Parasitol Res (2006) 99: 429–433 DOI 10.1007/s00436-006-0153-8 ORIGINAL PAPER Alessandra Jorqueira . Robson M. Gouvêa . Vitor F. Ferreira . Milton N. da Silva . Maria C. B. V. de Souza . Aline A. Zuma . Danielle F. B. Cavalcanti . Humberto P. Araújo . Dilvani O. Santos . Saulo C. Bourguignon Oxyrane derivative of α-lapachone is potent growth inhibitor of Trypanosoma cruzi epimastigote forms Received: 7 November 2005 / Accepted: 6 February 2006 / Published online: 5 April 2006 # Springer-Verlag 2006 Abstract The investigation of trypanocidal effects against Trypanosoma cruzi and cytotoxicity in VERO cell line of several oxyranes structurally related to β-lapachone, nor-β- lapachone, α-lapachone, and 4-methoxy-1,2-naphthoqui- none is described. It was found that the oxyranes 10 derived from α-lapachone showed an approximately the same trypanocidal activity of β-lapachone. In addition, all the oxyranes showed less cytotoxicity than the corresponding naphthoquinones. Introduction Several old and new medical problems for mankind are driving research to find out improved treatments. In this respect, the quinones have been largely studied for antitumor (Subramanian et al. 1998) trypanocidal (Marr and DoCampo 1986; Ferreira et al. 1992; Pinto et al. 1977), molluscicidal (Santos et al. 2000; Dos Santos et al. 2001), leishmanicidal (Teixeira et al. 2001), anti-inflammatory (Almeida 1990), and antifungal (Gafner et al. 1996). These reports indicate that a diversity of biological activities of the quinones are centered on the ortho- or para-quinonoid moiety, which in many cases accept one and/or two electrons (redox cycling) to form in situ reactive oxygen species (ROS) accelerating the intracellular hypoxic conditions (Babior 1997), which cause damage to several cell components (Santos et al. 2004; Silva et al. 2003). The redox cycling and oxygen activation leading to increased levels of ROS is closely related to the quinone redox potential (Monks et al. 1992). In fact, electron density on quinone moiety is affected by substituents resident on the quinonoid moiety structure. It should be noted that interstrand cross-links by alkylation of the DNA are also possible pathways for the toxicity of quinones (Abreu et al. 2002), including the possibility to interfere with enzyme bioactivities, known as topoisomerases, a group of enzymes critical to DNA duplication. β-lapachone (1a, 3,4-dihydro-2,2-dimethyl-2H-naphtho [1,2-b pyran-5,6-dione) is a 1,2-naphthoquinone (Fig. 1) present in the heartwood of Tabebuia sp., whose extract has been used in popular medicine for centuries against several diseases (Pinto et al. 1977). Its effectiveness at micromolar concentrations against a variety of in vitro tumor cells might indicate a probable antitumor potential of these compounds upon reduction of tumorigenesis process. Thus, a greater interest on β- lapachone (1a) is concentrated on clinical use in cancer chemotherapy (Pardee et al. 2002; Ravelo et al. 2004). The detailed mechanism of cell death induced by 1a is not yet revealed. However, it has been suggested that topoisomerases I (Chiang et al. 1993) and II (Frydman et al. 1997), known by their action on the topological structure of DNA, are the biochemical targets involved in the apoptosis, but now, their role in cell death is not yet clear. Compound 1a displays cytotoxic effect against a variety of drug sensitive and drug resistant in vitro tumor cell lines, including MDR1-overexpressing cell lines resistant to camptothecin, and atypical multidrug-resistant CEM/V-1 cell line (Frydman et al. 1997). In addition, the 1a compound also shows a variety of pharmacological effects, including antibacterial, antifungal, and trypano- cidal activities (Dubin et al. 2001). Several studies have been addressed to chemical modifications at quinonoid center upon researching pharmacologically important derivatives of 1a compound. Then, Di Chenna et al. (2001) reported the synthesis of A. Jorqueira . R. M. Gouvêa . V. F. Ferreira (*) . M. N. da Silva . M. C. B. V. de Souza Departamento de Química Orgânica-PQO, Instituto de Química, Universidade Federal Fluminense, 24020-150 Niterói, Rio de Janeiro, Brazil e-mail: cegvito@vm.uff.br Tel.: +55-21-26292345 H. P. Araújo . D. O. Santos Departamento de Imunologia, Fundação Oswaldo Cruz, INCQS, RJ, Rio de Janeiro, Brazil A. A. Zuma . D. F. B. Cavalcanti . S. C. Bourguignon Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, 24020-150 Niterói, Rio de Janeiro, Brazil