Julia Lorenzo | Universitat Autònoma de Barcelona (original) (raw)
Papers by Julia Lorenzo
International Journal of Molecular Sciences
The need for non-invasive therapies capable of conserving drug efficiency and stability while hav... more The need for non-invasive therapies capable of conserving drug efficiency and stability while having specific targetability against colorectal cancer (CRC), has made nanoparticles preferable vehicles and principal building blocks for the development of complex and multi-action anti-tumoral approaches. For that purpose, we herein report the production of a combinatory anti-tumoral nanotherapy using the production of a new targeting towards CRC lines. To do so, Magneto-fluorescent NANO3 nanoparticles were used as nanocarriers for a combination of the drugs doxorubicin (DOX) and ofloxacin (OFLO). NANO3 nanoparticles’ surface was modified with two different targeting agents, a newly synthesized (anti-CA IX acetazolamide derivative (AZM-SH)) and a commercially available (anti-epidermal growth factor receptor (EGFR), Cetuximab). The cytotoxicity revealed that only DOX-containing nanosystems showed significant and even competitive cytotoxicity when compared to that of free DOX. Interesting...
Si bien los inhibidores de proteasas han sido considerados por mucho tiempo como factores anti-nu... more Si bien los inhibidores de proteasas han sido considerados por mucho tiempo como factores anti-nutricionales; estudios recientes han demostrado la capacidad de estas moleculas de resistir el proceso gastrointestinal, atravesar el tracto digestivo y llegar a la sangre de manera intacta. De este modo, podrian ejercer su actividad biologica en sangre y tejidos perifericos como moleculas anticancerigenas, antitromboticas, antimalaricas y antiangiogenicas, entre otras. Varias de estas actividades biologicas han sido descritas para los inhibidores de metalocarboxipeptidasas (IMCP). Los IMCPs estan escasamente investigados en el reino vegetal, la mayoria de ellos pertenece a la familia Solanaceae y poseen caracteristicas estructurales especiales que les proporcionan una extrema estabilidad biofisicoquimica. En este trabajo reportamos el aislamiento y purificacion parcial del primer IMCP aislado de Capsicum annuum al que denominamos YBPCI. El extracto crudo fue parcialmente purificado media...
Il a ete decouvert que l'inhibiteur proteique de la carboxypeptidase de la pomme de terre (PC... more Il a ete decouvert que l'inhibiteur proteique de la carboxypeptidase de la pomme de terre (PCI) inhibe la croissance du parasite Plasmodium falciparum responsable du paludisme. Concretement, la cible therapeutique a laquelle est associe cet inhibiteur PCI pour inhiber la croissance du parasite est une metallocarboxypeptidase de P. falciparum nommee PfNna1, ce qui transforme ladite metallocarboxypeptidase en une cible therapeutique utile pour identifier de nouveaux composes dans le traitement du paludisme.
Se ha descubierto que el inhibidor proteico de la carboxipeptidasa de patata (PCI) inhibe el crec... more Se ha descubierto que el inhibidor proteico de la carboxipeptidasa de patata (PCI) inhibe el crecimiento del parasito Plasmodium falciparum causante de malaria. En concreto, la diana terapeutica a la que se une dicho PCI para inhibir el crecimiento del parasito es una metalocarboxipeptidasa de P. falciparum denominada PfNnal, lo que convierte a dicha metalocarboxipeptidasa en una diana terapeutica util para identificar nuevos compuestos en el tratamiento de la malaria.
El cancer de pancreas presenta un pronostico desalentador con una incidencia creciente y un trata... more El cancer de pancreas presenta un pronostico desalentador con una incidencia creciente y un tratamiento inefectivo. El mal pronositco de este cancer se debe a la dificultad de ser diagnosticado proecozmente, ya que las manifestaciones iniciales de la enfermedad suelen ser vagas e inespecificas. En el momento del diagnostico un 85% de los pacientes presentan metastasis. El diagnostico precoz podria aumentar la eficacia de las medidas terapeuticas disponibles, por lo que el desarrollo de tests para el diagnositco precoz del cancer de pancreas es un objetivo importante. Desafortunadamente,no se han descrito marcadores tumorales especificos para esta neoplasia. La utilidad de los marcadores serologicos es limitada ya que el pancreas no es el unico tejido origen de estas enzimas, pero la busqueda de otras enizmas pacreaticas en suero con implicaciones diagnosticas ha sido en gran medida inutil. Nuestros esfuerzos se han basado en el estudio del sistema procarboxipeptidasa/carboxipeptidas...
