Marco Pallavicini

4‐Oxystilbene compounds are selective ligands for neuronal nicotinic αBungarotoxin receptors

1 Starting from the structure of an old 4‐oxystilbene derivate with ganglioplegic activity (MG624), we synthesized two further derivates (F2 and F3) and two stereoisomers of F3 (F3A and F3B), and studied their selective effect on neuronal nicotinic acetylcholine receptor (AChR) subtypes. 2 MG 624, F3, F3A and F3B inhibited of 125I‐αBungarotoxin (αBgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited 125I‐αBgtx binding to TE671 cell‐expressed muscle‐type AChR only at much higher concentrations. 3 We immobilized the α7, β2 and β4 containing chick neuronal nicotinic AChR subtypes using anti‐subunit specific antibodies. MG 624, F3, F3A and F3B inhibited 125I‐αBgtx binding to the α7‐containing receptors with nm affinity, but inhibited 3H‐Epi binding to β2‐containing receptors only at very high concentrations (more than 35 μm); their affinity for the β4‐containing receptors was ten times more than for the β2‐containing subtype. 4 Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte‐expressed chick α7 receptors with an IC50 of respectively 94 and 119 nm. 5 High doses of both MG 624 and F3 depressed the contractile response to vagus nerve stimulation in guinea pig nerve‐stomach preparations although at different IC50s (49.4 vs 166.2 μm) The effect of MG624 on rat nerve‐hemidiaphragm preparations was 33 times less potent than that of F3 (IC50 486 vs 14.5 μm). 6 In conclusion, MG624 and F3 have a high degree of antagonist selectivity for neuronal nicotinic αBgtx receptors containing the α7 subunit.

Synthesis of (R)- and (S)-isopropylidene glycerol ☆

Abstract The preparation of (R)- and (S)-isopropylidene glycerol 1 of high enantiomeric excess (> 98%) was accomplished through salt formation between their hydrogen phthalates with (S)- and (R)-1-methylbenzylamine [MBA] respectively, selective crystallization of these salts and subsequent regeneration of optically active compounds 1 by saponification. The progress of resolution was followed by HPLC analysis on Chiralcel OJ, after converting the hydrogen phthalates into the corresponding mono methyl esters by diazomethane.

New asymmetric synthesis of (−)-esermethole

Abstract A new synthesis of (−)-esermethole, based on the asymmetric alkylation at C(3) of racemic 1,3-dimethyl-5-methoxyoxindole ( 3 ), is described. The chloroacetyl derivatives of (−)-menthol and (S)-N-methyl-(1-phenylethyl) amine were chosen as chiral alkylating agents and used under different reaction conditions (temperature, solvent and base). In particular, the latter reacted with 3 in toluene at 10°C, in the presence of t -butyllitium, giving (3S,1′S)-N-methyl-N-(1′-phenylethyl)-1,3-dimethyl-5-methoxyoxindol-3-ilacetamide ( 10 ) with a 63% d.e.. This intermediate was easily separated from the undesired minor (3R,1′S) diastereomer ( 11 ) and converted to (−)-esermethole (99.6% e.e.) in two steps.

Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing internal dipeptide AA with 4-amino-2-phenylbenzoic acid and cysteine (C) with 2-amino-4-thiazolyl-, 2-mercapto-4-thiazolyl-, 2-mercapto-4-imidazolyl- and 2-methylmercapto-4-thiazolyl-acetic or propionic acid. The compound in which C is replaced by 2-amino-4-thiazolylacetic acid inhibited FTase activity in the low nanomolar range and showed antiproliferative effect on rat aortic smooth muscle cells interfering with Ras farnesylation. On the basis of these results, 2-aminothiazole can be considered as an alternative to heterocycles, such as pyridine and imidazole, normally used in FTase inhibitors designed as non-thiol CAAX mimetics.

6-methoxy-7-benzofuranoxy and 6-methoxy-7-indolyloxy analogues of 2-[2-(2,6-Dimethoxyphenoxy)ethyl]aminomethyl-1,4-benzodioxane (WB4101):1 discovery of a potent and selective α1D-adrenoceptor antagonist.

