RESUMEN
New sugar derivatives of ristocetin were prepared by copper-catalyzed 1,3-dipolar cycloaddition reaction using azido-ristocetin aglycon and various propargyl glycosides. Some of them were found to be active against gram-positive bacteria and showed favorable antiviral activity against the H1N1 subtype of influenza A virus.
Asunto(s)
Antibacterianos/síntesis química , Antivirales/síntesis química , Doxorrubicina/análogos & derivados , Ristocetina/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacología , Antivirales/química , Antivirales/farmacología , Catálisis , Cobre/química , Doxorrubicina/química , Humanos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Ristocetina/síntesis química , Ristocetina/farmacologíaRESUMEN
The water-soluble N-methoxy-PEG-yl-, N-beta-D-glucopyranosyl- and N-beta-D-maltosylthioureido aglyco-ristocetin were prepared which, in contrast to ristocetin A, did not induce thrombocyte aggregation. The antibacterial activity of N-beta-D-maltosylthioureido aglyco-ristocetin A against MRSA was comparable to that of ristocetin A, while its activity against Enterococcus faecalis (VRE, TSE) is somewhat stronger when compared to those of vancomycin and ristocetin A.
Asunto(s)
Agregación Plaquetaria/efectos de los fármacos , Ristocetina/farmacología , Bacterias/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Ristocetina/síntesis química , Ristocetina/químicaRESUMEN
A series of methyl ether derivatives of the vancomycin, teicoplanin, and ristocetin aglycon methyl esters was synthesized and their antimicrobial activity was established. These derivatives exhibit increased activity against VanB resistant strains of bacteria equipotent with that observed with sensitive bacteria.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Ristocetina/análogos & derivados , Teicoplanina/análogos & derivados , Vancomicina/análogos & derivados , Enterococcus faecalis/efectos de los fármacos , Éteres Metílicos/síntesis química , Éteres Metílicos/farmacología , Pruebas de Sensibilidad Microbiana , Ristocetina/síntesis química , Ristocetina/farmacología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Teicoplanina/síntesis química , Teicoplanina/farmacología , Vancomicina/síntesis química , Vancomicina/farmacología , Resistencia a la VancomicinaRESUMEN
Binding constants between the glycopeptides teicoplanin (Teic) and ristocetin (Rist) and their derivatives to D-Ala-D-Ala terminus peptides were determined by on-column receptor synthesis coupled to partial-filling affinity capillary electrophoresis (PFACE) or affinity capillary electrophoresis (ACE). In these techniques, the column is first partially filled with increasing concentrations of D-Ala-D-Ala terminus peptides. This is followed by plugs of buffer, antibiotic and two noninteracting standards, and acetic and/or succinic anhydride (and buffer in the case of ACE). The order of the reagent plugs containing the antibiotic and anhydride varies with the charge of the glycopeptide. Upon electrophoresis, the antibiotic reacts with the anhydride yielding a derivative of Teic or Rist. Continued electrophoresis results in the overlap of the derivatized antibiotic and the plug of D-Ala-D-Ala peptide. Analysis of the change in the relative migration time ratio (RMTR) of the new glycopeptide relative to the standards, as a function of the concentration of the D-Ala-D-Ala ligand yields a value for the binding constant K(b). The techniques described here can be used to assess how the derivatization of drugs alters their affinities for target molecules.
Asunto(s)
Antibacterianos/química , Electroforesis Capilar/métodos , Ristocetina/química , Teicoplanina/química , Anhídridos Acéticos/química , Antibacterianos/síntesis química , Tampones (Química) , Dipéptidos/química , Electroforesis Capilar/instrumentación , Matemática , Estructura Molecular , Preparaciones Farmacéuticas , Ristocetina/síntesis química , Anhídridos Succínicos/química , Teicoplanina/síntesis químicaRESUMEN
Ruthenium-promoted intramolecular S(N)Ar reaction has allowed the construction of the fully functionalized 16-membered DEF macrocycle 4 of ristocetin A that incorporates the required arylglycine and arylserine residues as the F and E ring, respectively.
