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1.
J Antibiot (Tokyo) ; 46(10): 1589-97, 1993 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8244888

RESUMEN

In a screen of pradimicin-nonproducing mutants derived from Actinomadura verrucosospora subsp. neohibisca R103-3, we found a strain capable of producing 11-hydroxyl analogs of pradimicins A and FA-1, designated pradimicins H and FH, respectively. Feeding of pradimicins H and FH to growing cultures of an actinomycete strain AA3798 produced 11-O-L-xylosylpradimicins H and FH, respectively. These 11-O-L-xylosylpradimicins had a broad spectrum of antifungal activity and demonstrated in vivo efficacies against Candida albicans in mice.


Asunto(s)
Actinomyces/química , Antraciclinas , Antibióticos Antineoplásicos/aislamiento & purificación , Antifúngicos/aislamiento & purificación , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Candidiasis/tratamiento farmacológico , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad
2.
J Antibiot (Tokyo) ; 46(9): 1447-57, 1993 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8226323

RESUMEN

Synthesis and antifungal activity of pradimicin analogs modified on the aglycone part is described. Upon modification studies at various sites of the aglycone part using pradimicin A (PRM A), C-11 position was found to be the sole site to be modified without loosing antifungal activity. Further modification studies at C-11 position were carried out with 11-OH derivative of pradimicin T1 (PRM T1) because of its easy availability. Among the compounds prepared, 11-demethoxy derivative of PRM A (12) and 11-O-ethyl (13) and 11-O-fluoroethyl (14) derivatives of PRM T1 showed promising antifungal activity comparable to that of PRM A.


Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Antifúngicos/síntesis química , Antibióticos Antineoplásicos/farmacología , Antifúngicos/farmacología , Secuencia de Carbohidratos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Estructura Molecular
3.
J Antibiot (Tokyo) ; 46(4): 598-605, 1993 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8501002

RESUMEN

Pradimicins T1 and T2 are new members of the pradimicin family of antibiotics produced by an actinomycete strain AA3798. Pradimicins T1 and T2 are dihydrobenzo[a]naphthacenequinones substituted with 3 and 2 sugar moieties, respectively. The salient feature in their structures is an L-xylose attached to the phenolic hydroxyl group at C-11. Bioconversion experiments using a blocked mutant B-54 of strain AA3798 not only explored a plausible biosynthetic pathway of pradimicins T1 and T2, but also provided evidence of 5S,6S configuration.


Asunto(s)
Actinomycetaceae/química , Antraciclinas , Antibióticos Antineoplásicos/biosíntesis , Antifúngicos/biosíntesis , Antibióticos Antineoplásicos/química , Antifúngicos/química , Estereoisomerismo
4.
J Antibiot (Tokyo) ; 46(4): 631-40, 1993 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8501006

RESUMEN

Modifications at the sugar part of pradimicins were carried out by glycosidations of the aglycones or chemical transformations of natural pradimicins and their antifungal activity was evaluated. Among them, some of the D-xylose-modified derivatives (14, 17, 24) showed activity comparable to that of pradimicin A. The structure-activity relationships obtained through there studies clarified the role of the sugar part in the manifestation of antifungal activity: The 5-O-(6-deoxy-beta-D-sugar) is essential for activity and 2'-epi, 3'-oxo and 4'-deoxy sugar derivatives retain activity against yeasts.


Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Monosacáridos/química , Disacáridos/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad
5.
J Antibiot (Tokyo) ; 44(6): 646-58, 1991 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-2071490

RESUMEN

The synthesis and biological properties of 1-N-[4-(substituted)amidino and guanidino-2-hydroxybutyryl]kanamycins A and B are described. Reaction of 3,3",6'-tri-N-tert-butoxycarbonyl-amikacin with an appropriate amidinating or guanidinating reagent and subsequent deblocking gave a series of amikacin derivatives having an amidino or guanidino group on the 4"'-position. The corresponding kanamycin B analogs were also prepared by a similar procedure. Among these derivatives, 1-N-(4-formamidino- and guanidino-2-hydroxybutyryl)kanamycins A (7a and 7k) and B (11 and 14) exhibited antibacterial activity similar to the corresponding 4-amino analogs. The nephrotoxic potential of selected compounds is also briefly discussed.


