Beta-lactam: Difference between revisions
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{{Short description|Family of chemical compounds}} |
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{{about|the chemical compound|the related antibiotics|β-Lactam antibiotic}} |
{{about|the chemical compound|the related antibiotics|β-Lactam antibiotic}} |
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[[File:Beta-lactam.svg|thumb|120px|right| |
[[File:Beta-lactam.svg|thumb|120px|right|2-Azetidinone, the simplest β-lactam]] |
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A '''beta-lactam''' ('''β-lactam''') ring is a four-membered [[lactam]].<ref>{{cite book | vauthors = Gilchrist T | title = Heterocyclic Chemistry | publisher = Longman Scientific | location = Harlow | year = 1987 | isbn = 978-0-582-01421-3}}</ref> A ''lactam'' is a cyclic [[amide]], and ''beta''-lactams are named so because the nitrogen atom is attached to the [[Β carbon|β-carbon]] atom relative to the carbonyl. The simplest β-lactam possible is |
A '''beta-lactam''' ('''β-lactam''') ring is a four-membered [[lactam]].<ref>{{cite book | vauthors = Gilchrist T | title = Heterocyclic Chemistry | publisher = Longman Scientific | location = Harlow | year = 1987 | isbn = 978-0-582-01421-3}}</ref> A ''lactam'' is a cyclic [[amide]], and ''beta''-lactams are named so because the nitrogen atom is attached to the [[Β carbon|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 [[Beta-lactam antibiotic|β-lactam antibiotic]]s.<ref>{{Cite journal |
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| last1 = Fisher | first1 = J. F. |
| last1 = Fisher | first1 = J. F. |
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| last2 = Meroueh | first2 = S. O. |
| last2 = Meroueh | first2 = S. O. |
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| year = 2005 |
| year = 2005 |
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| pmid = 15700950 |
| pmid = 15700950 |
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| ⚫ | }}</ref> 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.<ref>{{cite book | vauthors = Flynn EH |title=Cephalosporins and Penicillins : Chemistry and Biology|year=1972|publisher=Academic Press|location=New York and London}}</ref><ref name="pmid30209477">{{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 }}</ref> |
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}}</ref> and have number of pharmacological activities.<ref>{{Cite journal|last1=Kaur|first1=Rajneesh|last2=Singh|first2=Raman|last3=Ahlawat|first3=Priyanka|last4=Kaushik|first4=Parul|last5=Singh|first5=Kuldeep|date=2020-01-07|title=Contemporary advances in therapeutic portfolio of 2-Azetidinones|url=http://www.pubs.iscience.in/journal/index.php/cbl/article/view/987|journal=Chemical Biology Letters|language=en|volume=7|issue=1|pages=13–26}}</ref> |
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==Clinical significance== |
==Clinical significance== |
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{{main|β-Lactam antibiotic}} |
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[[Image:Penicillin core.svg|thumb|180px|Penicillin core structure]] |
[[Image:Penicillin core.svg|thumb|180px|Penicillin core structure]] |
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The β-lactam ring is part of the core structure of several [[antibiotic]] families, the principal ones being the [[penicillin]]s, [[cephalosporin]]s, [[carbapenem]]s, and [[monobactam]]s, which are, therefore, also called [[β-lactam antibiotic]]s. 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 [[antibiotic resistance|resistant]] to β-lactam antibiotics. [[antibiotic resistance|Bacterial resistance]] occurs as a result of the expression of one of many genes for the production of [[beta-lactamase|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.<ref name=Brandt>{{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 }}</ref> These enzymes vary widely in their chemical structure and catalytic efficiencies.<ref name=Ehmann>{{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 }}</ref> 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 |
The β-lactam ring is part of the core structure of several [[antibiotic]] families, the principal ones being the [[penicillin]]s, [[cephalosporin]]s, [[carbapenem]]s, and [[monobactam]]s, which are, therefore, also called [[β-lactam antibiotic]]s. 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 [[antibiotic resistance|resistant]] to β-lactam antibiotics. [[antibiotic resistance|Bacterial resistance]] occurs as a result of the expression of one of many genes for the production of [[beta-lactamase|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.<ref name=Brandt>{{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 }}</ref> These enzymes vary widely in their chemical structure and catalytic efficiencies.<ref name=Ehmann>{{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 }}</ref> 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.<ref name="pmid5219821">{{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 }}</ref> |