Asunto(s)
Antibacterianos/síntesis química , Ristocetina/síntesis química , Rutenio/química , Teicoplanina/síntesis química , Vancomicina/síntesis químicaRESUMEN
Various bifunctional reagents by the free NH2 group of ristomycinic acid of ristomycin A were used for selective chemical modification of the antibiotic. The bifunctional reagents were the following: di-N-hydroxysuccinimide ether of suberic acid and 4,4'-difluoro-3,3'-dinitrodiphenylsulfone. Bis-N,N'-derivatives of ristomycin A were prepared using these reagents. The derivatives inhibited the growth of Bac. subtilis but the concentrations required for the inhibition were 2-4 times higher than those of ristomycin A. It was noted that the MIC of the bis-N,N'-derivatives depended on the length and flexibility of the "binding foot". The MIC of the bis-N,N'-derivative prepared with using suberic acid was 2 times higher than that of the derivative prepared with the use of 4,4'-difluoro-3,3'-dinitrodiphenylsulfone.
Asunto(s)
Caprilatos , Ristocetina/síntesis química , Bacillus subtilis/efectos de los fármacos , Fenómenos Químicos , Química Física , Ácidos Dicarboxílicos/farmacología , Dinitrofluorobenceno/análogos & derivados , Dinitrofluorobenceno/farmacología , Interacciones Farmacológicas , Indicadores y Reactivos/farmacología , Ristocetina/farmacología , Relación Estructura-Actividad , Succinimidas/farmacologíaRESUMEN
Selective chemical modification of ristomycin A (I) by the free NH2 groups was performed. 6 different N-acyl and N-aminoacyl derivatives of I were obtained. 5 of them showed antibacterial activity within 0.4-10.0 micrograms/ml against 4 test microbes. The biological activity of the derivatives depended on the substituent type and the molecule total charge: mono-N-L-isoleucyl-I with the charge of +2 had the highest activity and N,N'-disuccinyl-I had the lowest activity.
Asunto(s)
Ristocetina/síntesis química , Acilación , Aminas , Aminoácidos/análisis , Bacterias/efectos de los fármacos , Electroforesis en Papel , Ristocetina/análisis , Ristocetina/farmacología , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
A series of ristocetin analogues with modifications (OH, C=O, C=NOH, NCOCH3) at the C-1' amino group was synthesized and found to possess antibacterial activity against gram-positive bacteria and to bind to Ac2-Lys-D-Ala-D-Ala, a model for the antibiotic's site of action. Due to the lack of a positively charged amino group, the active analogues could not form a salt bridge, indicating that an electrostatic interaction between the positively charged 1'-amino group of ristocetin and the carboxylate anion of the peptide is not required for complex formation. The only compound that did not exhibit good antibacterial activity was epiristocetin aglycone (an analogue with the 1'amino group in the opposite configuration (S) as ristocetin). On the basis of NMR studies of epiristocetin aglycone in solution, the 1'-amino group is located in the proposed carboxylate binding pocket and may sterically block complex formation.
Asunto(s)
Ristocetina/análogos & derivados , Fenómenos Químicos , Química , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Oligopéptidos/metabolismo , Ristocetina/síntesis química , Ristocetina/farmacología , Relación Estructura-ActividadRESUMEN
Proof is given by synthesis confirming the structure of ristobiose as 2-O-alpha-D-mannopyranosyl-D-glucose (IV) and ristotriose as O-alpha-L-rhamnopyranosyl (1 leads to 6)-O-[alpha-D-mannopyranosyl (1 leads to 2)]-D-glucose (X) which are obtained from ristomycin A upon mild acid hydrolysis. Both oligosaccharides, IV and X, have been detected for the first time as the components of an antibiotic.