β-Lactam

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β-Lactam
Beta-lactam.svg
Identifiers
CAS number 930-21-2
PubChem 136721
ChemSpider 120480
Jmol-3D images Image 1
Properties
Molecular formula C3H5NO
Molar mass 71.08 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 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.

Clinical significance

Penicillin core structure.

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

The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene34 in a [2+2]cycloaddition:

StaudingerLactam.svg

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.5

Nomenclature

Penam Carbapenam Oxapenam Penem Carbapenem Monobactam Cephem Carbacephem Oxacephem
The β-lactam core structures. (A) A penam. (B) A carbapenam. (C) An oxapenam. (D) A penem. (E) A carbapenem. (F) A monobactam. (G) A cephem. (H) A carbacephem. (I) An oxacephem.

β-Lactams are classified according to their core ring structures.6

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 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 monolactams 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

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.7 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.8

Other applications

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. 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.910

See also

References

  1. ^ Gilchrist, T. (1987). Heterocyclic Chemistry. Harlow: Longman Scientific. ISBN 0-582-01421-2. 
  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.
  3. ^ 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. 
  4. ^ H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51 – 123.
  5. ^ Flynn, E.H. (1972). Cephalosporins and Penicillins : Chemistry and Biology. New York and London: Academic Press. 
  6. ^ 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.  
  7. ^ Woodward, R.B. (1980) "Penems and related substances." Phil Trans Royal Soc Chem B 289(1036), 239–50.
  8. ^ Nangia, A.; Biradha, K.; Desiraju, G.R. (1996) "Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters: A Cambridge database study." J Chem Soc, Perkin Trans 2 (5), 943–53.
  9. ^ O'Boyle, Niamh; Miriam Carr; Lisa Greene; Orla Bergin; Seema M. Nathwani; Thomas McCabe; David G. Lloyd; Daniela M. Zisterer; 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. PMID 21080725. 
  10. ^ O'Boyle, Niamh; Lisa Greene; Orla Bergin; Jean-Baptiste Fichet; Thomas McCabe; David G. Lloyd; Daniela M Zisterer; Mary J. Meegan (2011). "Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones". Bioorganic and Medicinal Chemistry 19 (7): 2306–2625. doi:10.1016/j.bmc.2011.02.022. 

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