A Cyclobutanone Analogue Mimics Penicillin in Binding to Isopenicillin N Synthase

Stewart, Amanda C.; Clifton, I.J.; Adlington, Robert M.; Baldwin, Jack E.; Rutledge, Peter J.

doi:10.1002/cbic.200700176

Cited by 21 publications

(40 citation statements)

References 34 publications

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“…78 and 79), the corresponding 3-hydroxy compounds (thiolactols) and the elimination product 80. [30,31] For this, the 2,2-dimethyl-2,3-dihydrothiophene-3-carboxylate 87 (made in four steps from commercially available triethylphosphono acetate) was used in the key [2+ +2] cycloaddition reactionw ith dichloroketene( Scheme 17). [28] Penem analogue 73 was generated by treating am ixture of epimeric acetals 70 and 71 with methanesulfonic acid to eliminate methanol; dechlorination of 73 under established zinc/acetic acid conditions yielded 72 in low yield.…”

Section: More Complex Systemsmentioning

confidence: 99%

“…[27] In order to separatet he 3a (70)a nd 3b (71)e pimerso ft he 3-methoxy penam analogue, it provede xpedient to work with the corresponding benzhydryl esters 81 and 82,w hich were separated by ac ombination of fractional crystallisation and chromatography and then deprotected by reactingw ith TFA (Scheme 15). [29][30][31] The resulting cycloadduct was readily dechlorinatedt o88,t hen converted into acyl azide 89 and tricyclicc arbamate 90 by adapting Lowe's nitrene chemistry for insertion into the thiabicyclo system. [28] Analogues of penicillin Na nd isopenicillin N Baldwin and co-workers took this chemistryf urthert om ake cyclobutanones 83 and 84 as direct analogueso fp enicillin N (85)a nd isopenicillin N( IPN, 86)r espectively (Scheme 16).…”

Section: More Complex Systemsmentioning

confidence: 99%

“…a) Cl 2 CHCOCl, Et 3 N, RT,1 .5 h; b) 50 %H F, MeCN, reflux, 35 min; c) Jones reagent, acetone,208C, 45 min; d) Ph 2 CN 2 ,EtOAc, RT,1h; e) Zn, THF,HOAc, RT,6h; f) PhSH,E t 3 N, THF,RT, 1h;g )SO 2 Cl 2 ,p yridine, CH 2 Cl 2 , À60 8C, 30 min;h)LiN(SiMe 3 ) 2 ,C p 2 ZrCl 2 ,C H 3 CHO, THF, À78 8C, 1h.R= CHPh 2 . [31] Chemical Biology Cyclobutanone analogues of penam (68)(69)(70)(71)and penem (72, 73)r ing systems.…”

Section: More Complex Systemsmentioning

confidence: 99%

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Cyclobutanone Analogues of β‐Lactam Antibiotics: β‐Lactamase Inhibitors with Untapped Potential?

Devi

Rutledge

2017

ChemBioChem

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β-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to β-lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with β-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N is substituted by a tertiary C-H α to a ketone. Cyclobutanone analogues of various β-lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the β-lactamase enzymes that impart resistance to β-lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of β-lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of β-lactamase; other compounds from this family inhibit Streptomyces R61 dd-carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area.

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Section: More Complex Systemsmentioning

confidence: 99%

Section: More Complex Systemsmentioning

confidence: 99%

Section: More Complex Systemsmentioning

confidence: 99%

See 1 more Smart Citation

Cyclobutanone Analogues of β‐Lactam Antibiotics: β‐Lactamase Inhibitors with Untapped Potential?

Devi

Rutledge

2017

ChemBioChem

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“…However, addition of a series of substrate analogs to IPNS was used to help determine the sequence of oxidative cyclization. 24–27 One substrate analog, (1-( S )-carboxy-2-thiomethyl)ethyl ester (AC O mC), was oxidized by IPNS to give a sulfenato (singly oxygenated sulfur) derivative (Figure 1c). 28 The iron(II) site of IPNS is normally five-coordinate upon addition of substrate or substrate analogs prior to the binding of O 2 , but AC O mC coordinates in a bidentate fashion, with the S -methyl sulfur bound in the proposed oxygen binding site.…”

Section: Introductionmentioning

confidence: 99%

Sulfur oxygenation in biomimetic non-heme iron–thiolate complexes

McQuilken

Goldberg

2012

Dalton Trans.

