-
ChemMedChem 01/2008; 2(12):1693-700. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: [reaction: see text] Condensation between N-alkyl, N'-aryl carbodiimides and malonic acid monoesters leads to a high-yield formation of N-acyl urea derivatives that could be cyclized to C-monosubstituted barbiturates by addition of a suitable base in a one-pot sequential fashion. In the presence of an electrophile, the last step gives rise to a one-pot, three-component sequential synthesis of fully substituted barbiturates.
Organic Letters 04/2007; 9(5):841-4. · 5.86 Impact Factor
-
Gabriele Candiani,
Massimo Frigerio,
Fiorenza Viani,
Chiara Verpelli,
Carlo Sala,
Luca Chiamenti,
Nadia Zaffaroni,
Marco Folini,
Monica Sani,
Walter Panzeri, Matteo Zanda
ChemMedChem 04/2007; 2(3):292-6. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Aza-Michael additions of alpha-amino esters to fluorinated acceptors take place in a highly stereoselective manner, to give partially modified Psi[NHCH2]retropeptides incorporating a hydrolytically stable trifluoroalanine mimic. The reaction mechanism has been investigated experimentally and theoretically, in order to explain the effect of the trifluoromethyl group on the reactivity and the origins of the experimentally observed stereocontrol. The reaction is a two-step process, involving a tandem aza-Michael addition followed by a stereoselective hydrogen transfer. Both steps are base-catalyzed. The high level of stereocontrol is the result of a combination of electrostatic interactions and steric effects.
Chemistry 02/2007; 13(30):8530-42. · 5.93 Impact Factor
-
Angewandte Chemie International Edition 01/2007; 46(19):3526-9. · 13.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A u t h o r ' s p e r s o n a l c o p y New functionalized, differently fluorinated building-blocks via Michael addition to g-fluoro-a-nitroalkenes Abstract The Michael addition of ketone-derived enamines, metalated methylene active compounds and N-methyl pyrroles to g-fluoro-a-nitroalkenes provided in moderate to good isolated yields the corresponding b-fluoroalkyl nitro compounds, which represent new interesting, highly functionalized building blocks in organofluorine chemistry.
Journal of Fluorine Chemistry 05/2006; · 2.03 Impact Factor
-
ChemMedChem 03/2006; 1(2):175-80. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Two bis-trifluoromethyl pepstatin A analogues, carboxylic acid 1 and its methyl ester 2, have been synthesised in order to probe the properties and size of the trifluoromethyl (Tfm) group and compare it to the "bigger" isobutyl that is present in pepstatin A. The results demonstrate that Tfm can effectively replace the isobutyl chain as far as inhibitory activity against plasmepsin II (PM II), an aspartic proteinase from Plasmodium falciparum, is concerned. On the other hand, replacement of isobutyl by Tfm selectively affected activity against other aspartic proteinases tested. Two lines of evidence led to these conclusions. Firstly, compounds 1 and 2 retained single-digit nanomolar inhibitory activity against PM II, but were markedly less active against PM IV, cathepsin D and cathepsin E. Secondly, the X-ray crystal structures of the three complexes of PM II with 1, 2 and pepstatin A were obtained at 2.8, 2.4 and 1.7 A resolution, respectively. High overall similarity among the three complexes indicated that the central Tfm was well accommodated in the lipophilic S1 pocket of PM II, where it was involved in tight hydrophobic contacts. The interaction of PM II with Phe111 appeared to be crucial. Comparison of the crystal structures presented here, with X-ray structures or structural models of PM IV and cathepsin D, allowed an interpretation of the inhibition profiles of pepstatin A and its Tfm variants against these three enzymes. Interactions of the P1 side chain with amino acids that point into the S1 pocket appear to be critical for inhibitory activity. In summary, Tfm can be used to replace an isobutyl group and can affect the selectivity profile of a compound. These findings have implications for the design of novel bioactive molecules and synthetic mimics of natural compounds.
