work some of us demonstrated that gallium(III) complexes with 2-pyridineformamide-derived thiosemicarbazones exhibit potent cytotoxic activity against glioblastoma cells [18]. In the context of a research program that aims to contribute to the * Corresponding author. Tel.: þ55 31 3499 5740; fax: þ55 31 3499 5700. E-mail address: hberaldo@ufmg.br (H. Beraldo). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2012.01.051 European Journal of Medicinal Chemistry 50 (2012) 163e172