Beta-lactam
| β-Lactam | |
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2-Azetidinone |
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| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) | |
| Infobox references |
A β-lactam (beta-lactam) ring, is a four-membered lactam.[1] (A lactam is a cyclic amide.) It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.
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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. Bacteria do, however contain within their populations, in smaller quantities, bacteria that are resistant against β-lactam antibiotics. They do this by expressing one of many β-lactamase genes. More than 1,000 different β-lactamase enzymes have been documented in various species of bacteria.[2] These enzymes vary widely in their chemical structure and catalytic efficiencies.[2] When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and therefore more virulent.
History [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[3][4] in a [2+2]cycloaddition:
Nomenclature [edit]
β-Lactams are classified according to their core ring structures.[5]
- β-Lactams fused to saturated five-membered rings:
- β-Lactams containing thiazolidine rings are named penams.
- β-Lactams containing pyrrolidine rings are named carbapenams.
- β-Lactams fused to oxazolidine rings are named oxapenams or clavams.
- β-Lactams fused to unsaturated five-membered rings:
- β-Lactams containing 2,3-dihydrothiazole rings are named penems.
- β-Lactams containing 2,3-dihydro-1H-pyrrole rings are named carbapenems.
- β-Lactams fused to unsaturated six-membered rings:
- β-Lactams containing 3,6-dihydro-2H-1,3-thiazine rings are named cephems.
- β-Lactams containing 1,2,3,4-tetrahydropyridine rings are named carbacephems.
- β-Lactams containing 3,6-dihydro-2H-1,3-oxazine rings are named oxacephems.
- β-Lactams not fused to any other ring are named monobactams.
By convention, the bicyclic β-lactams are numbered starting with the position occupied by sulfur in the penams and cephems, regardless of which atom it is in a given class. That is, position 1 is always adjacent to the β-carbon of β-lactam ring. The The numbering continues clockwise from position one until the β-carbon of β-lactam is reached, at which point numbering continues counterclockwise around the lactam ring to number the remaining to carbons. For example, the nitrogen atom of all bicyclic β-lactams fused to five-membered rings is labelled position 4, as it is in penams, while in cephems, the nitrogen is position 5.
The numbering of monobactams follows that of the IUPAC; the nitrogen atom is position 1, the carbonyl carbon is 2, the α-carbon is 3, and the β-carbon 4.
Reactivity [edit]
Due to ring strain, β-lactams are more reactive to hydrolysis conditions than are 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 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.[6] 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.[7]
New application [edit]
A new study has suggested that β-lactams can undergo ring-openening polymerization to form amide bonds, to become nylon-3 polymers. The backbones of these polymers are identical to peptides, which offer them biofunctionality. A recent study has showed that these nylon-3 polymers can either mimic host defense peptides or act as signals to stimulate 3T3 stem cell function.[citation needed] Antiproliferative agents that target tubulin with β-lactams in their structure have also been reported.[8][9]
See also [edit]
External links [edit]
References [edit]
- ^ Gilchrist, T. (1987). Heterocyclic Chemistry. Harlow: Longman Scientific. ISBN 0-582-01421-2.
- ^ a b Ehmann, David E. et al. (2012). "Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor." PNAS. 109(29):11663-11668.
- ^ Tidwell, Thomas T. (2008). "Hugo (Ugo) Schiff, Schiff Bases, and a Century of β-Lactam Synthesis". Angewandte Chemie International Edition 47 (6): 1016. doi:10.1002/anie.200702965. PMID 18022986.
- ^ H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51 – 123.
- ^ Dalhoff, A.; Janjic, N.; Echols, R. (2006). "Redefining penems". Biochemical Pharmacology 71 (7): 1085–1095. doi:10.1016/j.bcp.2005.12.003. PMID 16413506.
- ^ Woodward, R.B. (1980) "Penems and related substances." Phil Trans Royal Soc Chem B 289(1036), 239–50.
- ^ Nangia, A.; Biradha, K.; Desiraju, G.R. (1996) "Correlation of biological activity in β-lactam anitbiotics with Woodward and Cohen structural parameters: A Camridge database study." J Chem Soc, Perkin Trans 2 (5), 943–53.
- ^ O'Boyle, Niamh; Miriam Carr, Lisa Greene, Orla Bergin, Seema M. Nathwani, Thomas McCabe, David G. Lloyd, Daniela M. Zisterer and Mary J. Meegan (December 2010). "Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents". Journal of Medicinal Chemistry 53 (24): 8569–8584. doi:10.1021/jm101115u.
- ^ O'Boyle, Niamh; Lisa Greene, Orla Bergin, Jean-Baptiste Fichet, Thomas McCabe, David G. Lloyd, Daniela M Zisterer and Mary J. Meegan (2011). "Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones". Bioorganic and Medicinal Chemistry 19: 2306–2625. doi:10.1016/j.bmc.2011.02.022.