Bioorganic & Medicinal Chemistry, Feb 1, 2008
The platinum(II) complex cis-[(1S,2R,3S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diamine]dichlor... more The platinum(II) complex cis-[(1S,2R,3S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diamine]dichloroplatinum(II) (1) and its enantiomer (2) have been synthesized and physically and spectroscopically characterized. To obtain the enantiopure complexes the chiral pool approach was applied. The synthetic pathway has four steps, starting from (+/-)-diphenylethylenediamine (DPEDA) (3) and the natural products (1S)-camphorquinone or (1R)-camphorquinone to obtain enantiomers 1 and 2, respectively. The interaction of the Pt(II) complexes with DNA was studied by several techniques: circular dichroism, electrophoresis on agarose gel and atomic force microscopy (AFM). These studies showed differences in the degree of interaction between both enantiomers and DNA (calf thymus DNA and plasmid pBR322 DNA). The cytotoxicity of enantiomers 1 and 2 against the HL-60 cell line was studied by in vitro tests of antiproliferative activity, incubating during both 24 h and 72 h. An important difference of activity was found between both enantiomers regarding the IC50 data at 24 h of incubation. Thus, complex 1 showed to be much more active than its enantiomer 2.
ChemBioChem, Oct 13, 2005
The synthesis and chemical characterization of two new trans platinum complexes, trans‐[PtCl2NH3(... more The synthesis and chemical characterization of two new trans platinum complexes, trans‐[PtCl2NH3(4‐hydroxymethylpyridine)] (1) and trans‐[PtCl4NH3(4‐hydroxymethylpyridine)] (2) are described. Their ability to interact with 5′‐GMP by themselves and in the presence of reducing agents in the case of trans‐[PtCl4NH3(4‐hydroxymethylpyridine)] were tested. Circular dichroism, electrophoretic mobility in agarose gel, and atomic force microscopy studies showed that the interaction of complex 1 with DNA is stronger than that of complex 2. Cytotoxicity tests against HL‐60 tumor cells also showed higher activity for trans‐[PtCl2NH3(4‐hydroxymethylpyridine)] than for trans‐[PtCl4NH3(4‐hydroxymethylpyridine)]. Complex 1 presents similar behavior to cisplatin, but with a lower IC50 at 24 h. Complex 1 also showed high apoptosis induction.
Inorganic Chemistry, Feb 17, 2021
Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold an... more Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold and bearing varying aromatic substituents (-H,-Cl,-Br) have been synthesized and characterized. The experimental and computational data obtained suggest that all three complexes exist in dimeric form in the solid state and adopt 2 the same conformation. MS and EPR results indicate that the dimeric structure coexists with the monomeric form in solution upon solvent (DMSO and water) coordination. The three synthesized Cu(II) complexes exhibit high potentiality as ROS generators, with the Cu(II)/Cu(I) redox potential inside the biological redox window, and thus being able to biologically undergo Cu(II)/Cu(I) redox cycling. The formation of ROS is one of the most promising reported cell-death mechanisms for metal complexes to offer an inherent selectivity to cancer cells. In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblasts cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 µM in HeLa cells, which is in the range of cisplatin and improved respect to carboplatin), hence placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds.
Biomaterials Science, 2019
A novel chemical approach integrating the benefits of nanoparticles with the versatility of coord... more A novel chemical approach integrating the benefits of nanoparticles with the versatility of coordination chemistry is reported here to increase the effectiveness of well-known HIV antiretroviral drugs. The novelty of our approach is illustrated using a catechol ligand tethered to the known antiretroviral AZT as a consitutive building block of the nanoparticles. The resulting nanoscale coordination polymers ensure good encapsulation yields and equivalent antiretroviral activity while significantly diminishing its cytotoxicity. Moreover, this novel family of nanoparticles also offer: i) long lasting drug release dissimilar inside and outside the cells depending on pH, ii) triggering in the presence of esterases, activating in an on-off manner the antiviral activity, thanks to a proper chemical design of the ligand and iii) improved colloidal stabilities and cellular uptakes (up to 50 fold increase). The presence of the iron nodes also adds multifunctionality as possible contrast agents. The present study demonstrates the suitability of NCPs bearing pharmacologically active ligands as an alternative to conventional antiretroviral treatments.
