Five-membered ring lactams, known as γ-lactams, are important structural motifs in biologically active natural products, but γ-lactams that are substituted at the 1-position (nitrogen) are less common in drug leads. Although the substituted γ-lactams and the unsubstituted γ-lactams share the main γ-lactam core, a major difference between the two is the substitution at the nitrogen; the unsubstituted γ-lactams are also known as N-H lactam. This difference is substitution is seen in Figure 1 through a natural product Heliotropamide,[1] a γ-lactam substituted at the 1-position and Salinosporamide,[2] a γ-lactam unsubstituted at the 1-position. A survey of γ-lactams in preclinical and clinical development showed a nearly two-to-one ratio of N-H lactams over their substituted counter parts. [3] This is perhaps due to synthetic limitations.
HO CO2H O
NH
O
HN HO Cl
H3CO HN HO2C
O OH HO CH OCH3 OO3
OH
Salinosporamide
Heliotropamide
Figure 1: Examples of N-substituted γ-lactam and an “N-H” γ-lactams Jared Shaw and co-workers at the University of California- Davis, USA, have reported a multicomponent methodology for the synthesis of unsubstituted γ-lactams and their subsequent N-functionalization. By employing ammonium acetate as their starting material in a previously reported four-component reaction (4CR), the research team demonstrated a range of N-H lactam structures that could be produced. These substrates could then be functionalized at the nitrogen through acylation or arylation to provide the structural diversity unavailable through the original 4CR. [3] The mechanistically distinct four-component reaction previously reported in another study by Shaw enables the assembly of γ-lactams in a single synthetic step in high yield and dias...
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...g and attractive because it demonstrates that their previously established lactam-forming 4CR serves as a useful starting reaction in the preparation of unsubstituted γ-lactams. Additionally, these substrates can be further functionalized through acylation or arylation processes. The distinct products are useful starting blocks for the discovery of biological probes and medicinal leads.
Works Cited
1) Younai, A.; Chin, G. F.; Shaw J. T. J. Org. Chem. 2010, 75, 8333-8337. 2) Satoh, N.; Yokoshima, S.; Fukuyama T. Org. Lett. 2011, 13, 3028-3031. 3) Tan, D. Q.; Martin, K. S.; Fettinger, J. C.; Shaw, J. T. Proc. Natl. Acad. Sci. 2011, 108, 6781-6786. 4) Wei, J.; Shaw, J. T. Org. Lett, 2007, 9, 4077–4080. 5) Organic Chemistry Portal 6) 7) Thompson, M. J.; Chen, B. J. Org. Chem. 2009, 74, 7084–7093.
and Gram-negative bacteria.[139] Mannich reaction also plays a significant role in bioactive skeleton target synthesis. Chernov et al. reported the synthesis of alkaloid-like molecules 22 and 23 from lambertianic acid via Mannich-type intramolecular ring closure reaction (Figure 6).[140]
Constrains bacterial cell wall synthesis at a site different than beta-lactam. The Beta lactams attack the enzyme , where as Vancomycin attacks the substrate itself.
Monosodium glutamate can be produced by three common methods which are hydrolysis of proteins, synthesis, and microbial fermentation. In the hydrolysis method, the protein is hydrolyzed with a strong mineral acid to free amino acids, and the glutamic acid is then separated from the mixture, purified, and converted to monosodium glutamat...
...Coauthor, ChemBioChem 2006, 7, 1-10; b) A. Author, B. Coauthor, Angew. Chem. 2006, 118, 1-5; Angew. Chem. Int. Ed. 2006, 45, 1-5.))
the resulting amino acid would be sodium glycinate (see fig. 3), an example of a
In the 1930’s Sandoz Pharmaceuticals in Switzerland began experimenting with new drugs. Albert Hofmann, a young chemist at Sandoz, was planning to discover a cure for individuals with respiratory and circulatory system issues. Hofmann started experimenting with the lysergic acid that is found in the Clavica pupurea fungus, rye, and other grains. Lysergic acid is used to cure headaches; Hofmann thought that the lysergic acid had potential to cure more than headaches. With the lysergic acid, he thought that diethylamide might be a possible match for a drug that could cure. Diethylamide is an amide that has the ability to bond with many proteins in the body. The brain is especially responsive to the diethylamide (Petechuk 12). In 1938 Hofmann synthesized lysergic acid with diethylamide. He then named the compou...
The New Delhi metallo--lactamase (NDM-1) from K. pneumoniae is highly efficient in the inactivation of doripenem. Briefly discuss the properties of NDM-1 and the mechanism of doripenem inactivation. (10 marks)
Schreuder, Jolanda A. H.; Roelen, Corné A. M.; van Zweeden, Nely F.; Jongsma, Dianne; van der Klink, Jac J. L.; Groothoff, Johan W.
David and John Free. (26 Nov 2006). MadSci Network: Chemistry. Retrieved on March 6, 2011, from http://www.madsci.org/posts/archives/2007-02/1171045656.Ch.r.html
Product 3 was isolated in a low yield of 27% and with some solvent impurities as shown by the analytical techniques but it was indeed synthesised successfully.
As the use of paracetamol increased, scientists and reserachers have looked into the most efficient methods of synthesizing the compound. In 1997, demand for paracetamol in the United States was estimated at 30-35 thousand tons per year(IARC 73). Global demand was similarly heavy in many other countries. There are numerous synthetic pathways that are presently known that seek to produce the compound most efficient manner. In determining efficiency, the many factors must be taken into account. The most important ones include the cost of the reagents,...
The detailed mechanism of BoNT pathogenicity and the structure-function relationship of BoNT provide invaluable targets for development of the antidotes and inhibitors against botulism. The BoNT molecule is divided in clear functional domains that can operate independently. This feature provides multiple targets for designing therapeutics to treat botulism. High throughput screening and the combinatorial chemistry provide another useful tool for screening the inhibitors against botulism (Cai and Singh, 2007). Early work with zinc metalloprotease inhibitors focused on the well-characterized agents captopril ((2S)-1-[(2S)-2-methyl-3-sulfanyl-propanoyl] pyrrolidine-2-carboxylic acid) and phosphoramidon (N-alpha-L-rhamno pyranosyl oxy [hydroxyl phosphinyl]-L-leucyl-L-tryptophan). These compounds, however, were found to have little inhibitory activity against BoNT (Adler et al., 1994, 1999a). Phosphoramidon analogs in which Leu–Trp was replaced by Phe–Glu to resemble the cleavage site of synaptobrevin exhibited little increase in inhibitory activity (Adler et al., 1999a).
In homogeneous catalysis, oxidation of alcohols to corresponding aldehyde and ketone requires a stoichiometric amount of oxidant such as chromium(VI), permanganate, DMSO and DDQ (Cardona and Permeggiani, 2015). Consequently, all of these oxidants suffer drawbacks of generating high amounts of organic and inorganic toxic side products after the reaction. Furthermore, these methods are usually carried
J. Clayden, N. Greeves, S. Warren, P. Wothers. Organic Chemistry. 8th ed. 2007, Oxford University Press, p. 1186-1191.
Recently 4á, 5á,6á-trihydroxygeranyl acetat; 6-(9,9-dimethylbutyl) phenol; 1-cyclohexyl-3, 4-dihydroxybenzene; 2, 3, 12, 13-tetrahydroxy-10, 15[a, f] – phenyl xanth-17-one; 2, 3, 13, 14- tetrahydroxy-15, 16-[a, f] – phynyl-7H-anthracen-18-one and 3- hydroxynaphthalenyl-6, 7-ã-lactone have been isolated (Indu, Ali & Onkar, 2006).