- Design, synthesis, and biological evaluation of novel fluorinated ethanolamines
-
The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)-type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA-derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed compounds with remarkable BACE1 inhibitory activity. Docking studies revealed the influence of the fluorine atoms in the binding mode of the synthesized ligands. Furthermore, the biological evaluation of our final products and synthesis intermediates led to the discovery of compounds with antimicrobial activity against Mycobacterium and Nocardia species.
- Fustero, Santos,Cunat, Ana C.,Flores, Sonia,Baez, Claribel,Oliver, Judit,Cynamon, Michael,Guetschow, Michael,Mertens, Matthias D.,Delgado, Oscar,Tresadern, Gary,Trabanco, Andres A.
-
scheme or table
p. 14772 - 14784
(2012/02/03)
-
- Amino acid derived epoxide ring opening under microwave irradiation
-
A solvent-free microwave-assisted methodology for the obtainment of the hydroxyethylamine (HEA) isostere is described. A phenylalanine derived aminoalkyl epoxide is allowed to react with a dipeptide amine using basic alumina partially deactivated with water under microwave irradiation. The HEA is obtained in very short time (3 min). This methodology is amenable to application in a parallel or automatic sequential format. Copyright
- Vaiana, Nadia,Rizzi, Luca,Romeo, Sergio
-
p. 648 - 649
(2008/02/07)
-
- Stereoselective synthesis of erythro α-amino epoxides
-
The stereoselective reduction of bromomethyl ketones derived from leucine, phenylalanine, alanine and valine is described using borohydride reagents. The Boc-amino alcohol product has erythro stereochemistry at the carbinol center as deduced by conversion to Boc-amino epoxides. These oxiranes are useful for the preparation of hydroxyethylene peptide isosteres.
- Rotella, David P.
-
p. 5453 - 5456
(2007/10/02)
-
- Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
-
Ro 31-8959 (1), a potent and selective inhibitor of HIV proteinase, is currently in phase III clinical trials.Six approaches for the large-scale synthesis of this compound have been studied.All routes employ an initial disconnection to an electrophilic L-phenylalanine homologue equivalent 13 and the decahydroisoquinoline derivative 5.They differ in adopting either an epoxide, a cyclic sulfate, or an aldehyde as the electrophilic entity and develop chirality from L-phenylalanine, dimethyl D-tartrate, or a Sharpless epoxidation.The preferred route starts from N-phthaloyl-L-phenylalaninyl chloride and uses tris((trimethylsilyl)oxy)ethene to effect homologation to hydroxy ketone 30, which is elaborated in a five-step two-pot procedure to N-phthaloyl epoxide 33 and hence 1.Kilogram quantities of Ro 31-8959 have been prepared using this route.
- Parkes, Kevin E. B.,Bushnell, David J.,Crackett, Peter H.,Dunsdon, Stephen J.,Freeman, Andrew C.,et al.
-
p. 3656 - 3664
(2007/10/02)
-
- Substrate Analogue Renin Inhibitors Containing Replacements of Histidine in P2 or Isosteres of the Amide Bond between P3 and P2 Sites
-
Incorporation of β-alanine or γ-aminobutyric acid in position P2 of ACHPA or LeuΨVal-based tetrapeptides gave highly active renin inhibitors (compounds V,VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin.Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range.Oral activity was achieved by incorporation of polar functionalities at the N-terminus of β-alanine-containing tetrapeptides.One of these compounds (XXVIII) was chosen for further studies.This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.
- Raddatz, Peter,Jonczyk, Alfred,Minck, Klaus-Otto,Schmitges, Claus Jochen,Sombroek, Jan
-
p. 3267 - 3280
(2007/10/02)
-