Cancers, Oct 10, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Chemico-Biological Interactions, Jun 1, 2019
Aldehyde dehydrogenases (ALDHs) are enzymes catalyzing the NAD(P)+-dependent oxidation of aldehyd... more Aldehyde dehydrogenases (ALDHs) are enzymes catalyzing the NAD(P)+-dependent oxidation of aldehydes to their corresponding carboxylic acids. High ALDH activity has been related to some important features of cancer stem cells. ALDH1A enzymes, involved in the retinoic acid signaling pathway, are promising drug targets for cancer therapy, and the design of selective ALDH1A inhibitors has a growing pharmacological interest. In the present work, two already known compounds (DEAB and WIN 18,446) and novel thiazolidinedione and pyrimido quinoline acetic acid derivatives (compounds 5a and 64, formerly described as aldo-keto reductase inhibitors) were tested as inhibitors of the ALDH1A enzymes (namely, ALDH1A1, ALDH1A2 and ALDH1A3) as a first step to develop some potential drugs for cancer therapy. The inhibitory capacity of these compounds against the ALDH1A activity was characterized in vitro by using purified recombinant proteins. The IC50 values of each compound were determined indicating that the most potent inhibitors against ALDH1A1, ALDH1A2 and ALDH1A3 were DEAB, WIN 18,446 and compound 64, respectively. Type of inhibition and Ki values were determined for DEAB against ALDH1A1 (competitive, Ki = 0.13 μM) and compound 64 against ALDH1A3 (non-competitive, Ki = 1.77 μM). The effect of these inhibitors on A549 human lung cancer cell viability was assessed, being compound 64 the only inhibitor showing an important reduction of cell survival. We also tested the effect of the ALDH substrate, retinaldehyde, which was cytotoxic above 10 μM. This toxicity was enhanced in the presence of DEAB. Both DEAB and compound 64 were able to inhibit the ALDH1A activity in A549 cells. The current work suggests that, by blocking ALDH activity, drug inactivation may be avoided. Thus these results may be relevant to design novel combination therapies to fight cancer cell chemoresistance, using both enzyme inhibitors and chemotherapeutic agents.
Inorganic Chemistry, Jul 1, 2008
The new complexes [Pd(dmba)( N10-9AA)(PPh 3)]ClO 4 ( 1), [Pt(dmba)( N9-9AA)(PPh 3)]ClO 4 ( 2), [P... more The new complexes [Pd(dmba)( N10-9AA)(PPh 3)]ClO 4 ( 1), [Pt(dmba)( N9-9AA)(PPh 3)]ClO 4 ( 2), [Pd(dmba)( N10-9AA)Cl] ( 3), and [Pd(C 6F 5)( N10-9AA)(PPh 3)Cl] ( 4) (9-AA = 9-aminoacridine; dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl) have been prepared. The crystal structures have been established by X-ray diffraction. In complex 2, an anagostic C-H...Pt interaction is observed. All complexes are luminescent in the solid state at room temperature, showing important differences between the palladium and platinum complexes. Complex 2 shows two structured emission bands at high and low energies in the solid state, and the lifetimes are in agreement with excited states of triplet parentage. Density functional theory and time-dependent density functional theory calculations for complex 2 have been done. Values of IC 50 were also calculated for the new complexes 1- 4 against the tumor cell line HL-60. All of the new complexes were more active than cisplatin (up to 30-fold in some cases). The DNA adduct formation of the new complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the complexes on plasmid DNA pB R322 were also obtained.