Previous results have shown that replacement of one of the two o-methoxy groups at the phenoxy residue of the potent, but not subtype-selective, α1-AR antagonist (S)-WB4101 [(S)-1] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits α1D-AR antagonist affinity. Such observations inspired the design of four new analogues of 1 bearing, in lieu of the 2,6-dimethoxyphenoxy residue, a 6-methoxy-substituted 7-benzofuranoxy or 7-indolyloxy group or, alternatively, their corresponding 2,3-dihydro form. Of these new compounds, which maintain, rigidified, the characteristic ortho heterodisubstituted phenoxy substructure of 1, the S enantiomer of the dihydrobenzofuranoxy derivative exhibited the highest α1D-AR antagonist affinity (pA2 9.58) with significant α1D/α1A and α1D/α1B selectivity. In addition, compared both to α1D-AR antagonists structurally related to 1 and to the well-known α1D-AR antagonist BMY7378, this derivative had modest 5-HT1A affinity and neutral α1-AR antagonist behavior.

Benzodioxane-benzamides as new bacterial cell division inhibitors.

A SAR study was performed on 3-substituted 2,6-difluorobenzamides, known inhibitors of the essential bacterial cell division protein FtsZ, through a series of modifications first of 2,6-difluoro-3-nonyloxybenzamide and then of its 3-pyridothiazolylmethoxy analogue PC190723. The study led to the identification of chiral 2,6-difluorobenzamides bearing 1,4-benzodioxane-2-methyl residue at the 3-position as potent antistaphylococcal compounds.

Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis

OBJECTIVES This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them. METHODS A series of 20 dipeptides of general structure NH(2)-L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1), pK(2) and pK(3)) and lipophilicity parameters (log P(N) and log D(7.4)) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log P(MLP), meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds). RESULTS Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters. CONCLUSION This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression.

RESOLUTION OF AMINES WITH ISOPROPYLIDENE GLYCEROL HYDROGEN PHTHALATE

Abstract The hydrogen phthalate of isopropylidene glycerol has been recently described as an efficient resolving agent of 1-arylethylamines. In order to gain more information on its versatility and to develop a rationale which accounts for its effectiveness, further 1-arylethylamines and other racemic amines were subjected to the same resolution process. A preliminary qualitative analysis of the results reported herein allows to identify some structural features of the aminic substrates conditioning the feasibility of the resolution.

Isopropylidene glycerol hydrogen phthalate: a new resolving agent. Application to the resolution of 1-arylethylamines

Abstract Hydrogen phthalates of ( R )- and ( S )-isopropylidene glycerol, obtainable from racemic isopropylidene glycerol by reaction with phthalic anhydride and successive resolution with ( S )- and ( R )-1-phenylethylamine or, alternatively, from ( R )-and ( S )-isopropylidene glycerol, were regarded as potential new resolving agents. A range of important 1-arylethylamines was selected to test their resolving capability. In particular, trial resolutions were carried out using equivalent amounts of racemic and hydrogen phthalate of ( R )-isopropylidene glycerol. The salts of the S isomers selectively crystallized from methanol or 2-propanol allowing to recover the ( S )-1-arylethylamines in high chemical and optical yields.

Modelling of full-length human α4β2 nicotinic receptor by fragmental approach and analysis of its binding modes

The objective of the study was to generate a full-length model for the heteropentameric structure of human alpha4beta2 nicotinic receptor. The monomers structure was derived using a fragmental approach and the pentamer was assembled by protein-protein docking. The reliability of the model was assessed docking a representative set of known nicotinic ligands. Docking results unveiled that the ligand affinity depends on key interactions that the ligands charged moiety realizes with conserved apolar residues of alpha4 monomer, whereas the H-bond acceptor group interacts with a less conserved and more heterogeneous subpocket, involving polar residues of beta2 subunit. The consistency of docking results and the agreement with the experimental data afford an encouraging validation for the proposed model and emphasize the soundness of such a fragmental approach to model any transmembrane protein.