Publications (46)171.73 Total impact
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Article: Exploiting RNA as a New Biomolecular Target for Synthetic Polyamines.
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ABSTRACT: Anticancer chemotherapy is strongly hampered by the low therapeutic index of most anticancer drugs and the development of chemoresistance. Therefore, there is a continue need for the identification of new molecular targets in order to selectively hit cancer cells. RNA has been recently validated as a cancer target by the use of different specific ligands and/or by different agents able to destroy its diverse forms. The ability of synthetic polyamines to interact and to alter the RNA structure has been already reported. In the present paper the interaction and the ability to damage RNA structure by several synthetic polyamines were evaluated and quantified by microfluid capillary electrophoresis. This technique allowed us to visualize both the RNA impairment through different electropherograms and to assess the RNA integrity number. Finally, the ability to discriminate between RNA and DNA by these synthetic polyamines was also evaluated.Gene 04/2013; · 2.34 Impact Factor -
Article: Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer's Disease.
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ABSTRACT: Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).Journal of Medicinal Chemistry 10/2012; · 4.80 Impact Factor -
Article: Synthesis of monomeric derivatives to probe memoquin's bivalent interactions.
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ABSTRACT: Eight monomeric congeners, related to the multitarget lead candidate memoquin, were prepared and evaluated at multiple targets to determine their profile against Alzheimer's disease. 2-4 bind to AChE with similar low nanomolar affinities and function as effective inhibitors of amyloid aggregation. The most potent monovalent ligand 2 also inhibits BACE-1 in vitro and APP metabolism in primary chicken telencephalic neurons.Journal of Medicinal Chemistry 11/2011; 54(24):8299-304. · 4.80 Impact Factor -
Article: Multitarget-directed ligands: innovative chemical probes and therapeutic tools against Alzheimer's disease.
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ABSTRACT: Multitarget agents directed at selected molecular targets involved in the pathogenic cascade of Alzheimer's disease (AD) have been increasingly sought after in recent years, with the aim of achieving enhanced therapeutic efficiency with respect to single-target drugs and drug candidates. At the same time, much attention has been devoted to identifying high quality pharmacological tools to help explore the molecular mechanisms underlying AD without being exposed to physicochemical challenges. Herein, we discuss several examples of both types of compounds, taken from our own research and derived from the leads memoquin, lipocrine and bis(7)tacrine.Current topics in medicinal chemistry 11/2011; 11(22):2797-806. · 4.47 Impact Factor -
Article: Reversible human serum albumin binding of lipocrine: a circular dichroism study.
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ABSTRACT: Lipocrine has been selected as an effective candidate for in vivo investigation because of its multiple biological properties, namely inhibition of AChE and BChE activities, inhibition of AChE-induced Aβ aggregation, and ability to protect cells against reactive oxygen species. To evaluate the possibility for lipocrine to become a lead and to be developed as a multipotent drug for the treatment of Alzheimer's disease, ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters need to be determined. Among ADMET parameters, distribution plays a key role in determining the lead drugability, and the drug binding to plasma proteins greatly influences the drug distribution. Here, the human serum albumin (HSA) binding of lipocrine has been studied by circular dichroism (CD) spectroscopy. The reversible binding of lipocrine is stereoselective as shown by the well-defined induced CD spectrum in its binding to HSA. The intensity of the CD signal changes upon changing the [drug]/[HSA] molar ratio, showing a different behavior for a [drug]/[HSA] up to 2/1 or over this molar ratio, suggesting a binding to multiple sites. Competition experiments show that lipocrine interacts significantly with all the main binding sites on the serum carrier. A direct competition has been monitored for site II and bilirubin-binding site, whereas a noncooperative binding should better describe the displacement observed at site I. Rac-lipocrine and its enantiomers are characterized by two different binding modes. Almost the same induced CD spectra were obtained for both (R)- and (S)-lipocrine complexed to HSA, suggesting a similar stereochemistry for the bound enantiomers.Chirality 10/2011; 23(9):827-32. · 2.35 Impact Factor -
Article: Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer's disease.
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ABSTRACT: 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 Alzheimer's 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 1's 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.European journal of medicinal chemistry 09/2011; 46(11):5435-42. · 3.27 Impact Factor -
Article: Hybrid lipoic acid derivatives to attack prion disease on multiple fronts.
ChemMedChem 03/2011; 6(4):601-5. · 3.15 Impact Factor -
Article: Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity.
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ABSTRACT: Memoquin (1) is a lead compound multitargeted against Alzheimer's 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.Bioorganic & medicinal chemistry letters 12/2010; 21(9):2655-8. · 2.65 Impact Factor -
Article: Polyamine conjugation of curcumin analogues toward the discovery of mitochondria-directed neuroprotective agents.
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ABSTRACT: Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery.Journal of Medicinal Chemistry 10/2010; 53(19):7264-8. · 4.80 Impact Factor -
Article: Polyamines in drug discovery: from the universal template approach to the multitarget-directed ligand design strategy.
Journal of Medicinal Chemistry 08/2010; 53(16):5906-14. · 4.80 Impact Factor -
Article: Bis(7)-tacrine derivatives as multitarget-directed ligands: Focus on anticholinesterase and antiamyloid activities.