Tercera Época, Nov 1, 2014
LIST OF ABBREVIATIONS ACE Angiotensin-converting enzyme APR Aggregation prone region CCP Cytosoli... more LIST OF ABBREVIATIONS ACE Angiotensin-converting enzyme APR Aggregation prone region CCP Cytosolic carboxypeptidase CD Catalytic domain COFRADIC COmbined FRActional DIagonal Chromatography CP Carboxypeptidase CPs Carboxypeptidases CPAs A-type carboxypeptidases CPA1 Carboxypeptidase A1 CPA2 Carboxypeptidase A2 CPA3 Carboxypeptidase A3 CPA4 Carboxypeptidase A4 CPA6 Carboxypeptidase A6 CPB Carboxypeptidase B CPU Carboxypeptidase U Opioid Pro-enkephalyn (PENK), pro-opiomelanocortin (POMC) Vasopresin/Oxitocin Vasopresin (AVP), Oxytocin (OXT) CCK/Gastrin Gastrin (GAST), Cholecystokinin (CCK) Oxitocin Somatostatin (SST), Cortistatin (CST) F and Y amide Neuropetide FF (NPFF), Neuropeptide Y (NPY) Calcitonin Calcitonin (CALCA), Adrenomedullin (ADM) Natriuretic Factor Atrial natriuretic factor (NPPA), Brain natriuretic factor (NPPB) Bombesin like Gastrin releasing peptide (GRP), Neuromedin B (NMB) Endotelin Endotelin 1-3 (END 1-3) Glucagon/Secretin Glucagon (CGC), Secretin (SCT), Vasoactive intestinal peptide (VIP) CRH Corticotropin releasing hormone (CRH), Urocortin (UCN), Urotensin (VTS) Kinin Pre-protachykinin A and B (TAC 1 y TAC 3) Neuromedin Neuromedin S (NMS), Neuromedin U (NMU) Tensins / Kinins Angiotensin (AGT), Neurotensin (NTS) Granins Chromogranin A (CHGA), Chromogranin B (CHGB), Secretogranin (SCG) Motilin Motilin (MLN), Ghrelin (GHRL)
The synthesis, full characterization, photochemical properties, and cytotoxic activity toward cis... more The synthesis, full characterization, photochemical properties, and cytotoxic activity toward cisplatin-resistant cancer cell lines of new semisquaraine-type Pt(II) complexes are presented. The synthesis of eight semisquaraine-type ligands has been carried out by means of an innovative, straightforward methodology. A thorough structural NMR and X-ray diffraction analysis of the new ligands and complexes has been done. Density functional theory calculations have allowed to assign the trans configuration of the platinum center. Through the structural modification of the ligands, it has been possible to synthesize some complexes, which have turned out to be photoactive at wavelengths that allow their activation in cell cultures and, importantly, two of them show remarkable solubility in biological media. Photodegradation processes have been studied in depth, including the structural identification of photoproducts, thus justifying the changes observed after irradiation. From biological assessment, complexes C7 and C8 have been demonstrated to behave as promising photoactivatable compounds in the assayed cancer cell lines. Upon photoactivation, both complexes are capable of inducing a higher cytotoxic effect on the tested cells compared with nonphotoactivated compounds. Among the observed results, it is remarkable to note that C7 showed a PI > 50 in HeLa cells, and C8 showed a PI > 40 in A2780 cells, being also effective over cisplatin-resistant A2780cis cells (PI = 7 and PI = 4, respectively). The mechanism of action of these complexes has been studied, revealing that these photoactivated platinum complexes would actually present a combined mode of action, a therapeutically potential advantage.
Oficina Española de Patentes y Marcas, Jul 20, 2015
International Journal of Molecular Sciences
The need for non-invasive therapies capable of conserving drug efficiency and stability while hav... more The need for non-invasive therapies capable of conserving drug efficiency and stability while having specific targetability against colorectal cancer (CRC), has made nanoparticles preferable vehicles and principal building blocks for the development of complex and multi-action anti-tumoral approaches. For that purpose, we herein report the production of a combinatory anti-tumoral nanotherapy using the production of a new targeting towards CRC lines. To do so, Magneto-fluorescent NANO3 nanoparticles were used as nanocarriers for a combination of the drugs doxorubicin (DOX) and ofloxacin (OFLO). NANO3 nanoparticles’ surface was modified with two different targeting agents, a newly synthesized (anti-CA IX acetazolamide derivative (AZM-SH)) and a commercially available (anti-epidermal growth factor receptor (EGFR), Cetuximab). The cytotoxicity revealed that only DOX-containing nanosystems showed significant and even competitive cytotoxicity when compared to that of free DOX. Interesting...
