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Molecules 2012, 17(6), 6784-6807; doi:10.3390/molecules17066784

Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

Laboratory of Nano-Biotechnology, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel
Nephrology Laboratory, Department of Clinical Biochemistry, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel
Author to whom correspondence should be addressed.
Received: 7 March 2012 / Revised: 23 May 2012 / Accepted: 30 May 2012 / Published: 4 June 2012
(This article belongs to the Collection Bioactive Compounds)
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Ketamine is an analgesic/anesthetic drug, which, in combination with other drugs, has been used as anesthetic for over 40 years. Ketamine induces its analgesic activities by blocking the N-methyl-D-aspartate (NMDA) receptor in the central nervous system (CNS). We have reported that low doses of ketamine administrated to patients before incision significantly reduced post-operative inflammation as reflected by reduced interleukin-6 (IL-6) sera-levels. Our data demonstrated in a rat model of Gram-negative bacterial-sepsis that if we inject a low dose of ketamine following bacterial inoculation we reduce mortality from approximately 75% to 25%. Similar to what we have observed in operated patients, the levels of TNF-α and IL-6 in ketamine-treated rats were significantly lower than in septic animals not treated with ketamine. On the base of these results, we have designed and synthesized series of new analogues of ketamine applying a thermal rearrangement of alicyclic α-hydroxyimines to a-aminoketones in parallel arrays. One of the analogues (compound 6e) displayed high activity in down-regulating the levels of IL-6 and TNF-α in vivo as compared to ketamine.
Keywords: sepsis; IL-6; TNF-α; thermal rearrangement; α-amino-ketone; microwave sepsis; IL-6; TNF-α; thermal rearrangement; α-amino-ketone; microwave

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Elhawi, H.; Eini, H.; Douvdevani, A.; Byk, G. Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates. Molecules 2012, 17, 6784-6807.

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