ChemBioChem 02/2006; 7(1):181-6. · 3.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have developed a simple and high yielding one-step method for the synthesis of hydroxamate derivatives directly from a broad range of unactivated esters and the anion of O-benzyl-hydroxylamine generated in situ. The reaction takes place in minutes at -78 degrees C. Very importantly, the method was successfully employed with enolizable esters, including chiral alpha-amino acid esters and peptides, with no trace of racemization/epimerization at the alpha carbon detected.
The Journal of Organic Chemistry 09/2005; 70(17):6925-8. · 4.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The racemic α-trifluoromethyl-α-amino-β-sulfone hydroxamates 1 were synthesized by means of a nucleophilic addition of sulfur-stabilized carbanions to a N-Cbz imine of trifluoropyruvate (4). The free amino derivative 1a was the most potent inhibitor of both MMP-3 (stromelysin-1) and MMP-9 (gelatinase-B), showing an IC50 = 14 nM and 1 nM, respectively, and excellent selectivity versus MMP-1 (>5000-fold difference in inhibitory capacity). The N-Me derivative 1b was the most selective for MMP-3 with respect to MMP-9 (62-fold difference).
Tetrahedron Letters 09/2005; 46(38):6515-8. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The γ-trifluoromethyl γ-sulfone hydroxamate 1 was synthesized both in racemic and enantiomerically pure forms by means of a thia-Michael reaction of p-methoxythiophenol on achiral and chiral 3,3,3-trifluorocrotonoyl Michael acceptors. The (R)-1 enantiomer was the most potent inhibitor of MMP-3 (stromelysin-1), showing an IC50 = 3.2 nM, as well as the most selective with respect to MMP-9 (65-fold).
Tetrahedron Letters 04/2005; 46(14):2393–2396. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: [reaction: see text] Carbodiimides and suitably activated alpha,beta-unsaturated carboxylic acids react effectively to afford a vast array of 1,3,5-trisubstituted hydantoins by means of a regiospecific domino condensation/aza-Michael/N-->O acyl migration. The reaction works well in very mild conditions (20 degrees C, dichloromethane) with fumaric acid derivatives bearing an electron-withdrawing group in the beta position. Good results have been obtained also with less activated substrates bearing only one electron-withdrawing group in the beta position, using more polar solvents (acetonitrile, DMF), and in the presence of a base (2,4,6-trimethylpyridine). Reactions with asymmetric carbodiimides are generally highly chemo- and regioselective, giving rise to the formation of a single regioisomeric hydantoin. However, asymmetric carbodiimides bearing one alkyl group and one aryl group can produce variable amounts of N-acylurea byproducts. The latter could be easily recovered and transformed into the corresponding hydantoins. A detailed study of the influence of key reaction parameters such as solvent, base, and structure of the reactants on the reaction outcome and mechanism is presented. This methodology is particularly convenient for the synthesis of trifluoromethyl-substituted hydantoins, which could be interesting as bioactive compounds in medicinal chemistry, as well as precursors of the corresponding alpha-amino acids.
The Journal of Organic Chemistry 03/2005; 70(6):2161-70. · 4.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A novel synthesis of enantiopure hydroxyethylamine isosteres 1 has been developed. Reaction of lithiated b-sulfinyl-ethylamines 3 with N-Cbz-imines generated in situ from a-amino-sulfones 4 afforded in good to excellent yields and moderate stereocontrol the 2-sulfinyl-1,3-diamines 2. The latter were submitted to the nonoxidative Pummerer reaction (NOPR) in CH 2 Cl 2 , that produced the target compounds 1 in very good yields with inversion of configuration. In some cases, the use of acetonitrile as solvent resulted in a double-inversion pathway, leading for example to the oxazolidinone 5. The total synthesis of an epimer of Saquinavir has been achieved by this method. Among the most successful approaches to the develop-ment of potent enzyme inhibitors, modification of a peptide backbone through the incorporation of hydr-oxyethylamine dipeptide isosteres 1 (Scheme 1) has proven to be extremely valuable. 1 As an example, of the six FDA approved drugs that function as inhibitors for HIV protease, three (Saquinavir, Nelfinavir and Am-prenavir) feature a hydroxyethylamine module. 2 Many routes to hydroxyethylamine isosteres 1 have been described, 3 but the syntheses on an industrial scale of Saquinavir, 4 Nelfinavir, 5 and Amprenavir 6 should be considered as benchmarks from the point of view of synthetic efficiency. In this communication we describe a conceptually new, two-step approach to hydroxy-ethyl-amine isosteres 1, based on: (1) assembly of the hydroxyethylamine carbon framework through C–C bond forming reaction of chiral a-lithium b-sulfinyl-ethylamines 3 (Scheme 1) with the a-amino sulfones 4, which are N-Cbz imines precursors; (2) stereoselective displacement of the sulfinyl by hydroxy group from the intermediate 2-sulfinyl-1,3-diamines 2 through the nonoxidative Pummerer reaction (NOPR). 7
Tetrahedron Letters 01/2004; 45:5125. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: [reaction: see text] A novel class of peptidomimetics having a stereogenic [CH(CF(3))NH] replacement for a [CONH] peptide bond has been synthesized. The new compounds have been obtained in a stereocontrolled fashion using a kinetically controlled aza-Michael addition of chiral alpha-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. The stereoselectivity is strongly influenced by the solvent, the base, its stoichiometry, and the R side-chain. Diastereomeric ratios higher than 11:1 were achieved using H-Val-OtBu.HCl in toluene with 1.1 equiv of DIPEA.
