Β-Lactam
{{Short description|Family of chemical compounds}}
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{{about|the class of chemical compounds|the related antibiotics|β-Lactam antibiotic}}
A β-lactam (beta-lactam) ring is a four-membered lactam.{{cite book | vauthors = Gilchrist T | title = Heterocyclic Chemistry | publisher = Longman Scientific | location = Harlow | year = 1987 | isbn = 978-0-582-01421-3}} A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines as manifested in many β-lactam antibiotics.{{Cite journal
| last1 = Fisher | first1 = J. F.
| last2 = Meroueh | first2 = S. O.
| last3 = Mobashery | first3 = S.
| title = Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity
| doi = 10.1021/cr030102i
| journal = Chemical Reviews
| volume = 105
| issue = 2
| pages = 395–424
| year = 2005
| pmid = 15700950
}} Up to 1970, most β-lactam research was concerned with the penicillin and cephalosporin groups, but since then, a wide variety of structures have been described.{{cite book | vauthors = Flynn EH |title=Cephalosporins and Penicillins : Chemistry and Biology|year=1972|publisher=Academic Press|location=New York and London}}{{cite journal | vauthors = Hosseyni S, Jarrahpour A | title = Recent advances in β-lactam synthesis | journal = Organic & Biomolecular Chemistry | volume = 16 | issue = 38 | pages = 6840–6852 | date = October 2018 | pmid = 30209477 | doi = 10.1039/c8ob01833b }}
Clinical significance
{{main|β-Lactam antibiotic}}
The β-lactam ring is part of the core structure of several antibiotic families, the principal ones being the penicillins, cephalosporins, carbapenems, and monobactams, which are, therefore, also called β-lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterial cell wall biosynthesis. This has a lethal effect on bacteria, although any given bacteria population will typically contain a subgroup that is resistant to β-lactam antibiotics. Bacterial resistance occurs as a result of the expression of one of many genes for the production of β-lactamases, a class of enzymes that break open the β-lactam ring. More than 1,800 different β-lactamase enzymes have been documented in various species of bacteria.{{cite journal | vauthors = Brandt C, Braun SD, Stein C, Slickers P, Ehricht R, Pletz MW, Makarewicz O | title = In silico serine β-lactamases analysis reveals a huge potential resistome in environmental and pathogenic species | journal = Scientific Reports | volume = 7 | pages = 43232 | date = February 2017 | pmid = 28233789 | pmc = 5324141 | doi = 10.1038/srep43232 | bibcode = 2017NatSR...743232B }} These enzymes vary widely in their chemical structure and catalytic efficiencies.{{cite journal | vauthors = Ehmann DE, Jahić H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL | title = Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 29 | pages = 11663–8 | date = July 2012 | pmid = 22753474 | pmc = 3406822 | doi = 10.1073/pnas.1205073109 | bibcode = 2012PNAS..10911663E | doi-access = free }} When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and therefore more virulent. β-lactam derived antibiotics can be considered one of the most important antibiotic classes but prone to clinical resistance. β-lactam exhibits its antibiotic properties by imitating the naturally occurring d-Ala-d-Ala substrate for the group of enzymes known as penicillin binding proteins (PBP), which have as function to cross-link the peptidoglycan part of the cell wall of the bacteria.{{cite journal | vauthors = Tipper DJ, Strominger JL | title = Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 54 | issue = 4 | pages = 1133–41 | date = October 1965 | pmid = 5219821 | pmc = 219812 | doi = 10.1073/pnas.54.4.1133 | bibcode = 1965PNAS...54.1133T | doi-access = free }}
The β-lactam ring is also found in some other drugs such as the cholesterol absorption inhibitor drug ezetimibe.
