F. Javier Sardina

Computer-Aided Structure-Based Design of Multitarget Leads for Alzheimer’s Disease

Alzheimers disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level.

Host–Guest Chemistry of a Water-Soluble Pillar[5]arene: Evidence for an Ionic-Exchange Recognition Process and Different Complexation Modes

The complexation of an anionic guest by a cationic water-soluble pillararene is reported. Isothermal titration calorimetry (ITC), (1)H NMR, (1)H and (19)F DOSY, and STD NMR experiments were performed to characterize the complex formed under aqueous neutral conditions. The results of ITC and (1)H NMR analyses showed the inclusion of the guest inside the cavity of the pillar[5]arene, with the binding constant and thermodynamic parameters influenced by the counter ion of the macrocycle. NMR diffusion experiments showed that although a fraction of the counter ions are expelled from the host cavity by exchange with the guest, a complex with both counter ions and the guest inside the pillararene is formed. The results also showed that at higher concentrations of guest in solution, in addition to the inclusion of one guest molecule in the cavity, the pillararene can also form an external complex with a second guest molecule.

Determination of the Effect of Cation-π Interactions on the Stability of α-Oxy-Organolithium Compounds

Sn-Li exchange equilibria have allowed the quantification of the stabilizing effect of cation-pi interactions in organolithium chemistry. Stabilization energy data on the effect of Li-pi complexation of an aromatic ring or a CC double bond in organolithium compounds are presented. The amount of stabilization gained by complexation of the Li atom with a pi system in alpha-oxy-organolithium compounds is quite comparable to the one observed in systems containing Li-N or Li-O interactions.

Asymmetric synthesis of 3S, 4R-dihydroxypyrrolidines by regio- and stereoselective hydroxylation of 4-oxoproline enolate

Abstract A short, efficient and stereoselective synthesis of enantiomerically pure (2 R , 3 S , 4 R ) 3,4-dihydroxy-2-hydroxymethylpyrrolidine, a galactosidase inhibitor, from 4-hydroxy-L-proline is presented. The key steps are the regio- and stereoselective hydroxylation of a 4-oxoproline enolate and the stereoselective reduction of the resulting ketoalcohol. An N -(9-phenylfluoren-9-yl) moiety is used not only as an N -protecting group but as a regio- and stereochemical control element as well.

A stereodivergent chirospecific synthesis of (3R) and (3S) 3-hydroxyaspartates by hydroxylation of aspartate diester enolates

Abstract A chirospecific and stereodivergent synthesis of N-(9-phenylfluorenyl)-3-hydroxyaspartates by hydroxylation of aspartate enolates is described. The stereochemistry of the newly created chiral center is controlled by the nature of the enolate counterion and the ligand coordinating ability of the solvents.

A versatile, enantioselective, stereocontrolled synthesis of (1S,2R)-imidazoleglycerol

Abstract An efficient (21% overall yield), enantio- and diastereoseleclive, 11-step synthesis of (1 S ,2 R )-imidazoleglycerol has been developed. The key steps are the stereoselective hydroxylation of an acyloxazolidinone enolate, the alkylation of a thioester with (MOMOCH 2 ) 2 CuLi and the stereodivergent reduction of the resulting ketone. The scope of the reaction of the enolate derived from 10 with heteroatom electrophiles has been studied.

Enantiospecific synthesis of γ-keto-α,β-diamino acid derivatives. Stereoselective synthesis of a precursor of streptolidine lactam

Abstract The reaction of dimethyl (4S,5S)-1-benzyl-2-oxo-3-(9″-phenylfluoren-9″-yl)-imidazolidine-4,5-dicarboxylate ( 3 ) with several organolithium reagents afforded the corresponding enantiomerically pure monoketones ( 4a-e ) in good to excellent yields. Chloromethyl-ketone 4b was ultimately transformed into ureido-amide 8 which incorporates the bicyclic core of streptolidine lactam ( 1 ), a component of the streptrothricin antibiotics.

Enantiospecific synthesis of α-amino ketones and β-amino alcohols from the reaction of N-(9-phenylfluoren-9-yl)-alanine oxazolidinone with organolithium reagents

Enantiomerically pure N-(9-phenylfluoren-9-yl) α-amino ketones were prepared by reaction of the N-Pf-alanine-derived oxazolidinone with organolithium reagents. α-Amino ketones thus obtained could be stereoselectively reduced to the corresponding syn or anti β-amino alcohols depending upon the nature of the reducing agent.

Mechanism of the deprotonation reaction of alkyl benzyl ethers with n-butyllithium.

Kinetic study of the α-lithiation of benzyl methyl ether (BME) by nBuLi has revealed that increasing the concentration of the organolithium compound does not necessarily increase the reactivity, and this is a consequence of the reactivities of the different nBuLi aggregates present in solution. We propose a dimer-based mechanism, in which a pre-complexation step is a key process for substrates bearing a donor oxygen atom that can interact with the lithium cation to form mixed dimers. For these studies, we have developed a system based on UV/Vis spectroscopy that allows kinetic measurements to be conducted at -80 °C under argon.

A Two-Step, Stereoselective Synthesis of Nine- and Ten-Membered Carbocycles from Phthalates

A two-step, stereoselective procedure for the synthesis of nine- and ten-membered carbocycles from readily available phthalates is described. A variety of dialkyl phthalates have been transformed into [6,n]-fused bicyclo systems (n = 5, 6, 7) by a dearomatization/cyclization process and then converted into cyclonona- and cyclodecadienes through a bond cleavage reaction, whereby both processes are promoted by alkaline metals in THF.