Organic Letters 11/2003; 5(21):3887-90. · 5.86 Impact Factor
-
Alessandro Volonterio,
Stefano Bellosta,
Fabio Bravin,
Maria Cristina Bellucci,
Luca Bruché,
Giorgio Colombo,
Luciana Malpezzi,
Stefania Mazzini,
Stefano V Meille,
Massimiliano Meli,
Carmen Ramírez De Arellano, Matteo Zanda
[show abstract]
[hide abstract]
ABSTRACT: Partially modified retro- (PMR) and retro-inverso (PMRI) psi[NHCH(CF(3))]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure alpha-amino esters and peptides with enantiomerically and geometrically pure N-4,4,4-trifluorocrotonoyl-oxazolidin-2-ones. The factors underlying the observed moderate to good diastereocontrol have been investigated. The conformations of model PMR-psi[NHCH(CF(3))]Gly tripeptides have been studied in solution by (1)H NMR spectroscopy supported by MD calculations, as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp(3) bonds in the [CO-CH(2)-CH(CF(3))-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF(3) group and the R side chain; 2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl(3) solution and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramolecular hydrogen bonding. The relative configuration of the -C*H(CF(3))NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochemistry. X-ray diffraction and ab initio computational studies showed that the [-CH(CF(3))NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analogue, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF(3))-NH-CH backbone angle close to 120 degrees, C-CF(3) bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O(-))NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron density on the CF(3) group, tetrahedral backbone carbon).
Chemistry 10/2003; 9(18):4510-22. · 5.93 Impact Factor
-
Angewandte Chemie International Edition 06/2003; 42(18):2060-3. · 13.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Angiogenesis, the growth of new blood vessels from preexisting vessels, is a rare event in the adult (except in the case of the female reproductive cycle), but is a characteristic feature of diseases such as cancer, blinding ocular disorders (e.g., retinopathies), and rheumatoid arthritis. The ED-B domain of fibronectin, a domain of 91 amino acids, inserted by a mechanism of alternative splicing of the primary transcript into the fibronectin molecule, is a high-quality marker of angiogenesis and a target for molecular intervention, characterized by a high number of acidic residues on its surface, as well as some solvent-exposed hydrophobic residues. A library of 113 low molecular-weight organic compounds, containing both an aromatic moiety and at least one positive charge, was screened for binding to the ED-B domain, using two-dimensional heteronuclear NMR spectroscopy. One lead compound, 2,2-diphenylethylamine, was found that binds specifically to the ED-B domain, albeit with a dissociation constant in the millimolar range. Chemical modification of this scaffold revealed structural determinants required for binding, as well as amino acid residues in the ED-B domain responsible for the interaction. The results presented represent the basis for the development of high-affinity, low molecular-weight binders by using a linked-fragment approach or elongating the scaffold by means of combinatorial chemistry. Drug Dev. Res. 58:268–282, 2003. © 2003 Wiley-Liss, Inc.
