Semisynthetic .beta.-lactam antibiotics. 2. Synthesis and properties of D- and L-.alpha.-sulfobenzylpenicillins

Morimoto, Shiro; Nomura, Hiroaki; Fugono, Takeshi; Azuma, Toshiyuki; Minami, Junko

doi:10.1021/jm00281a005

Cited by 26 publications

(16 citation statements)

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“…The high-performance liquid chromatographic assay was used to determine the stability of R + S moxalactam by spiking (i) pooled human serum and (ii) phosphate-buffered saline (pH 7.2) with 100 ,ig of R + S moxalactam per ml, incubating at 37°C, room temperature (about 20°C), 4°C, and -20°C, and measuring the total amount of material remaining at 1,2,4, 8, 30, 50, and 120 h. Standards were freshly prepared on each sampling occasion. …”

Section: Methodsmentioning

confidence: 99%

Epimers of moxalactam: in vitro comparison of activity and stability

Wise¹,

Wills²,

Bedford³

1981

Antimicrob Agents Chemother

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Moxalactam exists in two epimeric forms, R and S. The in vitro activity of these two epimers was compared with that of material available for clinical and laboratory use (R + S moxalactam). Generally, R moxalactam was twice as active as the S form. The stability of R + S moxalactam was studied at 37, 20, 4, and -20°C in buffer and serum. Only in serum at 37°C was there any appreciable loss of activity (half-life, 8 h). The stability of R and S epimers was studied separately, and the composition of the resulting equilibrium was investigated. At 37°C in serum, one-half of the excess of either R or S over the equilibrium mixture was converted into the equilibrium mixture in 1.5 h. The proportions of R to S in an equilibrium mixture in buffer were 50:50, but in serum they were 45:55. It is doubtful whether these differences in stability and activity will have any significant clinical importance.Moxalactam (LY127935, 6059S) is a broadspectrum oxa-f,-lactam (3). During a pharmacological study on this compound (6), it was observed that high-performance liquid chromatographic analysis of samples and standards yielded a double peak. Information from Lilly Research Centre Limited, Windlesham, U. K., indicated that these peaks corresponded to the two epimers of moxalactam. These epimers are known as R and S moxalactam and correspond to the D and L of prior nomenclature. This study compares two important properties of these epimers, the antimicrobial activity and stability. MATERIALS AND METHODSThe two epimners, R (potency, 773 ig/mg) and S (potency, ">85%"; taken as 90%) moxalactam, together with an R and S mixture (potency, 10 mg of diacid material per sealed vial) available for clinical studies and stated to be a 50:50 mixture of the two epimers, were supplied by Lilly Research Centre Limited. Only a small amount of S moxalactam was available, and this limited the studies which could be performed. Neither the R nor the S material was pure as each contained some of the other epimer (T. Yoshida, personal communication).The strains studied were identified by the API (API Laboratory Products Ltd., Farnborough, England) method, and the production of /3-lactamase by certain strains was verified by the nitrocefin method (4).The minimum inhibitory concentrations of R, S, and R + S moxalactam were measured for the organisms listed in Table 1 The stability of R, S, and R + S moxalactam was studied by high-performance liquid chromatography with an Applied Chromatography pump (Luton, England) and an ultraviolet detector at 254 nm. A 10-cm Hypersil 5-,um octadecylsilane column was used. The solvent was 14% methanol-0.1% nitric acid in water at a flow rate of 2 ml/min. Serum samples were prepared by mixing with an equal volume of saturated ammonium sulfate, centrifuging and injecting 20 pl of the supernatant. Buffer samples were injected without the initial precipitation step. With this procedure, a 95% base-line separation was achieved, and the retention times of R and S moxalactam were 6 and 8 min, respectively (Fig. 1).The high-pe...

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Section: Methodsmentioning

confidence: 99%

Epimers of moxalactam: in vitro comparison of activity and stability

Wise¹,

Wills²,

Bedford³

1981

Antimicrob Agents Chemother

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“…A known procedure for the synthesis of enantiopure ( R )‐2‐phenyl‐2‐sulfoacetic acid 3 ab is by using a resolution technique with L ‐lysine 6a. Until now, asymmetric catalysis with transition‐metal complexes for the construction of sulfonic acid has not been reported yet.…”

Section: Optimizing Conditions For the Allylic Sulfonation Of (E)‐cinmentioning

confidence: 99%

Asymmetric Synthesis of Allylic Sulfonic Acids: Enantio‐ and Regioselective Iridium‐Catalyzed Allylations of Na₂SO₃

Liu

Zhao

Zhang

et al. 2014

Chemistry A European J

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“…Amongthe a-sulfopenicillins tested, the athienyl and aM^-aminophenyl) homologues showed the greatest activity against Pseudomonasaeruginosa, and broad spectra comparable to that of <#-sulfobenzylpenicillin (1). With the exception of these two homologues, any modification in position or structure of the a-suMo or a-phenyl group of 1, diminished activity.…”

mentioning

confidence: 97%

“…and^-carboxy-S-thienylmethylpenicillin10'11^Among these new penicillins, <#-sulfo» benzylpenicillin (1) has recently been used clinicallyW3). This paper reports the structure-activity relationships of 32 sulfopenicillins which include related compounds.…”

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confidence: 99%