José Marco-Contelles

Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease.

With 27 million cases worldwide documented in 2006, Alzheimers disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one‐compound‐one‐target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium‐permeable channels such as voltage‐dependent calcium channels, N‐methyl‐D‐aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one‐compound‐various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD.  © 2011 Wiley Periodicals, Inc. Med Res Rev

Mechanistic insights on the cycloisomerization of polyunsaturated precursors catalyzed by platinum and gold complexes.

Organometallic chemistry provides powerful tools for the stereocontrolled synthesis of heterocycles and carbocycles. The electrophilic transition metals Pt(II) and Au(I, III) are efficient catalysts in these transitions and promote a variety of organic transformations of unsaturated precursors. These reactions produce functionalized cyclic and acyclic scaffolds for the synthesis of natural and non-natural products efficiently, under mild conditions, and with excellent chemoselectivity. Because these transformations are strongly substrate-dependent, they are versatile and may yield diverse molecular scaffolds. Therefore, synthetic chemists need a mechanistic interpretation to optimize this reaction process and design a new generation of catalysts. However, so far, no intermediate species has been isolated or characterized, so the formulated mechanistic hypotheses have been primarily based on labeling studies or trapping reactions. Recently, theoretical DFT studies have become a useful tool in our research, giving us insights into the key intermediates and into a variety of plausible reaction pathways. In this Account, we present a comprehensive mechanistic overview of transformations promoted by Pt and Au in a non-nucleophilic medium based on quantum-mechanical studies. The calculations are consistent with the experimental observations and provide fundamental insights into the versatility of these reaction processes. The reactivity of these metals results from their peculiar Lewis acid properties: the alkynophilic character of these soft metals and the pi-acid activation of unsaturated groups promotes the intra- or intermolecular attack of a nucleophile. 1,n-Enynes (n = 3-8) are particularly important precursors, and their transformation may yield a variety of cycloadducts depending on the molecular structure. However, the calculations suggest that these different cyclizations would have closely related reaction mechanisms, and we propose a unified mechanistic picture. The intramolecular nucleophilic attack of the double bond on the activated alkyne takes place by an endo-dig or exo-dig pathway to afford a cyclopropyl-metallocarbenoid. Through divergent routes, the cyclopropyl intermediate formed by exo-cyclopropanation could yield the metathesis adduct or bicyclic compounds. The endo-cyclization may be followed by a [1,2]-migration of the propargyl moiety to the internal acetylenic position to afford bicyclic [n.1.0] derivatives. This reaction mechanism is applicable for functional groups ranging from H to carboxylate propargyl substituents (Rautenstrauch reaction). In intramolecular reactions in which a shorter enyne bears a propargyl ester or in intermolecular reactions of an ester with an alkene, the ester preferentially attacks the activated alkyne because of enthalpic (ring strain) and entropic effects. Our calculations can predict the correct stereochemical outcome, which may aid the rational design of further stereoselective syntheses. The alkynes activated by electrophilic species can also react with other nucleophiles, such as aromatic rings. The calculations account for the high endo-selectivity observed and suggest that this transformation takes place through a Friedel-Crafts-type alkenylation mechanism, where the endo-dig cyclization promoted by PtCl(2) may involve a cyclopropylmetallacarbene as intermediate before the formation of the expected Wheland-type intermediate. These comparisons of the computational approach with experiment demonstrate the value of theory in the development of a solid mechanistic understanding of these reaction processes.

Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimers disease therapy.

Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease.

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta self-aggregation (34.9 +/- 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.

Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer's disease.

A summary of the recently published efforts on tacrine derivatives as a renewed potential therapeutic approach for the treatment of Alzheimers disease is presented.

The multifactorial nature of Alzheimer's disease for developing potential therapeutics

Alzheimers disease (AD) is a multifactorial neurodegenerative disorder with several target proteins contributing to its aetiology. Pathological, genetic, biochemical, and modeling studies all point to a critical role of Aβ aggregation in AD. Though there are still many enigmatic aspects of the Aβ cascade, none of the gaps invalidate the hypothesis. The amyloid hypothesis determines that the production, aggregation and accumulation of Aβ in the brain gives rise to a cascade of neurotoxic events that proceed to neuronal degeneration. Different targets of the disease include APP pathogenic cleavage, cytoskeletal destabilization, neurotransmitter and ion dyshomeostasis, metal ion accumulation, protein misfolding, oxidative stress, neuronal death and gene mutations. Thus, disease-modifying treatments for AD must interfere with the pathogenic steps responsible for the clinical symptoms: the deposition of extracellular Aβ plaques, the intracellular neurofibrillary tangles, inflammation, oxidative stress, iron deregulation, among others. The observations supporting the development of multifunctional compounds in association with the perception that several dual binding site AChEIs were able to reach different targets guided the development of a new drug design strategy, the multi-target-directed-ligand (MTDL) approach. This may be regarded as the buildup of hybrid molecules composed of distinct pharmacophores of different drugs. Thus, each pharmacophore of the new hybrid drug would preserve the capacity of interacting with their specific sites on the targets and, therefore, generate multiple specific pharmacological responses which would enable the treatment of multi-factorial diseases. This review summarizes a few current therapeutic trends on MTDL strategy intended to halt or revert the progression of the disease.

Carbocycles from carbohydrates via free radical cyclizations: new synthetic approaches to glycomimetics

Free radical cyclization of enantiomerically pure, acyclic presursors derived from carbohydrates is an excellent method for the synthesis of complex, densely functionalized chiral carbohydrate mimics (‘glycomimetics’). The extent of the acyclic diastereoselection can be modulated and is closely associated with the structure, rigidity and conformational aspects of the radical precursors. General models for a rationale of the stereochemical outcome of the cyclizations are shown.

Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimers disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

Regioselectivity Control in the Metal‐Catalyzed OC Functionalization of γ‐Allenols, Part 1: Experimental Study

We describe versatile regiocontrolled metal-catalyzed heterocyclization reactions of gamma-allenol derivatives leading to a variety of fused enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines. Regioselectivity control in the O-C functionalization of gamma-allenols can be achieved through the choice of catalyst: use of AuCl(3) exclusively affords tetrahydrofurans, use of La[N(SiMe(3))(2)](3) usually favors the formation of dihydropyrans, whereas use of PdCl(2) solely gives tetrahydrooxepines. In addition, it has been observed that for the Au-catalyzed cycloisomerization, the presence of a methoxymethyl protecting group not only masks a hydroxy functionality, but also exerts directing effects as a controlling unit in a regioselectivity reversal (7-endo versus 5-exo cyclization). In addition, the regioselectivity of the La-catalyzed cycloetherification can be tuned (5-exo versus 7-endo) simply through a subtle variation in the substitution pattern of the allene component (Ph versus Me). Thus, for the first time the regiocontrolled heterocyclization of gamma-allenol derivatives is both catalyst- and substrate-directable. These metal-catalyzed heterocyclization reactions have been developed experimentally (Part 1, this paper), and their mechanisms have additionally been investigated by a theoretical study (Part 2, accompanying paper).

New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties

In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthyridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca(2+)] elevation elicited by K(+) depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimers disease.