Cyclization-activated prodrugs. Basic esters of 5-bromo-2'-deoxyuridine

Saari, W. S.; Schwering, John E.; Lyle, Paulette A.; Smith, Steven J.; Engelhardt, Edward L.

doi:10.1021/jm00171a038

Cited by 39 publications

(23 citation statements)

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“…These findings demonstrated the need for a non-protonated amine function to activate the prodrug, being consistent with alcohol release through a cyclization reaction. Confirmation of this assumption was enabled by quantitative isolation of the piperazinone cyclization product (12) after prodrug incubation at 37 °C and pH 7.4 [26]. Last, but not least, compounds 11 displayed similar or even higher stability in human plasma, but reacted much faster in rat plasma.…”

Section: General Basic Amine Carriersmentioning

confidence: 70%

“…Last, but not least, compounds 11 displayed similar or even higher stability in human plasma, but reacted much faster in rat plasma. This was explained by the generally low esterase activity of human plasma, as compared to rodent plasma, and also by a possible stabilizing effect due to binding of the nucleoside ester to the human plasma proteins [26]. More recently, Nam et al have developed water-soluble prodrugs 13a-c of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2-(3,4,5-trimethoxyphenyl)cyclopent-2-ene-1-one (C, Scheme 9) based on β-, γ-and δ-amino acid carriers [27].…”

Section: General Basic Amine Carriersmentioning

confidence: 99%

“…The same authors developed in parallel three ester prodrugs 11 of 5-bromo-2'-deoxyuridine (ROH in Scheme 8), that were also found to be stable at pH 2.5 and to release the alcohol at a slower rate at pH 6.8 than at pH 7.4 [26]. At this pH, all three esters released the parent alcohol at virtually the same rate (t 1/2 =23, 26.7 and 29.7 min), with slight differences being correlated with steric constraints imposed by R (Scheme 8) in the course of the cyclization reaction.…”

Section: General Basic Amine Carriersmentioning

confidence: 99%

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Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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Section: General Basic Amine Carriersmentioning

confidence: 70%

Section: General Basic Amine Carriersmentioning

confidence: 99%

Section: General Basic Amine Carriersmentioning

confidence: 99%

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Cyclization-activated Prodrugs

2007

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“…Apesar de, até há relativamente pouco tempo, a utilização de pró-fármacos ativados pela via química se apresentar como um campo pouco explorado, nos últimos anos tem atraído um elevado número de adeptos (Saari et al, 1990;Shan et al, 1997;Testa, Mayer, 1998). A crescente busca deste tipo de pró-fármacos é explicada pelo fato de, nos casos de ativação pela via enzimática, a liberação do fármaco estar sujeita à variabilidade da atividade enzimática entre espécies ou entre indivíduos de mesma espécie.…”

Section: Introductionunclassified

“…A crescente busca deste tipo de pró-fármacos é explicada pelo fato de, nos casos de ativação pela via enzimática, a liberação do fármaco estar sujeita à variabilidade da atividade enzimática entre espécies ou entre indivíduos de mesma espécie. Essa variabilidade produz grandes diferenças na velocidade de liberação do princípio ativo, de indivíduo para indivíduo (Saari et al, 1990;Shan et al, 1997), comprometendo a previsibilidade destes parâmetros e tornando o pró-fármaco um sistema pouco atrativo para liberação do princípio ativo in vivo.…”

Section: Introductionunclassified

Ciclização intramolecular: uma estratégia promissora no desenvolvimento de pró-fármacos

Santos¹

2008

Rev. Bras. Cienc. Farm.

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Muitos fármacos estão associados a vários efeitos adversos INTRODUÇÃOMuitos fármacos que apresentam elevada atividade contra várias doenças estão relacionados com problemas que os tornam limitados ou inviáveis como sistemas terapêuticos eficazes (Guettari et al., 1997;Song et al., 2005). Solubilidade, estabilidade, absorção, distribuição, toxicidade e biodisponibilidade são aspectos fundamentais a serem levados em consideração quando da administração de um fármaco (Lynx et al., 2006;Otto, 2004;Vennerstrom et al., 1999;Thomsen et al., 2004). Um exemplo comum de fármacos que estão relacionados com vários problemas de natureza terapêutica é encontrado nos análogos das purinas e pirimidinas. Os fármacos contidos nestas classes de compostos são conhecidos pelas suas baixas biodisponibilidades orais (Thomsen et al., 2003). O aciclovir, por exemplo, é um análogo purínico que apresenta uma biodisponibilidade oral de cerca de 20% em adultos (Steingrimsdottir et al., 2000). Já a fluorouracila, que é um análogo pirimidínico, apresenta uma biodisponibilidade oral que varia entre indivíduos numa escala de 0-80% (Guo et al., 1995;Heyden et al., 1999;Zinutti et al., 1998). Além da reduzida biodisponibilidade destes fármacos, problemas associados à elevada toxicidade e baixa solubilidade, tanto em meio aquoso quanto em meio lipofílico, são um verdadeiro entrave nas suas aplicações terapêuticas (De Vrueh et al., 1998;Han et al., 1998;Zambonin et al., 1998).Um medicamento acabado é fruto de décadas de pesquisa química, farmacêutica e clínica. No entanto, muitas vezes subsistem problemas como os anteriormente menci-

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Principles of Drug Metabolism

Testa

Soine

2003

Burger's Medicinal Chemistry and Drug Discovery

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The focus of this chapter is mainly on drug metabolism reactions and connected information of significance to medicinal chemists. The types, selectivities, and consequences of drug metabolism are presented in the introduction. Oxidoreductases are discussed in the next section, together with a systematic and extensive treatment of the chemical groups they target and the functionalization reactions they catalyze. Particular attention is paid to cytochromes P450 and their multiplicity, specificities, and relative importance. Section 3 is dedicated to the transferases and the conjugation reactions they catalyze, e.g., glucuronidation and glutathione conjugation. The various biological factors influencing drug metabolism are examined in Section 4. These are subdivided into interindividual factors (that depend on the genome) and intraindividual factors (that can vary with time or because of external influences). The last section, which is particularly close to the interests of medicinal chemists, discusses structure‐metabolism relationships, prodrug design, and toxophoric groups.

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Cyclization-activated prodrugs. Basic esters of 5-bromo-2'-deoxyuridine

Cited by 39 publications

References 0 publications

Cyclization-activated Prodrugs

Cyclization-activated Prodrugs

Ciclização intramolecular: uma estratégia promissora no desenvolvimento de pró-fármacos

Principles of Drug Metabolism

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