RESUMO
This communication describes the stabilizing effect (ΔΔG° = -4 kJ mol-1) of a remote methyl group in the backbone of a cobalamin-enzyme mimic on intramolecular imidazole-cobalt coordination. For this purpose, two B12 derivatives with an appended imidazole base were synthesized and analysed with spectrophotometric pH titrations. Qualitative conformation analysis of the backbone structure suggests that a thermodynamically unfavoured gauche interaction in the base-off form of a model containing an (R)-configured CH3 group at position C176 of the linker between the corrin ring and the terminal imidazole ligand steers the base toward cobalt coordination.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/química , Cobalto/química , Complexos de Coordenação/química , Imidazóis/química , Vitamina B 12/química , Biomimética , Domínio Catalítico , Complexos de Coordenação/síntese química , Humanos , Ligantes , Estrutura Molecular , Termodinâmica , Vitamina B 12/análogos & derivados , Vitamina B 12/síntese químicaRESUMO
A realistic model for the active site of histidine-on cobalamin@protein complexes is reported and studied under homogeneous and immobilized conditions. Analysis of lower ligand modulation and its influence on the properties of the biomimetic compound are presented. The cofactor attachment by a protein's histidine residue was imitated by covalently linking an artificial imidazole-containing linker to cobyric acid. The resulting intramolecular coordination complex is an excellent structural model of its natural archetype, according to 2D 1H-NMR studies and molecular modeling. The effect of deprotonation of the axially coordinating imidazole ligand - as proposed for natural cofactor complexes - tunes significantly the position of the cathodic peak (ΔV = -203 mV) and stabilizes thereby the CoIII form. Partial deprotonation of the imidazole moiety through hydrogen bonding interactions was then achieved by immobilizing the biomimetic model on hydrophobic C18 silica, which yielded an unprecedented insight on how this class of Cbl-dependent proteins may fine-tune their properties in biological systems.
RESUMO
Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin-based drugs are still nowadays limited to antagonists of vitamins B9 and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin-based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B9 and B12 .
Assuntos
4-Hidroxicumarinas/farmacologia , Anticoagulantes/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Indenos/farmacologia , Vitamina B 12/antagonistas & inibidores , Vitamina K/antagonistas & inibidores , Vitaminas/antagonistas & inibidores , 4-Hidroxicumarinas/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Anticoagulantes/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Descoberta de Drogas , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/química , Humanos , Indenos/química , Modelos Moleculares , Neoplasias/tratamento farmacológico , Vitamina B 12/metabolismo , Vitamina K/química , Vitamina K/metabolismo , Vitamina K/farmacologia , Vitaminas/metabolismoRESUMO
The sophisticated and efficient delivery of vitamin B(12) ("B(12)") into cells offers promise for B(12)-bioconjugates in medicinal diagnosis and therapy. It is therefore surprising that rather little attention is presently paid to an alternative strategy in drug design: the development of structurally perfect, but catalytically inactive semi-artificial B(12) surrogates. Vitamin B(12) cofactors catalyse important biological transformations and are indispensible for humans and most other forms of life. This strong metabolic dependency exhibits enormous medicinal opportunities. Inhibitors of B(12) dependent enzymes are potential suppressors of fast proliferating cancer cells. This perspective article focuses on the design and study of backbone modified B(12) derivatives, particularly on peptide B(12) derivatives. Peptide B(12) is a recently introduced class of biomimetic cobalamins bearing an artificial peptide backbone with adjustable coordination and redox-properties. Pioneering biological studies demonstrated reduced catalytic activity, combined with inhibitory potential that is encouraging for future efforts in turning natural cofactors into new anti-proliferative agents.