Synthesis of new .beta.-lactam antibiotics

Kitamura, Takashi; Teraji, Tsutomu; Hashimoto, Masashi; Nakaguchi, Osamu; Oku, Teruo

doi:10.1021/ja00850a049

Cited by 31 publications

(10 citation statements)

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“…Utilizing the method of Kamiya (46), the protected penam sulfoxide 6 was heated in the presence of mercaptobenzothiazole to generate an intermediate sulfenic acid, which was trapped in situ to generate the disulfide 7 . The thiazolidine was regenerated by treatment with silver acetate in the presence of chloroacetic acid to stereoselectively produce the 2′β functionalized penam 8 , together with the cepham 9 .…”

Section: Resultsmentioning

confidence: 99%

“…As shown in SI Scheme 1, the carboxylic acid and amino functionalities of the commercially available 6-aminopenicillanic acid (6-APA) were sequentially protected by treatment with diphenyldiazomethane and allyl chloroformate, respectively, and the sulfur was oxidized to the corresponding sulfoxide with m CPBA. Utilizing the method of Kamiya, the protected penam sulfoxide 6 was heated in the presence of mercaptobenzothiazole to generate an intermediate sulfenic acid, which was trapped in situ to generate the disulfide 7 . The thiazolidine was regenerated by treatment with silver acetate in the presence of chloroacetic acid to stereoselectively produce the 2′β-functionalized penam 8 , together with the cepham 9 .…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of Acinetobacter baumannii OXA-24 Carbapenemase

et al. 2010

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Class D β-lactamases represent a growing and diverse class of penicillin inactivating enzymes that are usually resistant to commercial β-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel β-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2'-substituted penicillanic acid sulfones (1, 2, 3, 4, and 5) were synthesized and tested against OXA-24, a clinically important β-lactamase that inactivates carbapenems and found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 β-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC 50 values, against OXA-24, and two OXA-24 β-lactamase variants ranged from 10 ± 1 (4 vs. WT) to 338 ± 20 nM (5 vs. Tyr112Ala, Met223Ala). Compound 4 possessed the lowest K i (500 ± 80 nM vs. WT) and 1 possessed the highest inactivation efficiency (k inact /K i = 0.21 ± 0.02 μM -1 s -1 ). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0-2.6 Å) reveal there is formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2'-substituted penicillin sulfones are effective mechanism-based inactivators of class D β-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and * Corresponding authors:

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of Acinetobacter baumannii OXA-24 Carbapenemase

et al. 2010

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“…The data are obtained by comparing the relative areas of the absorptions due to the methylene protons in 9 and 5, respectively, these compounds being the only products formed under these conditions. (17) 1H NMR (CDCI3, 30°) 2.28 (s, 6 H), 2.33 (s, 6 H), 3.43 (d, J = 14 Hz, 1 H), 4.93 (d, J = 14 Hz, 1 H), 4.99 and 5.40 (AB-quartet, Jab = 13 Hz, 2 H); 13C NMR (CDCI3, 37°, relative to internal Me4Si; noise decoupled) 15.3; 15.9, 16.8, and 17.0 (CH3-carbons), 55.4 and 62. Synthesis of 2-Methyl-3-cephem Derivatives1 Sir:…”

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confidence: 99%

Studies on .beta.-lactam antibiotics. III. Synthesis of 2-methyl-3-cephem derivatives

Kitamura¹,

Teraji²,

Hashimoto³

et al. 1976

J. Am. Chem. Soc.

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“…The differences in reactivity for the low lying electronic states of sulfur atoms have been extensively characterized in systems where the atoms are photochemically generated. 3 In particular, changes in both reaction mechanisms and reaction rates are known to be associated with S('D) and S(3P) reactions. Direct use of the techniques employed in photochemical systems, however, has not led to an unambiguous interpretation of nuclear recoil systems.2 We have obtained evidence for the gas phase reactions of singlet sulfur atoms, S('D), generated by the 34S(n,7)35S nuclear recoil reaction in the presence of CS2.…”

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confidence: 99%