- Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability
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Herein we report novel hybrid compounds based on valproic acid and DNA-alkylating triazene moieties, 1, with therapeutic potential for glioblastoma multiforme chemotherapy. We identified hybrid compounds 1d and 1e to be remarkably more potent against glioma and more efficient in decreasing invasive cell properties than temozolomide and endowed with chemical and plasma stability. In contrast to temozolomide, which undergoes hydrolysis to release an alkylating metabolite, the valproate hybrids showed a low potential to alkylate DNA. Key physicochemical properties align for optimal CNS penetration, highlighting the potential of these effective triazene based-hybrids for enhanced anticancer chemotherapy.
- Braga, Cláudia,Vaz, Ana R.,Oliveira, M. Concei??o,Matilde Marques,Moreira, Rui,Brites, Dora,Perry, Maria J.
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- The selective cytotoxicity of new triazene compounds to human melanoma cells
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Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t??≥?48?h), and most of them showed to be slowly hydrolysed in human plasma (1.5?≤?t? (h)?≤?161). Compounds 3c–n revealed to be excellent tyrosinase substrates (0.74?≤?t? (min)?≤?6) with the best tyrosinase substrate 3l releasing MMT 45?s after tyrosinase activation. Structure-activity relationship studies allowed the identification of the better structural features for enzyme affinity. Furthermore, the derivatives 3l and 3m showed cell selectivity with significant cytotoxic effects (IC50 values of 46–65?μM) against melanoma cell lines with tyrosinase overexpression MNT-1 and B16F10.
- Sousa, Ana,Santos, Fábio,Gaspar, Maria Manuela,Calado, Susana,Pereira, Jo?o D.,Mendes, Eduarda,Francisco, Ana Paula,Perry, Maria Jesus
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p. 3900 - 3910
(2017/07/05)
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- Synthesis and evaluation of N-acylamino acids derivatives of triazenes. Activation by tyrosinase in human melanoma cell lines
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In this research work we report the synthesis of a new series of triazene prodrugs designed for Melanocyte-Directed Enzyme Prodrug Therapy (MDEPT). These compounds are derived from the N-acyltyrosine amino acid - a good enzyme substrate for the tyrosinase enzyme, which is significantly overexpressed in melanoma cells. We analysed their chemical stability and plasma enzymatic hydrolysis, and we also evaluated the release of the antitumoral drug in the presence of the tyrosinase. Subsequently, we performed the evaluation of the prodrug cytotoxicity in melanoma cell lines with different levels of tyrosinase activity. Prodrug 5c showed the highest cytotoxicity against melanoma cell lines, and this effect correlated well with the tyrosinase activity suggesting that prodrug cytotoxicity is tyrosinase-dependent.
- Monteiro, Ana Sofia,Almeida, Joana,Cabral, Guadalupe,Severino, Paulo,Videira, Paula A.,Sousa, Ana,Nunes, Rafael,Pereira, Jo?o D.,Francisco, Ana Paula,Perry, M. Jesus,Mendes, Eduarda
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- Development of triazene prodrugs for ADEPT strategy: New insights into drug delivery system based on carboxypeptidase G2 activation
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Six novel urea triazene prodrugs have been synthesized to apply in antibody-directed enzyme prodrug therapy (ADEPT). The chemical and plasmatic stability of l-glutamate triazene prodrugs were evaluated and the chemical reactivity was mainly attributed to
- Capucha, Veronica,Mendes, Eduarda,Francisco, Ana Paula,Perry, M. Jesus
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p. 6903 - 6908,6
(2020/09/02)
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- Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes
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A series of 3-acyloxymethyloxycarbonyl-1-aryl-3-methyltriazenes 5 was synthesised by the sequential reaction of 1-aryl-3-methyltriazenes with (i) chloromethyl chloroformate, (ii) NaI in dry acetone, and (iii) either the silver carboxylate or the carboxylic acids in the presence of silver carbonate. The hydrolysis of these compounds was studied in pH 7.7 isotonic phosphate buffer and in human plasma. Triazene acyloxycarbamates demonstrated their ability to act as substrates for plasma enzymes. For compound 5f, a pH-rate profile was obtained which showed the hydrolysis to involve acid-base catalysis. The reaction is also buffer catalysed. Thus, at pH 7.7, pH-independent, base-catalysed and buffer-catalysed processes all contribute to the hydrolysis reaction. The sensitivity of the hydrolysis reaction to various structural parameters in the substrates indicates that hydrolysis occurs at the ester rather than the carbamate functionality. In plasma, the rates of hydrolysis correlate with partition coefficients, the most lipophilic compounds being the most stable. An aspirin derivative suffers two consecutive enzymatic reactions, the scission of the aspirin acetyl group being followed by the scission of the acyloxy ester group. These results indicate that triazene acyloxymethyl carbamates are prodrugs of the antitumour monomethyltriazenes. They combine chemical stability with a rapid enzymatic hydrolysis, and are consequently good candidates for further prodrug development. Moreover, this type of derivative allowed the synthesis of mutual prodrugs, associating the antitumour monomethyltriazenes with anti-inflammatory NSAIDs as well as with the anticancer agent butyric acid. Copyright (C) 2000 Elsevier Science Ltd.
- Carvalho, Emilia,Francisco, Ana Paula,Iley, Jim,Rosa, Eduarda
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p. 1719 - 1725
(2007/10/03)
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- Triazene Drug Metabolites. Part 9. Base Catalysed Deacylation of 3-Acyl-3-alkyl-1-aryltriazenes in Ethanol.
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3-Acyl-3-alkyl-1-aryltriazenes undergo a base-catalysed deacylation reaction to liberate the corresponding cytotoxic 3-alkyl-1-aryltriazene.Reaction are first-order in both and .Second-order rate constants, k2, depend on the structure of both the substrate and the base.The values of k2 for the deformylation of 1-aryl-3-formyl-3-methyltriazenes by piperidine follow the Hammett relationship giving ρ +2.9; a similar correlation, ρ +1.6, is observed for the morpholine catalysed deacylation of 1-aryl-3-methyl-3-trifluoroacetyltriazenes.For 1-(4-cyanophenyl)-3-methyl-3-trifluoroacetyltriazene, a correlation between the aqueous pKa of the base and k2 is obtained, giving a Broensted β value of 0.36.The solvent deuterium isotope effect, k2EtOH/k2EtOD, for the piperidine-catalysed deacylation of 1-(3-pyridyl)-3-formyl-3-methyltriazene is 2.2, and 2,2,6,6-tetramethylpiperidine is some 2.4 times more effective than piperidine at catalysing the deformylation of this compound.Rate constants for the deacylation of 3-alkyltriazenes diminish in the order Me > Pr > Et.Rate constants also vary with the nature of the acyl group: thus CF3CO > HCO > MeCO > C8H17CO.The data are interpreted in terms of a mechanism that involves a rate-determining, general-base-catalysed attack of a solvent ethanol molecule at the carbonyl carbon atom of the group, followed by rapid collapse of the tetrahedral intermediate to form the monoalkyltriazene.
- Iley, Jim,Ruecroft, Graham,Carvalho, Emilia,Rosa, Eduarda
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p. 1264 - 1273
(2007/10/02)
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