67843-72-5Relevant academic research and scientific papers
Stereoselective synthesis and in vivo evaluation of the analgesic activity of polysubstituted bispidines
Plas, Aurelie,Troin, Yves,Chalard, Pierre,Marchand, Fabien,Eschalier, Alain
supporting information, p. 6070 - 6079,10 (2020/09/02)
Hetero-Michael addition on a chiral β'-amino α,β- unsaturated ketone gave, after some structural modifications, β,β'-diamino ketals. Mannich-type reactions of these diamines with an aldehyde led, with high diastereoselectivity, to trisubstituted piperidines. Another highly stereoselective Mannich cyclization, with an N-acyliminium ion generated in situ from the corresponding imide, allowed the preparation of original polycyclic bispidine derivatives. The antinociceptive effect of the three compounds prepared was evaluated in vivo by using the writhing test. If the biological results for the analgesic properties were disappointing, compared with the bispidine HZ2, which has a high affinity for opioid receptors, the modularity of the approach offered the possibility of introducing many substituents for new applications, which was promising because the bispidine core has been described to have many different activities. Total stereoselective synthesis of bispidine derivatives is achieved by using as two successive Mannich reactions key steps. This process constitutes a powerful approach toward the preparation of a polycyclic bispidine backbone with high enantioselectivity.
Diastereoselective synthesis of trisubstituted piperidines: A versatile synthon for elaboration of uncommon poly(aza)heterocyclic structures
Plas, Aurélie,Abrunhosa-Thomas, Isabelle,Chalard, Pierre,Troin, Yves
scheme or table, p. 6873 - 6876 (2012/02/05)
Hetero Michael addition on chiral β′-amino-α,β- unsaturated ketone furnished, after some structural modifications, β,β′-diaminoketals. Mannich type reaction of these diamines with an aldehyde led, with a high diastereoselectivity, to trisubstituted piperidines. Starting from a functionalized aldehyde and after subsequent deprotection of the amino group, an intramolecular Michael addition provided octahydro-2H-pyrrolo-[3,4-b]-pyridine, an uncommon framework found in compounds exhibiting biological activity.
Design and synthesis of C5 methylated L-arginine analogues as active site probes for nitric oxide synthase
Martin, Nathaniel I.,Woodward, Joshua J.,Winter, Michael B.,Beeson, William T.,Marletta, Michael A.
, p. 12563 - 12570 (2008/09/18)
The role of nitric oxide (NO) as a biological signaling molecule is well established. NO is produced by the nitric oxide synthases (NOSs, EC 1.14.13.39), a class of heme proteins capable of converting L-arginine to NO and L-citrulline. Despite the large body of knowledge associated with the NOSs, mechanistic details relating to the unique oxidative chemistry performed by these enzymes remain to be fully elucidated. Furthermore, a number of disease states are associated with either the over- or underproduction of NO, making the NOS pathway an attractive target for the development of therapeutics. For these reasons, molecular tools capable of providing mechanistic insights into the production of NO and/or the inhibition of the NOSs remain of interest. We report here the stereospecific synthesis and testing of a number of new L-arginine analogues bearing a minimal substitution, methylation at position 5 of the amino acid side chain (such analogues have not been previously reported). The synthetic approach employed a modified photolysis procedure whereby irradiation of the appropriate diacylperoxide precursors at 254 nm gave access to the required unnatural amino acids in good yields. A heme domain construct of the inducible NOS isoform (iNOSheme) was used to assess the binding of each compound to the enzyme active site. The compounds were also investigated as either inhibitors of, or alternate substrates for, the inducible NOS isoform. The results obtained provide new insight into the steric and stereochemical tolerance of the enzyme active site. These findings also further support the role of a conserved active site water molecule previously proposed to be necessary for NOS catalysis.
