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gThe pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC 50 s) of <10 M. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC 50 ‫؍‬ 1.2 ؎ 1.0 M). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series. N ew drugs for parasitic diseases are urgently needed, but these globally important infections are often "neglected" because they most commonly afflict poor and marginalized communities. Current therapies are limited by poor efficacy, toxicity, high costs, and parasite resistance. Chagas disease, African sleeping sickness, and schistosomiasis are examples of diseases for which new therapies are needed (1, 2). Among the most studied and exploited molecular targets for these diseases are cysteine proteases. These enzymes have essential roles in parasite nutrition, immune evasion, host cell invasion, and metacyclogenesis (3-6). Indeed, the cysteine proteases cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1) from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively, are validated molecular targets and have been the subject of numerous medicinal chemistry projects (7-17) that have yielded trypanocidal inhibitors, both in parasite culture and in animal models of infection (13,15,(18)(19)(20)(21).The diverse inhibitors of these enzymes comprise compound classes which bind noncovalently (11, 12) and scaffolds containing a "warhead" that binds covalently to the catalytic cysteine. Within the latter category, vinylsulfones (8,(22)(23)(24)(25), oxy-methyl ketones (7, 26), nitriles (16), epoxides, and thiosemicarbazones (13-15, 27-29) have been described previously. Thiosemicarbazones present as advantages their low molecular weight, low cost of synthesis, and nonpeptidic nature (27). Greenbaum and coworkers synthesized and evaluated the cysteine protease inhibitory and antiparasitic activities of a library of thiosemicarbazones, with promising results (13). According to those authors, the thiosemicarbazones are...

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Recebido em 17/8/01; aceito em 27/2/02 BIOREDUCTIVE ANTINEOPLASTIC AGENTS: A NEW APPROACH TO THE TREATMENT OF SOLID TUMORS. A problem often encountered in cancer therapy is the presence of tumor cell subpopulation that are resistant to treatment. Solid tumors frequently contain hypoxic cells that are resistant to killing by ionizing radiation and also by many chemotherapeutic agents. However, these hypoxic cells can be exploited for therapy by non-toxic hypoxic-activated prodrugs. Bioreductive drugs require metabolic reduction to generate cytotoxic metabolites. This process is facilitated by appropriate reductases and the lower oxygen conditions present in solid tumors. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy.Keywords: solid tumor; hypoxic cells; bioreductive prodrugs. INTRODUÇÃOO câncer é basicamente uma doença de células, caracterizada por um desvio dos mecanismos de controle que dirigem a proliferação e a diferenciação celulares. As células que sofreram transformação neoplásica proliferam excessivamente e formam tumores locais que podem comprimir ou invadir estruturas normais adjacentes 1 . Progressos importantes na quimioterapia foram registrados na área da biologia molecular e celular, o que facilitou, juntamente com o maior entendimento do mecanismo de ação de muitas substâncias, a aplicação mais racional dos quimioterápicos e o planejamento de novos fármacos. Muitas das substâncias citotóxicas mais potentes atuam em fases específicas do ciclo celular e, conseqüentemente, só exercem a sua atividade contra células que se encontram em processos de divisão 2 . Sendo assim, as neoplasias malignas humanas que, atualmente, são mais suscetíveis ao tratamento quimioterápico e, freqüentemente, curadas, são aquelas que possuem alta porcentagem de células em processo de divisão. Os tumores sólidos, que apresentam divisão celular relativamente lenta, tais como os carcinomas de pulmão, cólon e mama, constituem mais de 90% de todos os tipos de câncer do homem. Estes tipos de neoplasias, em geral, respondem pouco aos agentes quimioterápicos existentes e o tratamento curativo, utilizando qualquer umas das modalidades terapêu-ticas (cirurgia, radioterapia, quimioterapia, imunoterapia e fototerapia dinâmica) ou mesmo a combinação das diversas modalidades, é extremamente difícil 3 . Além disso, uma outra limitação da quimioterapia é que a maioria dos fármacos antineoplásicos é altamente tóxica para o paciente e deve ser administrada com extremo cuidado 2,4 . CARACTERÍSTICAS DOS TUMORES SÓLIDOSAo contrário da percepção popular, a estrutura de um tumor não consiste, simplesmente, em um aglomerado de células em constante proliferação. As células neoplásicas freqüentemente ocupam menos da metade do volume total do tumor. Os vasos sangüíneos que se entrelaçam dentro da massa tumoral preenchem 1 a 10% do volume do tumor. O espaço restante é preenchido por matriz rica em colágeno o interstício que envolve as células neoplásicas e pode separá-las da vascularizaçã...

