RESUMO
S-adenosyl-l-methionine-dependent methyltransferases (MTs) are involved in the C-methylation of a variety of natural products. The MTs SgvM from Streptomyces griseoviridis and MrsA from Pseudomonas syringae pv. syringae catalyze the methylation of the ß-carbon atom of α-keto acids in the biosynthesis of the antibiotic natural products viridogrisein and 3-methylarginine, respectively. MrsA shows high substrate selectivity for 5-guanidino-2-oxovalerate, while other α-keto acids, such as the SgvM substrates 4-methyl-2-oxovalerate, 2-oxovalerate, and phenylpyruvate, are not accepted. Here we report the crystal structures of SgvM and MrsA in the apo form and bound with substrate or S-adenosyl-l-methionine. By investigating key residues for substrate recognition in the active sites of both enzymes and engineering MrsA by site-directed mutagenesis, the substrate range of MrsA was extended to accept α-keto acid substrates of SgvM with uncharged and lipophilic ß-residues. Our results showcase the transfer of the substrate scope of α-keto acid MTs from different biosynthetic pathways by rational design.
RESUMO
A novel protocol is developed towards the preparation of alkylated ketones from alcohols in presence of catalytic amount of SmI2 and base with the elimination of water as a single by-product under microwave irradiation conditions. Furthermore, applicability of this methodology to the synthesis of Donepezil and late-stage functionalization in Pregnenolone is also reported. Successful application of this methodology in Friedländer quinolone synthesis using 2-aminobenzyl alcohol and various acetophenones expand the synthetic utility of this protocol.
Assuntos
Álcoois , Cetonas , Alquilação , Iodetos , Micro-Ondas , SamárioRESUMO
Evidence that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in the virus replication cycle has increased attention on cyclophilin inhibitors as attractive therapeutic targets in the treatment of HCV. Previous reports have described a number of non-immunosuppressive cyclophilin inhibitors, most of which require many synthetic steps for their preparation. Sasamura et al. have previously reported the isolation of bioconversion derivative 4. This analog is a convenient starting point for optimization due to the presence of the readily modifiable primary hydroxyl group and because it shows moderate anti-HCV activity and decreased immunosuppressive activity. We have also established an efficient C-alkylation reaction at the 3-position. Through a detailed structure-activity relationship study, we discovered a new type of clinical candidate 14 which requires a short synthetic process and has potent anti-HCV activity and reduced immunosuppressive activity, as well as improved aqueous solubility and pharmacokinetics.
Assuntos
Antivirais/síntese química , Ciclofilinas/antagonistas & inibidores , Ciclosporina/síntese química , Inibidores Enzimáticos/síntese química , Hepatite C/tratamento farmacológico , Alquilação , Sequência de Aminoácidos , Antivirais/farmacocinética , Ciclosporina/química , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Imunossupressores/farmacologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
This report describes a modular enzyme-catalyzed cascade reaction that transforms l- or d-α-amino acids to ß-methyl-α-amino acids. In this process an α-amino acid transaminase, an α-keto acid methyltransferase, and a halide methyltransferase cooperate in two orthogonal reaction cycles that mediate product formation and regeneration of the cofactor pyridoxal-5'-phosphate and the co-substrate S-adenosylmethionine. The only stoichiometric reagents consumed in this process are the unprotected l- or d-α-amino acid and methyl iodide.
Assuntos
Aminoácidos/metabolismo , Metiltransferases/metabolismo , Transaminases/metabolismo , Aminoácidos/química , Metilação , Estrutura Molecular , EstereoisomerismoRESUMO
The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave the product derived from attack on the carbonylic carbon- and/or oxygen-atom. The regioselectivity of the attack depends on the kind of substituents bound to the vinylic carbon atoms and on their relative position. The reaction between vinylmagnesium bromide and 2-methyl-1-propenylmagnesium bromide was carried out under different experimental conditions and in the presence of radical scavengers. The results indicate a plausible mechanistic pathway involving radical intermediates in the case of O-alkylation, but a polar ones in the case of classic C-alkylation. This agrees with our previous reports indicating a key role played by the delocalization ability of the substituents bound to the carbonyl group in driving the regioselectivity of the vinylmagnesium bromide attack towards O-alkylation. Further support of this was obtained by diffractometric analysis of four distinct bis(heteroaryl)ketones.
Assuntos
Cetonas/química , Triazóis/química , Compostos de Vinila/química , Alquilação , Carbono/química , Metais/química , Modelos Moleculares , Estrutura Molecular , Oxigênio/química , Solventes/química , Estereoisomerismo , Difração de Raios XRESUMO
The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2-Methyl-1-[11 C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 µmol) were needed. 1-Iodo-2-[11 C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1-iodo-2-[11 C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [11 C]2-methyl-1-propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/µmol at the end of synthesis. Altogether, the syntheses of 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol were achieved and applied as proof of their applicability.
Assuntos
1-Propanol/química , 1-Propanol/síntese química , Radioisótopos do Iodo/química , Propano/química , Propano/síntese química , Alquilação , Marcação por Isótopo , Tomografia por Emissão de Pósitrons , RadioquímicaRESUMO
A series of new C-4-derivatives of α-mangostin has been synthesized with the use of Mannich reaction and alkylation with 4-bromomethyl-2,6-dialkylphenols. It has been shown on a model of H2O2-induced erythrocyte hemolysis that the Mannich bases containing morpholinomethyl and piperidinomethyl fragments differ from parent α-mangostin by their high antioxidant and membrane-protective activity.