Synthesis
The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene{{cite journal | vauthors = Tidwell TT | title = Hugo (Ugo) Schiff, Schiff bases, and a century of beta-lactam synthesis | journal = Angewandte Chemie | volume = 47 | issue = 6 | pages = 1016–20 | year = 2008 | pmid = 18022986 | doi = 10.1002/anie.200702965 }}{{cite journal | vauthors = Staudinger H | journal = Justus Liebigs Ann. Chem. | title = Zur Kenntniss der Ketene. Diphenylketen | date = 1907 | volume = 356 | issue = 1–2 | pages = 51–123 | doi = 10.1002/jlac.19073560106 | author-link = Hermann Staudinger | url = https://zenodo.org/record/1427571 | access-date = 2019-06-27 | archive-date = 2020-08-02 | archive-url = https://web.archive.org/web/20200802214234/https://zenodo.org/record/1427571 | url-status = live }} in a [2+2] cycloaddition (Ph indicates a phenyl functional group):
Many methods have been developed for the synthesis of β-lactams.{{cite journal |doi=10.1021/cr0307300|title=Β-Lactams: Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products|year=2007|last1=Alcaide|first1=Benito|last2=Almendros|first2=Pedro|last3=Aragoncillo|first3=Cristina|journal=Chemical Reviews|volume=107|issue=11|pages=4437–4492|pmid=17649981}}{{Cite journal|last1=Hosseyni|first1=Seyedmorteza|last2=Jarrahpour|first2=Aliasghar|date=2018|title=Recent advances in β-lactam synthesis|url=http://xlink.rsc.org/?DOI=C8OB01833B|journal=Organic & Biomolecular Chemistry|language=en|volume=16|issue=38|pages=6840–6852|doi=10.1039/C8OB01833B|pmid=30209477|issn=1477-0520|url-access=subscription}}{{Cite journal|last1=Pitts|first1=Cody Ross|last2=Lectka|first2=Thomas|date=2014-08-27|title=Chemical Synthesis of β-Lactams: Asymmetric Catalysis and Other Recent Advances|url=https://pubs.acs.org/doi/10.1021/cr4005549|journal=Chemical Reviews|language=en|volume=114|issue=16|pages=7930–7953|doi=10.1021/cr4005549|pmid=24555548|issn=0009-2665|access-date=2020-12-17|archive-date=2022-07-21|archive-url=https://web.archive.org/web/20220721062126/https://pubs.acs.org/doi/10.1021/cr4005549|url-status=live|url-access=subscription}}
The Breckpot β-lactam synthesis{{Citation|title=Breckpot β-Lactam Synthesis|date=2010-09-15|url=http://doi.wiley.com/10.1002/9780470638859.conrr115|work=Comprehensive Organic Name Reactions and Reagents|pages=521–524|place=Hoboken, NJ, USA|publisher=John Wiley & Sons, Inc.|language=en|doi=10.1002/9780470638859.conrr115|isbn=978-0-470-63885-9|access-date=2021-02-04|archive-date=2024-01-16|archive-url=https://web.archive.org/web/20240116093300/https://onlinelibrary.wiley.com/doi/abs/10.1002/9780470638859.conrr115|url-status=live|url-access=subscription}} produces substituted β-lactams by the cyclization of beta amino acid esters by use of a Grignard reagent.{{cite web |url=http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/breckpot.htm |title=Breckpot Synthesis |vauthors=Bogdanov B, Zdravkovski Z, Hristovski K |website=Institute of Chemistry Skopje |access-date=2014-12-30 |archive-date=2015-11-06 |archive-url=https://web.archive.org/web/20151106234526/http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/breckpot.htm |url-status=dead }} Mukaiyama's reagent is also used in modified Breckpot synthesis.
Reactions
Due to ring strain, β-lactams are more readily hydrolyzed than linear amides or larger lactams. This strain is further increased by fusion to a second ring, as found in most β-lactam antibiotics. This trend is due to the amide character of the β-lactam being reduced by the aplanarity of the system. The nitrogen atom of an ideal amide is sp2-hybridized due to resonance, and sp2-hybridized atoms have trigonal planar bond geometry. As a pyramidal bond geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amide bond is reduced, and the carbonyl becomes more ketone-like. Nobel laureate Robert Burns Woodward described a parameter h as a measure of the height of the trigonal pyramid defined by the nitrogen (as the apex) and its three adjacent atoms. h corresponds to the strength of the β-lactam bond with lower numbers (more planar; more like ideal amides) being stronger and less reactive.{{cite journal | vauthors = Woodward RB | title = Penems and related substances | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 289 | issue = 1036 | pages = 239–50 | date = May 1980 | pmid = 6109320 | doi = 10.1098/rstb.1980.0042 | bibcode = 1980RSPTB.289..239W | doi-access = free }} Monobactams have h values between 0.05 and 0.10 angstroms (Å). Cephems have h values in of 0.20–0.25 Å. Penams have values in the range 0.40–0.50 Å, while carbapenems and clavams have values of 0.50–0.60 Å, being the most reactive of the β-lactams toward hydrolysis.{{cite journal | vauthors = Nangia A, Biradha K, Desiraju GR | year = 1996 | title = Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters: A Cambridge database study | journal = J. Chem. Soc. Perkin Trans. | volume = 2 | issue = 5| pages = 943–53 | doi=10.1039/p29960000943}}
See also
References
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