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URI permanente para esta coleçãohttps://locus.ufv.br/handle/123456789/11800
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Item Hederagenin amide derivatives as potential antiproliferative agents(European Journal of Medicinal Chemistry, 2019-04-15) Barbosa, Luiz C. A.; Demuner, Antonio J.; Rodríguez-Hernández, Diego; Martins, João Paulo Ataide; Csuk, René; Fischer (nee Heller), LucieIn this study, a series of C-28 amides derivatives of hederagenin with or without the presence of an acetyl group at positions 3 and 23 in ring A, were synthetized aiming to develop potent cytotoxic agents. Their structures were confirmed by MS, IR, 1H NMR and 13C NMR spectroscopic analyses and their cytotoxic activities were screened in SRB assays using a panel of six human cancer cell lines. The majority of the amide derivatives were cytotoxic for a variety of human tumor cell lines. In general, the hydroxylated derivatives (1a-1d; EC50 in the range 1.2–22.5 μM) were less active than the acetylated derivatives (2a-2n; EC50 in the range 0.4–9.0 μM). Hydroxylated derivative bearing pyrrolidinyl substituent 1c, was the most active for HT29 human line cells (EC50 = 1.2 μM), however their acetylated derivative 2c was the most potent and selective against A2780, FaDu, SW1736 cells, showing EC50 values between 0.4 and 1.7 μM and SI between 5.6 and 24. Staining experiments combined with fluorescence microscopy indicate that the cell membrane became permeable, and finally a process of secondary necrosis was observed. In addition, the docking results showed that acetylated compounds display more affinity to HER2 than to USP7, indicating that HER2 is a most probable receptor, both proteins found in tumor cell line A2780.Item Novel hederagenin–triazolyl derivatives as potential anti-cancer agents(European Journal of Medicinal Chemistry, 2016-06-10) Rodríguez-Hernández, Diego; Demuner, Antonio J.; Barbosa, Luiz C.A.; Heller, Lucie; Csuk, RenéA series of novel aryl-1H-1,2,3-triazol-4-yl methylester and amide derivatives of the natural product hederagenin was synthesized aiming to develop new antitumor agents, using Huisgen 1,3-dipolar cycloaddition reactions, with yields between 35% and 95%. The structures of all derivatives (2–31) were confirmed by MS, IR, ^1H NMR and ^13C NMR spectroscopic data. The cytotoxic activities of all compounds were screened against a panel of six human cancer cell lines using SRB assay. It was found that most of the compounds displayed higher levels of antitumor activities as compared to parent hederagenin. Compounds 4, 8 and 15 were the most potent against all human cancer cell lines. Furthermore, compound 11 was the most cytotoxic against cell HT29 showing EC50 = 1.6 μM and a selectivity index of 5.4.Item Highly potent anti-leishmanial derivatives of hederagenin, a triperpenoid from Sapindus saponaria L.(European Journal of Medicinal Chemistry, 2016-11-29) Rodríguez-Hernández, Diego; Barbosa, Luiz C.A.; Demuner, Antonio J.; Almeida, Raquel M.de; Fujiwara, Ricardo T.; Ferreira, Sebastião R.Leishmaniasis is a neglected tropical disease (NTDs), endemic in 88 countries that affect more than 12 million people. Current drugs are limited due to their toxicity, development of biological resistance, length of treatment and high cost. Thus, the search for new effective and less toxic treatments is an urgent need. In this study, we report the synthesis of 3 new amide derivatives of hederagenin (22–24) with yields between 70% and 90%, along with 57 other derivatives of hederagenin (1–21, 25–60) carrying different groups at C-28 previously reported by our group, and the results of their in vitro ability to inhibit the growth of Leishmania infantum. Some derivatives (3, 4, 44, 49 and 52), showed activity at micromolar level and low toxicity against BGM and HepG2 cells. Moreover, the ability of hederagenin derivatives 3 (IC50 = 9.7 μM), 4 (12 μM), 44 (11 μM) and 49 (2 μM), to prevent proliferation of intracellular amastigote forms of L. infantum and their higher selectivity index and low toxicity compared to commercial positive drug control of choice (potassium antimonyl tartrate trihydrate) (IC50 = 80 μM, SI = 0.1), make these compounds promising candidates for the treatment of leishmaniasis.Item Hederagenin as a triterpene template for the development of new antitumor compounds(European Journal of Medicinal Chemistry, 2015-11-13) Rodríguez-Hernández, Diego; Demuner, Antonio J.; Barbosa, Luiz C.A.; Csuk, René; Heller, LucieIn this study, a series of novel C-28 esters and amides derivatives of hederagenin (He) were designed and synthesized in attempt to develop potent antitumor agents. Their structures were confirmed by MS, IR, 1H NMR and ^13C NMR spectroscopic analyses and their cytotoxic activities were screened in SRB assays using a panel of six human cancer cell lines. Although most of the compounds displayed moderate to high levels of cytotoxic activity they were all more potent than the natural product He. The most active compounds had either an ethylpyrimidinyl (27) or an ethylpyrrolidinyl (28) substituent, with EC50 in the range of 1.1–6.5 μM for six human cancer cell lines. Notably, this corresponds to an approximately 30-fold times greater potency than He.