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The β-lactam ring is also found in some other drugs such as the [[cholesterol absorption inhibitor]] drug [[ezetimibe]]. |
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==History== |
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| ⚫ | The first synthetic β-lactam was prepared by [[Hermann Staudinger]] in 1907 by reaction of the [[Schiff base]] of [[aniline]] and [[benzaldehyde]] with [[diphenylketene]]<ref>{{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 }}</ref><ref>{{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 }}</ref> in a [2+2] [[cycloaddition]] (Ph indicates a phenyl functional group): |
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| ⚫ | |||
| ⚫ | The first synthetic β-lactam was prepared by [[Hermann Staudinger]] in 1907 by reaction of the [[Schiff base]] of [[aniline]] and [[benzaldehyde]] with [[diphenylketene]]<ref>{{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 }}</ref><ref>{{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 }}</ref> in a [2+2] [[cycloaddition]] (Ph indicates a [[Phenyl group|phenyl]] functional group): |
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:[[Image:StaudingerLactam.svg]] |
:[[Image:StaudingerLactam.svg]] |
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| ⚫ | Many methods have been developed for the synthesis of β-lactams.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref> |
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| ⚫ | 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.<ref>{{cite book | vauthors = Flynn EH |title=Cephalosporins and Penicillins : Chemistry and Biology|year=1972|publisher=Academic Press|location=New York and London}}</ref><ref name="pmid30209477">{{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 }}</ref> |
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| ⚫ | The '''Breckpot β-lactam synthesis'''<ref name=":0">{{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}}</ref> produces substituted β-lactams by the cyclization of beta amino acid esters by use of a [[Grignard reagent]].<ref>{{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 }}</ref> [[Mukaiyama's reagent]] is also used in modified Breckpot synthesis.<ref name=":0" /> |
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| ⚫ | |||
| ⚫ | Many methods have been developed for the synthesis of β-lactams.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref> |
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| ⚫ | The '''Breckpot β-lactam synthesis'''<ref name=":0">{{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= |
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: [[File:Breckpot synthesis.jpg|Breckpot synthesis]] |
: [[File:Breckpot synthesis.jpg|Breckpot synthesis]] |
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==Reactions== |
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Due to [[ring strain]], β-lactams are more readily [[hydrolysis|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 [[Plane (geometry)|aplanarity]] of the system. The nitrogen atom of an ideal amide is [[Orbital hybridisation|sp<sup>2</sup>-hybridized]] due to [[Resonance (chemistry)|resonance]], and sp<sup>2</sup>-hybridized atoms have [[Trigonal planar molecular geometry|trigonal planar bond geometry]]. As a [[Pyramid (geometry)|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 (geometry)|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.<ref>{{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 }}</ref> Monobactams have ''h'' values between 0.05 and 0.10 |
Due to [[ring strain]], β-lactams are more readily [[hydrolysis|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 [[Plane (geometry)|aplanarity]] of the system. The nitrogen atom of an ideal amide is [[Orbital hybridisation|sp<sup>2</sup>-hybridized]] due to [[Resonance (chemistry)|resonance]], and sp<sup>2</sup>-hybridized atoms have [[Trigonal planar molecular geometry|trigonal planar bond geometry]]. As a [[Pyramid (geometry)|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 (geometry)|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.<ref>{{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 }}</ref> Monobactams have ''h'' values between 0.05 and 0.10 [[angstrom]]s (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.<ref name = "Nangia_1996">{{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}}</ref> |
