RESUMO
Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective anti-cancer therapeutic approach, as demonstrated by the first-in-class agent bortezomib. Various new proteasome inhibitors are now in development, including peptide boronic acid analogs MLN9708 and CEP-18770, peptide epoxyketones carfilzomib and PR-047, and NPI-0052, a beta-lactone compound. All are potent inhibitors of proteasome activity in vitro but show differences in enzyme binding kinetics, which might affect their pharmacology and result in different efficacy and safety profiles. Here, we review the second-generation proteasome inhibitors and assess the potential pharmacologic impact of their different chemical properties.
Assuntos
Antineoplásicos/química , Ácidos Borônicos/química , Neoplasias/tratamento farmacológico , Inibidores de Proteases/química , Inibidores de Proteassoma , Pirazinas/química , Animais , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Humanos , Neoplasias/enzimologia , Inibidores de Proteases/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/uso terapêuticoRESUMO
The compound 8-methoxy-5'-deoxyadenosylcobalamin (8-MeOAdoCbl), has been synthesized in 37% yield and > or = 95% purity by HPLC, monitored at both 254 and 525 nm, or 90+/-2% purity as judged by the (1)H NMR spectrum of the aromatic cobalamin region. This is the first synthesis of this complex in which sufficient details are reported, where a yield and purity are reported, and where key problems in the synthesis and purification are overcome, so that 8-MeOAdoCbl can actually be obtained for use in other studies. Also demonstrated is the clean Co-C bond homolysis of 8-MeOAdoCbl to give initially 8-MeOAdoCbl and Co(II)Cbl in a UV-visible thermolysis experiment at 110 degrees C, results which show that the 8-MeO moiety suppresses the cyclization to the 8,5'-anhydro-adenosine otherwise seen for the adenosyl radical (Ado)*. Suppression of this cyclization pathway makes 8-MeOAdoCbl invaluable for studying the kinetic isotope effect (KIE) of the Ado* plus substrate H* abstraction reaction, a component of the first definitive test of Klinman's hypothesis that the optimization of enzyme catalysis may entail strategies that increase the probability of tunneling and thereby accelerate H* atom abstraction reaction rates.