Vascular and traumatic injuries of the central nervous system are recognized as global health pri... more Vascular and traumatic injuries of the central nervous system are recognized as global health priorities. A polypharmacology approach that is able to simultaneously target several injury factors by the combination of agents having synergistic effects appears to be promising. Herein, we designed a polymeric delivery system loaded with two drugs, ibuprofen (Ibu) and thyroid hormone triiodothyronine (T3) to in vitro release the suitable amount of the anti-inflammation and the remyelination drug. As a production method, electrospinning technology was used. First, Ibu-loaded micro (diameter circa 0.95–1.20 µm) and nano (diameter circa 0.70 µm) fibers were produced using poly(l-lactide) PLLA and PLGA with different lactide/glycolide ratios (50:50, 75:25, and 85:15) to select the most suitable polymer and fiber diameter. Based on the in vitro release results and in-house knowledge, PLLA nanofibers (mean diameter = 580 ± 120 nm) loaded with both Ibu and T3 were then successfully produced by...
International Review of Biophysical Chemistry, 2011
Depending on the experimental conditions, lipophilic guanosines (LipoGs) can undergo different se... more Depending on the experimental conditions, lipophilic guanosines (LipoGs) can undergo different self-assembly pathways based on different H-bonded motifs, e.g. the cyclic discrete G-quartet and the “infinite” tape-like G-ribbon. The switching between different supramolecular motifs have been obtained by a variety of external stimuli. After a general presentation of the LipoG self-assembly, in this mini-review we will discuss, the case of three different stimuli. A first example is represented by chemical stimuli: addition of an alkali metal ion stabilizes the G-quartet while its removal shifts the equilibrium toward the G-ribbon. In the second case, a lipoG armed with a terthiophene unit undergoes a pronounced variation of its supramolecular organisation by changing the polarity of the solvent: in chloroform the derivative assembles via H-bonding in a guanosine driven structure, while in the more polar (and H-bond competing) acetonitrile different aggregates are observed, where the t...
Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer... more Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi‐target‐directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD‐relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1‐based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4‐naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the “physicochemical challenge” typical of large hybrid‐based MTDLs. A preliminary investigation of their multi‐target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug‐like profile.
Alzheimer's disease represents an enormous global burden in terms of human suffering and econ... more Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.
The self-assembly of three novel lipophilic guanosine derivatives at the solid/liquid interface l... more The self-assembly of three novel lipophilic guanosine derivatives at the solid/liquid interface lead to the generation of either G-ribbons, lamellar G-dimer arrays or the G4 cation-free architectures.
Different substituted ferrocene−guanine conjugates were prepared, and their electrochemical behav... more Different substituted ferrocene−guanine conjugates were prepared, and their electrochemical behavior was investigated. A new approach for the introduction of ferrocene in guanine's 9-position through a quite effective S N 1-type reaction was disclosed. The electrochemical behavior of the various derivatives can be used as standard for the quantification and analysis of DNA strands.
Lipophilic guanilic derivatives (lipoGs) dissolved in organic solvents can undergo different self... more Lipophilic guanilic derivatives (lipoGs) dissolved in organic solvents can undergo different self-assembly pathways based on different H-bonded motifs, e.g., the cyclic discrete G-quartet, which forms in the presence of alkali-metal ions, and the "infinite" tape-like G-ribbon observed in the absence of ions. Using in-solution small-angle X-ray scattering, we analyzed a series of lipoGs dissolved in cyclohexane in the presence of different salts. The formation of G-quartet based supramolecular aggregates has been confirmed, evidencing the coexistence equilibrium of octamers and noncovalent molecular nanowires (the so-called G-quadruplexes). By global fitting the scattering data, the concentration of the two kinds of particles as well as the nanowire length have been derived as a function of temperature for the different compounds and salts. The thermodynamic parameters show that the self-assembly aggregation process is enthalpy driven, while the observed enthalpy-entropy compensation suggests that similar stacking interactions control the self-assembly of the different compounds. However, the strength of the stacking interactions, and then the nanowire stability, depends on the nature of templating cations and on their capacity to fill the central cavity of quadruplexes, with the order Sr(+) < Na(+) ≲ K(+).
