Andrea Milelli

Organocatalytic Asymmetric Synthesis of α,α-Disubstituted α-Amino Acids and Derivatives

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to alpha,beta-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted alpha,beta-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active alpha,alpha-disubstituted alpha-amino acids, alpha-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the alpha,beta-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the alpha,beta-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic alpha,beta-unsaturated aldehydes.

Asymmetric 1,4‐Addition of Oxazolones to Nitroalkenes by Bifunctional Cinchona Alkaloid Thiourea Organocatalysts: Synthesis of α,α‐Disubstituted α‐Amino Acids

An easy and simple synthetic approach to optically active alpha,alpha-quaternary alpha-amino acids using asymmetric organocatalysis is presented. The addition of oxazolones to nitroalkenes catalyzed by thiourea cinchona derivatives provides the corresponding alpha,alpha-quaternary alpha-amino acid derivatives with good yields, excellent diastereoselectivities (up to 98 % dr), and from moderate to good enantioselectivities (up to 92 % ee). The reaction can be performed on a large scale. The optically active oxazolone-nitroalkene addition products can be opened in a one-pot reaction to the corresponding ester-amide derivatives. Additional transformations are also presented, such as the synthesis of amino esters, amino acids, and transformation into 3,4-disubstituted pyrrolidin-2-ones.

Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer’s disease

Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimers disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1s enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.

Structure-Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone. 4. Further Investigation on the Inner Spacer

Novel multi-target-directed ligands were designed by replacing the inner dipiperidino function of 3 with less flexible or completely rigid moieties to obtain compounds endowed with multiple biological properties that might be relevant to Alzheimers disease. 15 was the most interesting, inhibiting AChE in the nanomolar range and inhibiting AChE-induced and self-promoted beta-amyloid aggregation in the micromolar range.

Multifunctional Tacrine Derivatives in Alzheimer’s Disease

Tacrine (1) was the first acetylcholinesterase inhibitor (AChEI) introduced in therapy for the treatment of Alzheimers disease (AD), but similarly to the most recent approved AChEIs and memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, it does not represent an effective drug in halting the progression of AD. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. On these bases, the development of new effective therapeutics becomes crucial and the design of molecules that address more than one specific AD target should represent thus a succeeded strategy for AD treatment. This review will focus on and summarize multifunctional 1 derivatives starting from our last paper published on the same topic in 2010. In the last three years, the design and synthesis of 1 homo- and heterodimers, as well as of 1-hybrid structures for AD therapy, was aimed mainly to discover safer drugs, with decreased hepatotoxicity in comparison to 1, taking also into account the multifactorial pathogenesis of the disease. Most of these new hetero/homo-dimers and/or hybrids of 1, although addressed mainly to acetylcholinesterase (AChE) and Aβ aggregation inhibition, are able to hit additional targets relevant to AD, among which, β-secretase (BACE1), reactive oxygen species (ROS), calcium channels, NMDAR and M1- muscarinic receptors.

Multitargeted drugs discovery: Balancing anti-amyloid and anticholinesterase capacity in a single chemical entity

Memoquin (1) is a lead compound multitargeted against Alzheimers disease (AD). It is an AChE inhibitor, free-radical scavenger, and inhibitor of amyloid-β (Aβ) aggregation. A new series of 1 derivatives was designed and synthesized by linking its 2,5-diamino-benzoquinone core with motifs that are present in the structure of known amyloid binding agents like curcumin, the benzofuran derivative SKF64346, or the benzothiazole bearing compounds KHG21834 and BTA-1. The weaker AChE inhibitory potencies and the concomitant nearly equipotent anti-amyloid activities of the new compounds with respect to 1 resulted in a more balanced biological profile against both targets. Selected compounds turned out to be effective Aβ aggregation inhibitors in a cell-based assay. By properly combining two or more distinct pharmacological properties in a molecule, we can achieve greater effectiveness compared to single-targeted drugs for investigating AD.

Design, Synthesis, and Biological Evaluation of Substituted Naphthalene Imides and Diimides as Anticancer Agent∞

Naphthalimmide (NI) and 1,4,5,8-naphthalentetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity. NDI derivatives 1-9 were more cytotoxic than the corresponding NI derivatives 10-18. The molecular mechanisms of 1 and 2 were investigated in comparison to mitonafide. They interacted with DNA, were not topoisomerase IIalpha poisons, triggered caspase activation, caused p53 protein accumulation, and down-regulated AKT survival. Furthermore, 1 and 2 caused a decrease of ERK1/2 and, unlike mitonafide, inhibited ERKs phosphorylation.

Bis(7)-tacrine Derivatives as Multitarget-Directed Ligands: Focus on Anticholinesterase and Antiamyloid Activities

However, despite several lead candi-dates progressing into AD pre-clinical testing in the lastdecade, to date none of these agents have been successful inlate-stages clinical trials. Beta-secretase (BACE-1) inhibition hasbeen a strategy actively pursued, however, progress in movinginhibitors to the clinic has been slow, partly as a consequenceof its aspartic proteinase character, which hampers the devel-opment of potent, selective and brain-permeable com-pounds.

Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.

Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.

Progress in acetylcholinesterase inhibitors for Alzheimer's disease: an update

Background: To date, the pharmacotherapy of Alzheimers disease (AD) has been based on acetylcholinesterase inhibitors (AChEIs), and more recently on an N-methyl-d-aspartate receptor antagonist. By increasing acetylcholine concentration in the brain, AChEIs slow behavioral and functional impairments, improving cognitive function. Objective: The review provides an update on novel analogs of approved AChEIs, their combination with other anti-AD agents, natural AChEIs, and modern multitarget-directed ligands (MTDLs) able to hit different biological targets. Methods: We reviewed patents filed during 2005 – 2007 dealing with new AChEIs and their potential application for AD treatment. We point out new chemical structures and scaffolds for designing new AD therapeutic agents as well as new combinations or MTDLs. Results and conclusions: Compared to the limited number of novel commercially available AChEI analogs, many new natural compounds were patented for AD treatment. These might represent a starting point for the rational design of new MTDLs.