Asunto(s)
Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Kanamicina/análogos & derivados , Riñón/efectos de los fármacos , Animales , Kanamicina/farmacocinética , Kanamicina/farmacología , Kanamicina/uso terapéutico , Kanamicina/toxicidad , Riñón/metabolismo , Dosificación Letal Mediana , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular
7.
J Antibiot (Tokyo) ; 43(7): 858-72, 1990 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2387779

RESUMEN

The synthesis and biological activity of kanamycin A derivatives with an omega-amino-alpha-fluoroalkanoyl side chain on the 1-amino group are described. The fluorinated amino acids (4) for the side chain were prepared by fluorination of the alpha-hydroxy esters (2) with diethylaminosulfur trifluoride (DAST) with accompanying the Walden inversion. The reaction products varied with the amino protective groups employed, chain length of the alkanoic acids and the presence or absence of base. The fluorinated side chain was introduced to 1-free-NH2 kanamycin A (12) by the conventional active ester method and subsequent deblocking reactions afforded the desired final products (13-17). Of the derivatives prepared, 1-N-[(S)-4-amino-2-fluorobutyryl]kanamycin A (2'''-deoxy-2'''-fluoroamikacin, 14) showed the best overall activity profile, nearly the same as that of amikacin. Preparation and antibacterial activity of several aminoglycoside antibiotics with the 1-N-(S)-4-amino-2-fluorobutyryl side chain are also discussed.


Asunto(s)
Amicacina/análogos & derivados , Bacterias/efectos de los fármacos , Amicacina/farmacología , Amicacina/toxicidad , Animales , Fenómenos Químicos , Química , Dietilaminas , Flúor , Indicadores y Reactivos , Ratones , Conformación Molecular , Estructura Molecular
8.
J Antibiot (Tokyo) ; 43(5): 533-43, 1990 May.
Artículo en Inglés | MEDLINE | ID: mdl-2358405

RESUMEN

The synthesis and antimicrobial activity of eight derivatives of 7-[(Z)-2-(2-aminothiazol-4-yl)- and 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido] cephalosporins having an (E) or (Z)-3-ammonio-1-propenyl group in the C-3 side chain are described. The (E)-propenyl derivatives were more active than their corresponding Z-isomers and showed well-balanced, broad antibacterial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.


Asunto(s)
Cefalosporinas/síntesis química , Bacterias/efectos de los fármacos , Cefalosporinas/farmacología , Fenómenos Químicos , Química , Cromatografía Líquida de Alta Presión , Isomerismo , Espectroscopía de Resonancia Magnética , Estructura Molecular , Relación Estructura-Actividad
9.
J Antibiot (Tokyo) ; 40(7): 991-1005, 1987 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-3624077

RESUMEN

The synthesis and structure-activity relationships of 7-[D-alpha-amino-alpha-(4-hydroxyphenyl)-acetamido]-3-[(Z)-1-propenyl]- 3-cephem-4-carboxylic acid (BMY-28100) and its analogs in the 3- and 7-side chains are described. The 3-(substituted-propenyl) groups were introduced by the Wittig reaction of the 3-phosphoniomethyl cephems which were derived from the 3-chloromethyl derivatives. The reaction gave predominantly the cis isomer regarding the 3-side chain. The cis and trans isomers showed characteristic UV and 1H NMR spectra. Most of cephems of this series were well-absorbed orally and more active both in vitro and in vivo than cephalexin and cefaclor against Gram-positive organisms. Their Gram-negative activity varied depending on the 3- and 7-substituents. Compounds with a cis-propenyl group showed the best Gram-negative activity among the 3-alkenyl analogs prepared, whereas the D-4-hydroxyphenylglycyl and D-4-hydroxy-3-methoxyphenylglycyl substitutions in the 7-side chain were found suitable to improve the Gram-negative activity of 3-cis-propenyl series of cephalosporins to the level favorably compared with that of cefaclor. The 3,4-dihydroxyphenyl analog was found to be metabolized in vivo to the 4-hydroxy-3-methoxyphenyl derivative and, therefore, showed nearly the same in vivo activity as that of the latter. BMY-28100 was selected for further evaluation and the results will be reported in the subsequent paper.


Asunto(s)
Antibacterianos/síntesis química , Cefalosporinas/síntesis química , Animales , Antibacterianos/sangre , Antibacterianos/orina , Cefalosporinas/sangre , Cefalosporinas/orina , Isomerismo , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Cefprozil
10.
J Antibiot (Tokyo) ; 39(8): 1092-107, 1986 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3759661

RESUMEN

The synthesis of a series of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-oxyiminoacetamido] -3-ammoniomethyl-3-cephems is described. Variations of an oxyimino moiety in the 7-side chain and a quaternary ammonium moiety in the 3-side chain were examined and structure-activity relationships studied. BMY-28142, the 3-(N-methylpyrrolidinio)methyl derivative of the 7-alpha-methoxyimino series of cephalosporins, exhibited broad antimicrobial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.


Asunto(s)
Cefalosporinas/síntesis química , Bacterias/efectos de los fármacos , Cefepima , Cefalosporinas/farmacología , Relación Estructura-Actividad
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