Vascular and traumatic injuries of the central nervous system are recognized as global health pri... more Vascular and traumatic injuries of the central nervous system are recognized as global health priorities. A polypharmacology approach that is able to simultaneously target several injury factors by the combination of agents having synergistic effects appears to be promising. Herein, we designed a polymeric delivery system loaded with two drugs, ibuprofen (Ibu) and thyroid hormone triiodothyronine (T3) to in vitro release the suitable amount of the anti-inflammation and the remyelination drug. As a production method, electrospinning technology was used. First, Ibu-loaded micro (diameter circa 0.95–1.20 µm) and nano (diameter circa 0.70 µm) fibers were produced using poly(l-lactide) PLLA and PLGA with different lactide/glycolide ratios (50:50, 75:25, and 85:15) to select the most suitable polymer and fiber diameter. Based on the in vitro release results and in-house knowledge, PLLA nanofibers (mean diameter = 580 ± 120 nm) loaded with both Ibu and T3 were then successfully produced by...
International Review of Biophysical Chemistry, 2011
Depending on the experimental conditions, lipophilic guanosines (LipoGs) can undergo different se... more Depending on the experimental conditions, lipophilic guanosines (LipoGs) can undergo different self-assembly pathways based on different H-bonded motifs, e.g. the cyclic discrete G-quartet and the “infinite” tape-like G-ribbon. The switching between different supramolecular motifs have been obtained by a variety of external stimuli. After a general presentation of the LipoG self-assembly, in this mini-review we will discuss, the case of three different stimuli. A first example is represented by chemical stimuli: addition of an alkali metal ion stabilizes the G-quartet while its removal shifts the equilibrium toward the G-ribbon. In the second case, a lipoG armed with a terthiophene unit undergoes a pronounced variation of its supramolecular organisation by changing the polarity of the solvent: in chloroform the derivative assembles via H-bonding in a guanosine driven structure, while in the more polar (and H-bond competing) acetonitrile different aggregates are observed, where the t...
Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer... more Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi‐target‐directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD‐relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1‐based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4‐naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the “physicochemical challenge” typical of large hybrid‐based MTDLs. A preliminary investigation of their multi‐target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug‐like profile.
Alzheimer's disease represents an enormous global burden in terms of human suffering and econ... more Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.
The self-assembly of three novel lipophilic guanosine derivatives at the solid/liquid interface l... more The self-assembly of three novel lipophilic guanosine derivatives at the solid/liquid interface lead to the generation of either G-ribbons, lamellar G-dimer arrays or the G4 cation-free architectures.
Different substituted ferrocene−guanine conjugates were prepared, and their electrochemical behav... more Different substituted ferrocene−guanine conjugates were prepared, and their electrochemical behavior was investigated. A new approach for the introduction of ferrocene in guanine's 9-position through a quite effective S N 1-type reaction was disclosed. The electrochemical behavior of the various derivatives can be used as standard for the quantification and analysis of DNA strands.
Lipophilic guanilic derivatives (lipoGs) dissolved in organic solvents can undergo different self... more Lipophilic guanilic derivatives (lipoGs) dissolved in organic solvents can undergo different self-assembly pathways based on different H-bonded motifs, e.g., the cyclic discrete G-quartet, which forms in the presence of alkali-metal ions, and the "infinite" tape-like G-ribbon observed in the absence of ions. Using in-solution small-angle X-ray scattering, we analyzed a series of lipoGs dissolved in cyclohexane in the presence of different salts. The formation of G-quartet based supramolecular aggregates has been confirmed, evidencing the coexistence equilibrium of octamers and noncovalent molecular nanowires (the so-called G-quadruplexes). By global fitting the scattering data, the concentration of the two kinds of particles as well as the nanowire length have been derived as a function of temperature for the different compounds and salts. The thermodynamic parameters show that the self-assembly aggregation process is enthalpy driven, while the observed enthalpy-entropy compensation suggests that similar stacking interactions control the self-assembly of the different compounds. However, the strength of the stacking interactions, and then the nanowire stability, depends on the nature of templating cations and on their capacity to fill the central cavity of quadruplexes, with the order Sr(+) < Na(+) ≲ K(+).
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Papers by Rosaria Perone