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==Other applications== |
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A new study has suggested that β-lactams can undergo ring-opening [[polymerization]] to form amide bonds, to become nylon-3 polymers. The backbones of these polymers are identical to peptides, which offer them biofunctionality. These nylon-3 polymers can either mimic [[host defense peptides]] or act as signals to stimulate [[3T3 cells|3T3]] [[stem cell]] function.<ref name = "Nangia_1996" /> |
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[[Antiproliferative agent]]s that target tubulin with β-lactams in their structure have also been reported.<ref>{{cite journal | vauthors = O'Boyle NM, Carr M, Greene LM, Bergin O, Nathwani SM, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ | title = Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 24 | pages = 8569–84 | date = December 2010 | pmid = 21080725 | doi = 10.1021/jm101115u | url = http://arrow.dit.ie/scschcpsart/62 | hdl = 2262/81779 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = O'Boyle NM, Greene LM, Bergin O, Fichet JB, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ | title = Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 7 | pages = 2306–25 | date = April 2011 | pmid = 21397510 | doi = 10.1016/j.bmc.2011.02.022 | url = http://www.tara.tcd.ie/bitstream/2262/54923/1/Synthesis%2c%20evaluation%20and%20structural%20studies%20of%20antiproliferative%20tubulin-targeting%20azetidin-2-ones.pdf | hdl = 2262/54923 | hdl-access = free }}</ref> |
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== See also == |
== See also == |
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[[Category: |
[[Category:Beta-lactams| ]] |
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[[Category:Four-membered rings]] |
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Latest revision as of 17:34, 24 January 2024
A beta-lactam (β-lactam) ring is a four-membered lactam.[1] 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.[2] 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.[3][4]
Clinical significance
[edit]
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.[5] These enzymes vary widely in their chemical structure and catalytic efficiencies.[6] 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.[7]
The β-lactam ring is also found in some other drugs such as the cholesterol absorption inhibitor drug ezetimibe.
Synthesis
[edit]The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene[8][9] in a [2+2] cycloaddition (Ph indicates a phenyl functional group):
Many methods have been developed for the synthesis of β-lactams.[10][11][12]
The Breckpot β-lactam synthesis[13] produces substituted β-lactams by the cyclization of beta amino acid esters by use of a Grignard reagent.[14] Mukaiyama's reagent is also used in modified Breckpot synthesis.[13]
Reactions
[edit]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.[15] 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.[16]
See also
[edit]References
[edit]- ^ Gilchrist T (1987). Heterocyclic Chemistry. Harlow: Longman Scientific. ISBN 978-0-582-01421-3.
- ^ Fisher, J. F.; Meroueh, S. O.; Mobashery, S. (2005). "Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity". Chemical Reviews. 105 (2): 395–424. doi:10.1021/cr030102i. PMID 15700950.
- ^ Flynn EH (1972). Cephalosporins and Penicillins : Chemistry and Biology. New York and London: Academic Press.
- ^ Hosseyni S, Jarrahpour A (October 2018). "Recent advances in β-lactam synthesis". Organic & Biomolecular Chemistry. 16 (38): 6840–6852. doi:10.1039/c8ob01833b. PMID 30209477.
- ^ Brandt C, Braun SD, Stein C, Slickers P, Ehricht R, Pletz MW, Makarewicz O (February 2017). "In silico serine β-lactamases analysis reveals a huge potential resistome in environmental and pathogenic species". Scientific Reports. 7: 43232. Bibcode:2017NatSR...743232B. doi:10.1038/srep43232. PMC 5324141. PMID 28233789.
- ^ Ehmann DE, Jahić H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL (July 2012). "Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor". Proceedings of the National Academy of Sciences of the United States of America. 109 (29): 11663–8. Bibcode:2012PNAS..10911663E. doi:10.1073/pnas.1205073109. PMC 3406822. PMID 22753474.
- ^ Tipper DJ, Strominger JL (October 1965). "Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine". Proceedings of the National Academy of Sciences of the United States of America. 54 (4): 1133–41. Bibcode:1965PNAS...54.1133T. doi:10.1073/pnas.54.4.1133. PMC 219812. PMID 5219821.
- ^ Tidwell TT (2008). "Hugo (Ugo) Schiff, Schiff bases, and a century of beta-lactam synthesis". Angewandte Chemie. 47 (6): 1016–20. doi:10.1002/anie.200702965. PMID 18022986.
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