著者

JUN-ICHI YAMASHITA SETSUO TAKEDA HIROSHI MATSUMOTO TADAFUMI TERADA NORIO UNEMI MITSUGI YASUMOTO

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.5, pp.2090-2094, 1987-05-25 (Released:2009-10-19)

参考文献数

14

被引用文献数

6 6

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Various O-acyl and N-acyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F3Thd) were synthesized; namely 5'-O-acyl, 3', 5'-di-O-acyl, N3-acyl, 3', 5'-di-O-acetyl-N3-acyl, 3', 5'-di-O-carbamoyl and 3', 5'-di-O-ethoxycarbonyl compounds. 5'-O-Acyl derivatives of 2'-deoxy-5-trifluoromethylcytidine were also synthesized.The antitumor activities of these compounds against sarcoma 180 were examined by oral administration to mice. Among the 5'-and 3', 5'-diester compounds with aliphatic acids, the 5'-O-hexanoyl compound showed the highest activity. Full protection of the sugar moiety with aroyl or carbamoyl groups considerably decreased the activities, and those of the 3', 5'-di-O-m-fluorobenzoyl and 3, 5'-di-O-butylcarbamoyl compounds were the smallest. N3-Benzoyl compounds were slightly more effective than F3Thd but none of them showed higher activity than the effective O-acyl compounds. In the case of 5'-O-acylates of 2'-deoxy-5-trifluoromethylcytidine, the 5'-O-benzoyl compound showed the highest activity.

著者

JUN-ICHI YAMASHITA SETSUO TAKEDA HIROSHI MATSUMOTO NORIO UNEMI MITSUGI YASUMOTO

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.6, pp.2373-2381, 1987-06-25 (Released:2009-10-19)

参考文献数

12

被引用文献数

3 3

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Various O-alkoxyalkyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F3Thd) were synthesized, and the antitumor activities of the compounds against sarcoma 180 were examined by oral administration to mice. Among the formal-type derivatives, 3', 5'-di-O-ethoxymethyl (3), 3', 5'-di-O-benzyloxymethyl (12), 5'-O-benzyloxymethyl (13) and 3'-O-benzyloxymethyl (14) compounds showed high activities, which were six-fold higher than that of F3Thd itself. Since acetal-type derivatives were unstable under acidic conditions, antitumor testing of the compounds was also carried out with co-administration of sodium bicarbonate. 5'-O- (1-Ethoxypropyl) -F3Thd (25) and 5'-O- (1-benzyloxypropyl) -F3Thd (37) showed the highest activities among the acetal-type derivatives, but the ED50 values of the compounds were not lower than those of effective formal-type compounds.These O-alkoxyalkyl derivatives of F3Thd are resistant to degradation by thymidine phosphorylase and are activated by microsomal drug-metabolizing enzymes after absorption.

著者

CHIEKO KUNUGITA FUSAHIRO HIGASHITANI AKIO HYODO NORIO UNEMI MATSUHISA INOUE

出版者

JAPAN ANTIBIOTICS RESEARCH ASSOCIATION

雑誌

The Journal of Antibiotics (ISSN:00218820)

巻号頁・発行日

vol.48, no.12, pp.1453-1459, 1995-12-25 (Released:2006-04-19)

参考文献数

27

被引用文献数

2 5

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A new extended spectrum β-lactamase was detected in Serratia marcescens 42039 that was isolated from urine of patients with complicated urinary tract infection in Japan. This strain produced three different β-lactamase types (TEM-1, a cephalosporinase, and a new β-lactamase: CKH-1). The TEM-1 and CKH-1 encoding genes were conjugated from S. marcescens 42039 to Escherichia coli K-12 at frequencies of 10-5 to 10-6. The MICs of β-lactams against the transconjugant were: ampicillin >1600, piperacillin 800, cephalothin 1600, ceftazidime 6.25, cefotaxime 100, and ceftriaxone 200μg/ml. The CKH-1 enzyme was purified to more than 90% by ion-exchange chromatography. The molecular weight of purified CKH-1 was 30 K dalton and the isoelectric point was 8, 2, Relative Vmax/Km values (cephaloridme=100) of penicillin G, cephalothin, and oxyiminocephalosporins such as cefuroxime, ceftriaxone, and cefotaxime, were 256, 226, 116, 87, and 49, respectively. The I50 values of tazobactam, BRL-42715, and clavulanic acid against CKH-1 enzyme were 0.0011, 0.0002, and 0.097μM, respectively. The enzymatic activity of CKH-1 was not inhibited by EDTA and anti-TEM-1 serum. These findings indicate that CKH-1 is a member of the groups of class A β-lactamases. This is the first report of a plasmid-mediated oxyiminocephalosporin hydrolyzing broad-spectrum β-lactamase from clinical isolates of S. marcescens.