Browsing by Author "Recabarren-Gajardo, Gonzalo"

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    Comparison between poly(azomethine)s and poly(p-phenylvinylene)s containing a di-R-diphenylsilane (R = methyl or phenyl) moiety. Optical, electronic and thermal properties
    (2021) Sobarzo, Patricio A.; Mariman, Andrea P.; Sanchez, Christian O.; Hauyon, Rene A.; Rodriguez-Gonzalez, Fidel E.; Medina, Jean; Jessop, Ignacio A.; Recabarren-Gajardo, Gonzalo; Tundidor-Camba, Alain; Terraza, Claudio A.
    Two new silicon-containing poly(azomethine)s (PAzM-Me and PAzM-Ph) and two new silicon-containing poly(pphenylvinylene)s (PPVSi-Me and PPVSi-Ph) were obtained from 4',4'''-(dimethylsilanediyl)bis([1,1 '-biphenyl]-4-carbaldehyde) and 4',4'''-(diphenyl silanediyl)bis([1,1 '-biphenyl]-4-carbaldehyde) with p-phenylendiamine for PAzMs or phenylenebis(methylene))bis(triphenylphosphonium) bromide for PPVSis. All polymers were structurally characterized by FT-IR, NMR and elemental analysis. The materials showed a high thermal stability (501-538 degrees C) with the TPS-core increasing this parameter. The absorption and emission of PAzMs and PPVSis were closely related with the nature of the silane-core in the backbone. All samples showed wide-band gaps where the TPS-core-based materials evidenced the lower energy transitions; PAzM-Ph (2.83 eV) and PPVSi-Ph (2.81 eV). This work lay the groundwork for new architectures of silane-based poly(azomethine)s and poly(p- phenylvinylene)s derivatives for potential optoelectronic applications.
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    Design of an innovative nanovehicle to enhance brain permeability of a novel 5-HT6 receptor antagonist
    (2024) Alvarez-Figueroa, Maria Javiera; Nunez-Navarro, Francisco; Recabarren-Gajardo, Gonzalo; Gonzalez-Aramundiz, Jose Vicente
    An innovative nanovehicle based on lipid nanocapsules (LNC) was designed to facilitate the passage of a new 5HT6 receptor antagonist, namely PUC-10, through the blood-brain barrier. PUC-10 is a new synthetic N-arylsulfonylindole that has demonstrated potent 5-HT6 receptor antagonist activity, but it exhibits poor solubility in water, which indicates limited absorption. The lipid nanocapsules designed had a nanometric size (53 nm), a monomodal distribution (PI<0.2), a negative Z potential (-17 +/- 7 mV) and allowed efficient PUC-10 encapsulation (74 %). Furthermore, the LNC demonstrated to be stable for at least 4 weeks at 4( degrees)C (storage conditions), for at least 4 h in DMEM at pH 7.4, and for 18 h in water with 5 % DMSO, with both latter conditions maintained at 37 C-degrees. They also demonstrated that cell viability was not affected at the different concentrations studied. Finally, in vitro studies that simulate the blood brain barrier (PAMPA-BBB) demonstrated that the nanoencapsulation of PUC-10 promoted their penetration through the blood-brain barrier, with a calculated permeability of 1.3 x 10(- 8 )cm/s, compared to the null permeability exhibited by non-nanoencapsulated PUC-10.
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    Design of benzimidazoles, benzoxazoles, benzothiazoles and thiazolopyridines as leukotriene A4 hydrolase inhibitors through 3D-QSAR, docking and molecular dynamics
    (2023) Lorca, Marcos; Faundez, Mario; Pessoa-Mahana, C. David; Recabarren-Gajardo, Gonzalo; Diethelm-Varela, Benjamin; Millan, Daniela; Celik, Ismail; Mellado, Marco; Araque, Ileana; Mella, Jaime; Romero-Parra, Javier
    Human leukotriene A4 hydrolase enzyme (LTA4H) catalyses the biotransformation of the inactive precursor leukotriene A4 (LTA4) to the bioactive Leukotriene B4 (LTB4), which causes many inflammatory responses in the human body. Therefore, the selective inhibition of this enzyme becomes a useful strategy for the treatment of several illnesses such as asthma, allergic rhinitis, cardiovascular diseases, and cancer. Herein we report a 3D-QSAR/ /CoMFA and CoMSIA study on a series of 47 benzimidazoles, benzoxazoles, benzothiazoles and thiazolopyridines reported as potent LTA4H inhibitors. Good statistical parameters were obtained for the best model (q2 = 0.568, r2 ncv = 0.891 and r2 test = 0.851). A new series of 10 compounds capable of inhibiting leukotriene A4 hydrolase with high potency was presented. All designed inhibitors showed low IC50 in nano- and sub-nanomolar ranges, when they were evaluated in 3D-QSAR models. Subsequently, the designed molecules, as well as the least and most active compounds were subjected to docking and molecular dynamics studies into LTA4H. In conclusion, we summarised a thorough structure-activity relationship (SAR) of LTA4H inhibitors of heterocyclic structure. These models can be used for the rational proposal of new inhibitors.
