Solid tumors are frequently affected by the presence of hypoxic cells, originating anomalous and disordered cell growth. This subpopulation presents resistance to conventional chemotherapy agents and radiotherapy, due to the difficulties of reaching the target region, the permanence in the G0 phase of cell cycle and the low local concentration of oxygen. The use of hypoxia activated prodrugs becomes, in this scenario, an effective and selective alternative in cancer therapy, though not yet available for clinical use in solid tumor treatment. Twenty years after the publication of the paper intitled “Agentes Antineoplásicos Biorredutíveis: Uma Nova Alternativa para o Tratamento de Tumores Sólidos” in the Química Nova journal (2002), the current essay aims to identify the advances in the pre-clinical and clinical studies regarding the development of new hypoxia-directed drugs and the improvement of the molecules previously studied. Moreover, to clarify the main challenges for the implementation and success of this drug class, in order to identify the hindrances for the preparation of a bioavailable, safe and selective drug. cells growth radiotherapy region G oxygen becomes scenario therapy treatment Agentes Biorredutíveis Sólidos 2002, 2002 , (2002) preclinical pre hypoxiadirected directed studied Moreover class bioavailable 200 (2002 20 (200 2 (20 (2 (

The compound 2-hydrazinyl-4-(4-methoxyphenyl)thiazole (PD76) is a novel thiazolyl hydrazine derivative with proven antifungal activity against different fungal species, mainly Candida and Cryptococcus. Considering the advantages of oral route for clinical therapy, the aim of this work was to evaluate the potential intestinal permeability of this new antifungal drug. For the quantitation of PD76, a high-performance liquid chromatography method was developed and fully validated. The cytotoxicity of the compound in Caco-2 cells was analyzed and intestinal permeability of PD76 was assessed by means of the comparison of in vitro assay in Caco-2 cells and in silico platforms ADMETlab and admetSAR. Cell viability above 70% was obtained at all PD76 studied concentrations. Using Caco-2 cell model, the compound showed apparent permeability coefficients (Papp) of 5.25 × 10-6 and 23.28 × 10-6 cm s-1 in apical-basolateral and basolateral-apical directions, respectively. Experiments performed using verapamil as P-gp inhibitor demonstrated that PD76 is slightly susceptible to active efflux. Both in silico platforms inferred that PD76 presents permeability in Caco-2 cells, with Log P values of 2.82 (ADMETlab) and 2.10 (admetSAR). The results obtained in permeability studies showed that PD76 presents moderate intestinal permeability and a promising profile for clinical application. 2hydrazinyl44methoxyphenylthiazole hydrazinylmethoxyphenylthiazole 2 hydrazinyl 4 methoxyphenyl thiazole PD (PD76 species Cryptococcus therapy drug highperformance high performance validated Caco2 Caco Caco- PD7 admetSAR 70 concentrations model Papp (Papp 525 5 25 5.2 106 10 6 10- 2328 23 28 23.2 s1 s 1 s- apicalbasolateral apical basolateral basolateralapical directions respectively Pgp gp efflux 282 82 2.8 (ADMETlab 210 2.1 . (admetSAR) application methoxyphenylthiazole (PD7 7 52 5. 232 23. 8 2. 21 (admetSAR (PD

RN104 (2-[2-(cyclohexylmethylene)hydrazinyl]-4-phenylthiazole) is a thiazolylhydrazone derivative with promising in vitro and in vivo antifungal activity. A stability indicating highperformance liquid chromatography with diode-array detection (HPLC-DAD) method was carried out using C18 end-capped column (250 × 4.6 mm, 5 μm) and a mobile phase composed of water and acetonitrile (15:85 v/v) at a flow rate of 1.2 mL min-1, injection volume 25 μL and DAD detection at 240 nm. The method showed to be selective, linear in the range of 20 to 240 μg mL-1, precise, accurate and robust. RN104 forced degradation study under different stress conditions (acidic, alkaline and neutral hydrolysis, oxidation, photolysis and thermolysis) was performed using the validated analytical method. The results showed that RN104 underwent significant degradation when subjected to alkaline hydrolysis and oxidation by metallic ions. Quantum mechanics calculations were carried out to assist in the structural elucidation of the formed degradation products. The obtained data may be useful for the development of future formulation based on RN104. RN RN10 22cyclohexylmethylenehydrazinyl4phenylthiazole cyclohexylmethylenehydrazinylphenylthiazole 2 cyclohexylmethylene hydrazinyl 4 phenylthiazole (2-[2-(cyclohexylmethylene)hydrazinyl]-4-phenylthiazole activity diodearray diode array HPLCDAD HPLC (HPLC-DAD C C1 endcapped end capped 250 (25 46 6 4. mm μm 1585 15 85 (15:8 v/v vv v 12 1 1. min1, min1 min 1, min-1 24 nm selective mL1, mL1 mL-1 precise robust acidic, acidic (acidic thermolysis ions products RN1 cyclohexylmethylenehydrazinyl (2 158 8 (15: min- mL- ( (15 (1

Trypanosoma cruzi is a protozoan parasite that causes a severe disease (Chagas'disease) in Central and South America. The currently available chemotherapeutic agents against this disease are still inadequate. The enzyme trypanothione reductase (TR) is considered a validated molecular target for the development of new drugs against this parasite. In this regard, a series of arylfurans based on 2,5-bis-(4-acetamidophenyl)furan was synthesized and tested for their in vitro inhibitory activity against TR. Molecular modeling studies of putative enzyme-inhibitor complexes revealed a possible mechanism of interaction. From synthesized compounds, a benzylaminofuran derivative was found to be more active than the lead compound.

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) inhibitors as well against the parasite's intracellular (amastigote) and bloodstream (trypomastigote) forms. Compound 12 was the most effective against TR with an IC50 of 48.5 µM while 7 and 14 were active against amastigotes, inhibiting the parasite development by 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).

Relata-se no presente trabalho a síntese dedelta-lactonas quirais derivadas de carboidratos, por meio de reações de ciclização radicalar regio- e estereosseletivas. A configuração do novo centro estereogênico depende da estrutura do carboidrato.

We describe in the present work the synthesis of carbohydrate-based chiral delta-lactones by regio- and stereoselective radical cyclization reactions. The configuration of the newly stereogenic center was found to depend on the structure of the carbohydrate moiety.

Fourteen compounds were evaluated for their activity against Trypanosoma cruzi blood stream forms at the concentration of 500 µg/ml. Six compounds were active and re-tested at lower concentrations.