Beta-lactam

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.[2]

2-Azetidinone, the simplest β-lactam

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, 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.[3] These enzymes vary widely in their chemical structure and catalytic efficiencies.[4] 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 as 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.[5]

History

The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene[6][7] in a [2+2] cycloaddition (Ph indicates a phenyl functional group):

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.[8][9]

Synthesis and reactivity

Many methods have been developed for the synthesis of β-lactams.[10]

Breckpot synthesis: The synthesis of substituted β-lactams from the cyclization of beta amino acid esters using the Grignard reagent.[11]

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.[12] 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.[13]

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. These nylon-3 polymers can either mimic host defense peptides or act as signals to stimulate 3T3 stem cell function.[13]

Antiproliferative agents that target tubulin with β-lactams in their structure have also been reported.[14][15]

gollark: Except you'd run into problems with the different sizez.
gollark: You can probably do that thing automatically, actually.
gollark: With some weirdly arbitrary and inconsistent backported features.
gollark: 5.1.
gollark: Strange.

See also

References
  1. Gilchrist T (1987). Heterocyclic Chemistry. Harlow: Longman Scientific. ISBN 978-0-582-01421-3.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Staudinger H (1907). "Zur Kenntniss der Ketene. Diphenylketen". Justus Liebigs Ann. Chem. 356 (1–2): 51–123. doi:10.1002/jlac.19073560106.
  8. Flynn EH (1972). Cephalosporins and Penicillins : Chemistry and Biology. New York and London: Academic Press.
  9. 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.
  10. Alcaide, Benito; Almendros, Pedro; Aragoncillo, Cristina (2007). "Β-Lactams: Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products". Chemical Reviews. 107 (11): 4437–4492. doi:10.1021/cr0307300. PMID 17649981.
  11. Bogdanov B, Zdravkovski Z, Hristovski K. "Breckpot Synthesis". Institute of Chemistry Skopje.
  12. Woodward RB (May 1980). "Penems and related substances". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 289 (1036): 239–50. Bibcode:1980RSPTB.289..239W. doi:10.1098/rstb.1980.0042. PMID 6109320.
  13. Nangia A, Biradha K, Desiraju GR (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. doi:10.1039/p29960000943.
  14. O'Boyle NM, Carr M, Greene LM, Bergin O, Nathwani SM, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ (December 2010). "Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents". Journal of Medicinal Chemistry. 53 (24): 8569–84. doi:10.1021/jm101115u. hdl:2262/81779. PMID 21080725.
  15. O'Boyle NM, Greene LM, Bergin O, Fichet JB, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ (April 2011). "Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones" (PDF). Bioorganic & Medicinal Chemistry. 19 (7): 2306–25. doi:10.1016/j.bmc.2011.02.022. hdl:2262/54923. PMID 21397510.
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