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    Molecular and physiological analysis of indole-3-acetic acid degradation in Bradyrhizobium japonicum E109
    (2021) Torres, Daniela; Mongiardini, Elias; Donadio, Florencia; Donoso, Raul; Recabarren-Gajardo, Gonzalo; Gualpa, Jose; Spaepen, Stijn; Defez, Roberto; Lopez, Gaston; Bianco, Carmen; Cassan, Fabricio
    Bradyrhizobium japonicum E109 is a bacterium widely used for inoculants production in Argentina. It is known for its ability to produce several phytohormones and degrade indole-3-acetic acid (IAA). The genome sequence of B. japonicum E109 was recently analyzed and it showed the presence of genes related to the synthesis of IAA by indole-3-acetonitrile, indole-3-acetamide and tryptamine pathways. Nevertheless, B. japonicum E109 is not able to produce IAA and instead has the ability to degrade this hormone under saprophytic culture conditions. This work aimed to study the molecular and physio-logical features of IAA degradation and identify the genes responsible of this activity. In B. japonicum E109 we identified two sequences coding for a putative 3-phenylpropionate dioxygenase (subunits a and b) responsible for the IAA degradation that were homologous to the canonical cluster of iacC and iacD of Pseudomonas putida 1290. These genes form a separate cluster together with three additional genes with unknown functions. The degradation activity was found to be constitutively expressed in B. japonicum E109. As products of IAA degradation, we identified two compounds, 3-indoleacetic acid 2,3-oxide and 2-(2-hydroperoxy-3-hydroxyindolin-3-yl) acetic acid. Our report proposes, for the first time, a model for IAA degradation in Bradyrhizobium.
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    Novel 5-HT6R modulators as mTOR-dependent neuronal autophagy inductors
    (Nature Portafolio, 2025) Alcaino Vergara, Jose Miguel; Vera, Gonzalo; Almarza, Gonzalo; Lagos, Carlos F.; Terraza Inostroza, Claudio; Del Campo Sfeir, Andrea; Recabarren-Gajardo, Gonzalo
    Autophagy is a natural process in which the cell degrades substances through the lysosomal pathway. One of the most studied mechanisms for regulating autophagy is the mTOR signaling pathway. Recent research has shown that the 5-HT6 receptor is linked to the mTOR pathway and can affect cognition in various neurodevelopmental models. Therefore, developing 5-HT6 receptor antagonists could improve cognition by inducing autophagy through the inhibition of the mTOR pathway. Our study reports two in-house-designed 5-HT6R antagonists, PUC-10 and its indazole analogue PUC-55, that induce mTOR-dependent autophagy. PUC-10, an indole-based 5-HT6 receptor antagonist with high binding affinity (K-i = 14.6 nM) and antagonist potency (IC50 = 32 nM), demonstrated more than 90% at 25 mu M cellular viability and a high capacity to induce autophagy in the neuroblastoma SH-SY5Y cell line. Similarly, its indazole analogue, PUC-55 (K-i = 37.5 nM), exhibited high cellular viability and potent autophagy-inducing activity. Both compounds induced overexpression of the 5-HT6 receptor after 24 h of stimulation, contrasting with the effects observed with Rapamycin (100 nM), a well-known mTOR inhibitor. Additionally, the signaling pathway was characterized, showing that both PUC-10 and PUC-55 induce autophagy by inhibiting the mTOR pathway, suggesting their potential therapeutic applications for neurological disorders.
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    Novel 5-HT6R modulators as mTOR-dependent neuronal autophagy inductors
    (2025) Alcaino Vergara, Jose Miguel; Vera, Gonzalo; Almarza, Gonzalo; Lagos, Carlos F.; Terraza Inostroza, Claudio; Del Campo Sfeir, Andrea; Recabarren-Gajardo, Gonzalo
    Autophagy is a natural process in which the cell degrades substances through the lysosomal pathway. One of the most studied mechanisms for regulating autophagy is the mTOR signaling pathway. Recent research has shown that the 5-HT6 receptor is linked to the mTOR pathway and can affect cognition in various neurodevelopmental models. Therefore, developing 5-HT6 receptor antagonists could improve cognition by inducing autophagy through the inhibition of the mTOR pathway. Our study reports two in-house-designed 5-HT6R antagonists, PUC-10 and its indazole analogue PUC-55, that induce mTOR-dependent autophagy. PUC-10, an indole-based 5-HT6 receptor antagonist with high binding affinity (K-i = 14.6 nM) and antagonist potency (IC50 = 32 nM), demonstrated more than 90% at 25 mu M cellular viability and a high capacity to induce autophagy in the neuroblastoma SH-SY5Y cell line. Similarly, its indazole analogue, PUC-55 (K-i = 37.5 nM), exhibited high cellular viability and potent autophagy-inducing activity. Both compounds induced overexpression of the 5-HT6 receptor after 24 h of stimulation, contrasting with the effects observed with Rapamycin (100 nM), a well-known mTOR inhibitor. Additionally, the signaling pathway was characterized, showing that both PUC-10 and PUC-55 induce autophagy by inhibiting the mTOR pathway, suggesting their potential therapeutic applications for neurological disorders.
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    Novel N-Arylsulfonylindoles Targeted as Ligands of the 5-HT6 Receptor. Insights on the Influence of C-5 Substitution on Ligand Affinity
    (2021) Arrieta-Rodriguez, Loreto; Espinoza-Rosales, Daniela; Vera, Gonzalo; Cho, Young Hwa; Cabezas, David; Vasquez-Velasquez, David; Mella-Raipan, Jaime; Lagos, Carlos F.; Recabarren-Gajardo, Gonzalo
    A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (K-i = 58-403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q(2) (0.653; 0.692) and r(2) (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature.
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    Synthesis and Biological Screening of Novel Indolalkyl Arenes Targeting the Serotonine Transporter
    (2014) Ojeda-Gomez, Claudia; Pessoa-Mahana, Hernan; Iturriaga-Vasquez, Patricio; David Pessoa-Mahana, Carlos; Recabarren-Gajardo, Gonzalo; Mendez-Rojas, Claudio
    A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K-i=33.0, 48.0, and 17nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.