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The S-oxygenation of cysteine with dioxygen to give cysteine sulfinic acid occurs at the non-heme iron active site of cysteine dioxygenase. Similar S-oxygenation events occur in other non-heme iron enzymes, including nitrile hydratase and isopenicillin N synthase, and these enzymes have inspired the development of a class of [NxSy]-Fe model complexes. Certain members of this class have provided some intriguing examples of S-oxygenation, and this article summarizes these results, focusing on the non-heme iron(II/III)-thiolate model complexes that are known to react with O2 or in some cases other O-atom transfer oxidants, to yield sulfur oxygenates. Key aspects of the synthesis, structure, and reactivity of these systems are presented, along with any mechanistic information available on the oxygenation reactions. A number of iron(III)-thiolate complexes react with O2 to give S-oxygenates, and the degree to which the thiolate sulfur donors are oxidized varies among the different complexes, depending upon the nature of the ligand, metal geometry, and spin state. The first examples of iron(II)-thiolate complexes that react with O2 to give selective S-oxygenation are just emerging. Mechanistic information on these transformations is limited, with isotope labeling studies providing much of the current mechanistic data. The many questions that remain unanswered for both models and enzymes provide strong motivation for future work in this area.

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“…The mechanism of IPNS has been studied using a wide range of ACV analogues in solution,12 in crystallisation studies,5, 6, 13, 14 and by turnover within the crystalline protein (with reaction initiated by exposing anaerobic crystals to pressurised oxygen gas) 7, 15, 16, 17, 18. IPNS catalyses an array of different oxidation reactions both in solution and in crystals; many of the ACV analogues studied, particularly those altered in the third residue (valine), are oxidised to alternative cyclic and acyclic products.…”

Section: Introductionmentioning

confidence: 99%

Terminally Truncated Isopenicillin N Synthase Generates a Dithioester Product: Evidence for a Thioaldehyde Intermediate during Catalysis and a New Mode of Reaction for Non‐Heme Iron Oxidases

McNeill

Brown

Sami

et al. 2017

Chemistry A European J

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Isopenicillin N synthase (IPNS) catalyses the four‐electron oxidation of a tripeptide, l‐δ‐(α‐aminoadipoyl)‐l‐cysteinyl‐d‐valine (ACV), to give isopenicillin N (IPN), the first‐formed β‐lactam in penicillin and cephalosporin biosynthesis. IPNS catalysis is dependent upon an iron(II) cofactor and oxygen as a co‐substrate. In the absence of substrate, the carbonyl oxygen of the side‐chain amide of the penultimate residue, Gln330, co‐ordinates to the active‐site metal iron. Substrate binding ablates the interaction between Gln330 and the metal, triggering rearrangement of seven C‐terminal residues, which move to take up a conformation that extends the final α‐helix and encloses ACV in the active site. Mutagenesis studies are reported, which probe the role of the C‐terminal and other aspects of the substrate binding pocket in IPNS. The hydrophobic nature of amino acid side‐chains around the ACV binding pocket is important in catalysis. Deletion of seven C‐terminal residues exposes the active site and leads to formation of a new type of thiol oxidation product. The isolated product is shown by LC‐MS and NMR analyses to be the ene‐thiol tautomer of a dithioester, made up from two molecules of ACV linked between the thiol sulfur of one tripeptide and the oxidised cysteinyl β‐carbon of the other. A mechanism for its formation is proposed, supported by an X‐ray crystal structure, which shows the substrate ACV bound at the active site, its cysteinyl β‐carbon exposed to attack by a second molecule of substrate, adjacent. Formation of this product constitutes a new mode of reaction for IPNS and non‐heme iron oxidases in general.

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A Cyclobutanone Analogue Mimics Penicillin in Binding to Isopenicillin N Synthase

Cited by 21 publications

References 34 publications

Cyclobutanone Analogues of β‐Lactam Antibiotics: β‐Lactamase Inhibitors with Untapped Potential?

Cyclobutanone Analogues of β‐Lactam Antibiotics: β‐Lactamase Inhibitors with Untapped Potential?

Sulfur oxygenation in biomimetic non-heme iron–thiolate complexes

Terminally Truncated Isopenicillin N Synthase Generates a Dithioester Product: Evidence for a Thioaldehyde Intermediate during Catalysis and a New Mode of Reaction for Non‐Heme Iron Oxidases

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