Browsing by Author "Cerasa, Laura S."

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New Bifunctional Antioxidant/Σ1 Agonist Ligands: Preliminary Chemico-Physical and Biological Evaluation
(Pergamon-Elsevier Science Ltd, 2016) Arena, Emanuela; Cacciatore, Ivana; Cerasa, Laura S.; Turkez, Hasan; Pittala, Valeria; Pasquinucci, Lorella; Prezzavento, Orazio
We previously reported bifunctional sigma-1 (sigma(1)) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivatives (7, 12) were synthesized. sigma(1) and sigma(2) affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong sigma(1) affinity, displayed improved sigma(1) selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed sigma(1) agonist pharmacological profile. Chemico-physical studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives 7 and 12 being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on sigma(1) selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new very selective compounds 7 and 12 could be promising tools to investigate the disorders in which sigma(1) receptor dysfunction and oxidative stress are contemporarily involved. (C) 2016 Elsevier Ltd. All rights reserved.
Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer's Disease
(MDPI, 2016) Cacciatore, Ivana; Marinelli, Lisa; Fornasari, Erika; Cerasa, Laura S.; Eusepi, Piera; Turkez, Hasan; Di Stefano, Antonio
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4-9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)--lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and A(25-35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1 and TNF- in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD.
Synthesis of a Novel Cyclic Prodrug of S-Allyl Able to Attenuate LPS-Induced ROS Production Through the Inhibition of MAPK Pathways in U937 Cells
(Amer Chemical Soc, 2015) Patruno, Antonia; Fornasari, Erika; Di Stefano, Antonio; Cerasa, Laura S.; Marinelli, Lisa; Baldassarre, Leonardo; Cacciatore, Ivana
A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 X 10(-6) cm s(-1), it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.