ChemMedChem 08/2010; 5(8):1215-20. · 3.15 Impact Factor -
Article: Synthetic polyamines: an overview of their multiple biological activities.
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ABSTRACT: The binding of polyamines to a variety of receptors and other defined recognition sites has been widely reported. It is well-known that polyamines interact with aspartate, glutamate, and aromatic residues of a given receptor and/or enzyme mainly through the formation of ion bonds, since at physiological pH, protonation of amino groups is nearly complete. From this, the hypothesis arises that a polyamine may be a universal template able to recognize different receptor systems. This hypothesis suggests that both affinity and selectivity may be fine-tuned by inserting appropriate substituents onto the amine functions and by varying the methylene chain lengths between them on the polyamine backbone. In this paper, we detail several application of this design strategy aimed at discovering potent and selective polyamines able to bind neurotransmitter receptors and enzymes, such as muscarinic receptor subtypes, muscle-type nicotinic receptors and acethylcholinesterase.Amino Acids 12/2009; 38(2):383-92. · 3.25 Impact Factor -
Article: Toward a rational design of multitarget-directed antioxidants: merging memoquin and lipoic acid molecular frameworks.
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ABSTRACT: Novel multitargeted antioxidants 3-6 were designed by combining the antioxidant features, namely, a benzoquinone fragment and a lipoyl function, of two multifunctional lead candidates. They were then evaluated to determine their profile against Alzheimer's disease. They showed antioxidant activity, improved following enzymatic reduction, in mitochondria and T67 cell line. They also displayed a balanced inhibitory profile against amyloid-beta aggregation and acetylcholinesterase, emerging as promising molecules for neuroprotectant lead discovery.Journal of Medicinal Chemistry 10/2009; 52(23):7883-6. · 4.80 Impact Factor -
Article: Alzheimer's disease: new approaches to drug discovery.
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ABSTRACT: In this work, we review and comment upon the challenges and the 'quo vadis' in Alzheimer's disease drug discovery at the beginning of the new millennium. We emphasize recent approaches that, moving on from a target-centric approach, have produced innovative molecular probes or drug candidates. In particular, the discovery of endosome-targeted BACE1 inhibitors and mitochondria-targeted antioxidants represents a significant advance in Alzheimer's research and therapy. The case study of the development of rasagiline provides an excellent example to support the validity of the multitarget-designed ligand approach to the search for effective medicines for combating Alzheimer's disease.Current opinion in chemical biology 06/2009; 13(3):303-8. · 8.30 Impact Factor -
Article: Structure-activity relationships of memoquin: Influence of the chain chirality in the multi-target mechanism of action.
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ABSTRACT: The present article expands on the study of structure-activity relationships of the novel class of quinone-bearing polyamines, as multi-target-directed ligands against Alzheimer's disease. Namely, the effect of inserting a methyl substituent at the alpha position of the terminal benzyl amine moieties of lead candidate 1 (memoquin) was evaluated at the multiple targets involved in the multifunctional mechanism of action. The RR stereoisomer 2 resulted more effective than 1 in reverting two important effects mediated by acetylcholinesterase (AChE), that is, acetylcholine hydrolysis and AChE-induced amyloid-beta aggregation.Bioorganic & medicinal chemistry letters 06/2009; 19(15):4312-5. · 2.65 Impact Factor -
Article: From dual binding site acetylcholinesterase inhibitors to multi-target-directed ligands (MTDLs): a step forward in the treatment of Alzheimer's disease.
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ABSTRACT: Alzheimer's disease is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-Alzheimer drugs. Recently, however, basis for a therapeutic strategy based on multi-target-directed ligands has been formed. In this context, dual binding site acetylcholinesterase inhibitors represent a suitable starting point. The rational modification of their structures to provide them with additional biological properties has emerged as a successful approach.Mini Reviews in Medicinal Chemistry 11/2008; 8(10):960-7. · 2.53 Impact Factor -
Article: Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 4. Further investigation on the inner spacer.
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ABSTRACT: 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 Alzheimer's 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.Journal of Medicinal Chemistry 11/2008; 51(22):7308-12. · 4.80 Impact Factor -
Article: Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush.
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ABSTRACT: Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced Abeta aggregation and display antioxidant properties, emerging as lead candidates for treating AD.Journal of Medicinal Chemistry 08/2008; 51(15):4381-4. · 4.80 Impact Factor -
Article: Inhibition of Acetylcholinesterase, β-Amyloid Aggregation, and NMDA Receptors in Alzheimer’s Disease: A Promising Direction for the Multi-target-Directed Ligands Gold Rush
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ABSTRACT: Alzheimer’s disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced Aβ aggregation and display antioxidant properties, emerging as lead candidates for treating AD.07/2008; -
Article: Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
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ABSTRACT: Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.Bioorganic & medicinal chemistry 07/2008; 16(15):7311-20. · 2.82 Impact Factor
Top co-authors
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Institutions
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1999–2011
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University of Bologna
- Department of Pharmacy and Biotechnology FaBiT
Bologna, Emilia-Romagna, Italy
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2004
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University of Nottingham
- School of Biology
Nottingham, ENG, United Kingdom
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