Drug Development Research 02/2003; 58(3):268 - 282. · 1.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The behaviour of di- and tri-fluorinated-ephedrines and -norephedrines has been studied by fast atom bombardment, atmospheric pressure chemical ionisation (APCI) and electrospray ionisation (ESI) experiments and compared with that of the unfluorinated analogues. Under all the employed ionisation conditions [MH](+) and [MH-H(2)O](+) species are mainly produced. Both high- and low-energy collisional experiments were performed on the protonated molecules to put in evidence any possible significant differences due to different ionisation methods. Multiple MS/MS experiments, performed by ion trap, allowed establishment of the decomposition pathways at lower activation energy. The data thus obtained indicate that the presence of fluorinated substituents leads to a higher stability of the molecular species, with strengthening of the C(1)-C(2) bond of the molecule and with a lower proclivity to thermally-induced dehydration.
Il Farmaco 02/2003; 58(1):69-77.
-
[show abstract]
[hide abstract]
ABSTRACT: The synthesis of a novel family of partially modified (PM) retro- and retro-inverso-peptidyl hydroxamates, each incorporating a [CH(CF3)CH2CO] unit as a surrogate for the conventional malonyl group, has been accomplished both in solution and in solid phase. The key step is the Michael-type N-addition of free or polymer-bound α-amino hydroxamates to 3-[(E)-enoyl]-1,3-oxazolidin-2-ones, which takes place in high yields, although with low stereocontrol. This method is suitable for the preparation of combinatorial libraries of PM retro-ψ[NHCH(CF3)]-peptidyl hydroxamates for screening as metalloprotease inhibitors. A number of tri- and tetrapeptidyl hydroxamates were indeed obtained either in diastereomerically pure form by solution-phase synthesis followed by chromatographic purification, or as mixtures of two epimers by solid-phase synthesis and release from the resin. X-ray diffraction of a Tfm-retropeptidyl hydroxamate showed an interesting turn-like conformation with an intramolecularly hydrogen-bonded nine-membered ring, and a nearly planar geometry of the NH group bound to the CH(CF3) group. Three retro-peptidyl hydroxamates were submitted to bioassays, and displayed the capacity to reduce MMP-9 (Gelatinase B) gelatinolytic activity.
Annalen der Chemie und Pharmacie 01/2002; 2002(3):428 - 438. · 3.10 Impact Factor
-
Paolo Ambrosi,
Alberto Arnone,
Pierfrancesco Bravo,
Luca Bruché,
Antonio De Cristofaro,
Valeria Francardi,
Massimo Frigerio,
Enzo Gatti,
Giacinto S. Germinara,
Walter Panzeri,
Fabrizio Pennacchio,
Cristina Pesenti,
Giuseppe Rotundo,
Pio F. Roversi,
Cristina Salvadori,
Fiorenza Viani, Matteo Zanda
[show abstract]
[hide abstract]
ABSTRACT: The stereoselective synthesis of both enantiomers of trifluoro frontalin (−)-(1S,5R)- and (+)-(1R,5S)-8, as well as of diastereomeric monofluoro frontalines (−)-(1R,2R,5R)-18 and (−)-(1R,2S,5R)-20, analogues of the bioactive component of the aggregation pheromone of the Scolytidae insect family, has been accomplished starting from (−)-(1R)- and (+)-(1S)-menthyl (S)-toluene-4-sulfinate as a source of chirality and methyl trifluoroacetate or fluoroacetate, respectively, as sources of fluorine. The C-1 stereocenters were installed via stereoselective epoxidation of β-sulfinyl ketones 2 and 13 with diazomethane. The bicyclic core was obtained by totally stereocontrolled and chemoselective tandem Wacker oxidation/intramolecular ketalization of the intermediate unsatured sulfinyl diols 5, 15, and 19. Axially fluorinated (−)-20 elicited a strong electroantennographic response in laboratory tests on females of Dendroctonus micans, whereas equatorially fluorinated (−)-18 and the trifluoroanalogue (−)-8 showed modest responses. Field trials using (−)-20 were not indicative owing to the locally scarce population of D. micans, but it showed some attractiveness for other Coleoptera families.
11/2001;