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The natural lignans veraguensin and grandisin have been reported to be active against Trypanosoma cruzi bloodstream forms. Aiming at the total synthesis of these and related compounds, we prepared three 2-arylfurans and eight 2,5-diarylfurans. They were evaluated for their potential as T. cruzi trypanothione reductase (TR) 60% at 20 µg/ml (59 and 90 µM, respectively). On the other hand, none of the compounds was significantly active against the parasite bloodstream forms even at 250 µg/ml (0.6-1.5 mM).Key words: tropical diseases -Chagas disease -arylfurans -trypanothione reductase Chagas disease, caused by the flagellate protozoan Trypanosoma cruzi, affects 18 million people in Latin America and is responsible for 13,000 deaths every year (WHO 2002). The treatment relies on only two available drugs, nifurtimox and benznidazole, which are relatively efficient in the acute phase of the disease, but almost ineffective in the chronic phase. Nowadays, one of the most important mechanisms of Chagas disease transmission in many countries is by blood transfusion (Schmuñis 1991). In highly endemic areas it is strongly recommended the use of chemoprophylatic measures such as the addition of gentian violet to clear trypomastigotes from blood banked for transfusion (Moraes-Souza et al. 1995). Although effective, this triphenylmethane dye is not well accepted because of undesirable effects such as coloring the skin and possible mutagenicity (Wendel 1993). Thus, new drugs to treat or prevent Chagas disease are still needed.Trypanosoma cruzi enzymes such as the trypanothione reductase (TR) represent a potential drug targets because they play an essential role in the life of this parasite. TR and its substrate trypanothione, the disulfide of a glutathione-spermidine conjugate [N 1 , N 8 -bis(glutathionyl)spermidine, T(SH) 2 ] 1, help to protect the parasite from oxidative stress by maintaining an intracellular reducing environment in a manner analogous to glutathione reductase (GR) and glutathione [L-γ-glutamyl-Lcysteiylglycine, GSH] 2 (Fig. 1a) in mammalian cells (Schmidt & Krauth-Siegel 2002). TR catalyses the NADPHdependent reduction of trypanothione disulfide TS 2 to its dithiol form, T(SH) 2 . Trypanothione may be oxidized back to TS 2 (Fig. 1b) following reaction with potentially damaging radicals and oxidants generated by aerobic metabolism. Another aspect that makes TR an even more attractive target is its structural differences from the human counterpart GR. GR has a narrow positively charged active site, to accommodate the glycine carboxylates of its substrate glutathione, whereas TR has a wider, noncharged, and more hydrophobic active site (Bond et al. 1999). These differences allowed the discovery of several promising selective inhibitors of TR (Schmidt & KrauthSiegel 2002).Lignans is a class of natural products that possess important biological properties (Jensen et al. 1993). Lopes et al. (1998) showed that the tetrahydrofuran lignans veraguensin 3 and grandisin 4 (Fig. 2) were active in vitro at 5 µg/ml aga...

This paper describes a comparative analysis of the physicochemical and structural properties of prodrugs and their corresponding drugs with regard to drug‐likeness rules. The dataset used in this work was obtained from the DrugBank. Sixty‐five pairs of prodrugs/drugs were retrieved and divided into the following categories: carrier‐linked to increase hydrophilic character, carrier‐linked to increase absorption, and bioprecursors. We compared the physicochemical properties related to drug‐likeness between prodrugs and drugs. Our results show that prodrugs do not always follow Lipinski's Rule of 5, especially as we observed 15 prodrugs with more than 10 hydrogen bond acceptors and 18 with a molecular weight greater than 500 Da. This fact highlights the importance of extending Lipinski's rules to encompass other parameters as both strategies (filtering of drug‐like chemical libraries and prodrug design) aim to improve the bioavailability of compounds. Therefore, critical reasoning is fundamental to determine whether a structure has drug‐like properties or could be considered a potential orally active compound in the drug‐design pipeline.