Si bien los inhibidores de proteasas han sido considerados por mucho tiempo como factores anti-nu... more Si bien los inhibidores de proteasas han sido considerados por mucho tiempo como factores anti-nutricionales; estudios recientes han demostrado la capacidad de estas moleculas de resistir el proceso gastrointestinal, atravesar el tracto digestivo y llegar a la sangre de manera intacta. De este modo, podrian ejercer su actividad biologica en sangre y tejidos perifericos como moleculas anticancerigenas, antitromboticas, antimalaricas y antiangiogenicas, entre otras. Varias de estas actividades biologicas han sido descritas para los inhibidores de metalocarboxipeptidasas (IMCP). Los IMCPs estan escasamente investigados en el reino vegetal, la mayoria de ellos pertenece a la familia Solanaceae y poseen caracteristicas estructurales especiales que les proporcionan una extrema estabilidad biofisicoquimica. En este trabajo reportamos el aislamiento y purificacion parcial del primer IMCP aislado de Capsicum annuum al que denominamos YBPCI. El extracto crudo fue parcialmente purificado media...
Il a ete decouvert que l'inhibiteur proteique de la carboxypeptidase de la pomme de terre (PC... more Il a ete decouvert que l'inhibiteur proteique de la carboxypeptidase de la pomme de terre (PCI) inhibe la croissance du parasite Plasmodium falciparum responsable du paludisme. Concretement, la cible therapeutique a laquelle est associe cet inhibiteur PCI pour inhiber la croissance du parasite est une metallocarboxypeptidase de P. falciparum nommee PfNna1, ce qui transforme ladite metallocarboxypeptidase en une cible therapeutique utile pour identifier de nouveaux composes dans le traitement du paludisme.
Se ha descubierto que el inhibidor proteico de la carboxipeptidasa de patata (PCI) inhibe el crec... more Se ha descubierto que el inhibidor proteico de la carboxipeptidasa de patata (PCI) inhibe el crecimiento del parasito Plasmodium falciparum causante de malaria. En concreto, la diana terapeutica a la que se une dicho PCI para inhibir el crecimiento del parasito es una metalocarboxipeptidasa de P. falciparum denominada PfNnal, lo que convierte a dicha metalocarboxipeptidasa en una diana terapeutica util para identificar nuevos compuestos en el tratamiento de la malaria.
El cancer de pancreas presenta un pronostico desalentador con una incidencia creciente y un trata... more El cancer de pancreas presenta un pronostico desalentador con una incidencia creciente y un tratamiento inefectivo. El mal pronositco de este cancer se debe a la dificultad de ser diagnosticado proecozmente, ya que las manifestaciones iniciales de la enfermedad suelen ser vagas e inespecificas. En el momento del diagnostico un 85% de los pacientes presentan metastasis. El diagnostico precoz podria aumentar la eficacia de las medidas terapeuticas disponibles, por lo que el desarrollo de tests para el diagnositco precoz del cancer de pancreas es un objetivo importante. Desafortunadamente,no se han descrito marcadores tumorales especificos para esta neoplasia. La utilidad de los marcadores serologicos es limitada ya que el pancreas no es el unico tejido origen de estas enzimas, pero la busqueda de otras enizmas pacreaticas en suero con implicaciones diagnosticas ha sido en gran medida inutil. Nuestros esfuerzos se han basado en el estudio del sistema procarboxipeptidasa/carboxipeptidas...
Bioorganic & Medicinal Chemistry, Feb 1, 2008
The platinum(II) complex cis-[(1S,2R,3S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diamine]dichlor... more The platinum(II) complex cis-[(1S,2R,3S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diamine]dichloroplatinum(II) (1) and its enantiomer (2) have been synthesized and physically and spectroscopically characterized. To obtain the enantiopure complexes the chiral pool approach was applied. The synthetic pathway has four steps, starting from (+/-)-diphenylethylenediamine (DPEDA) (3) and the natural products (1S)-camphorquinone or (1R)-camphorquinone to obtain enantiomers 1 and 2, respectively. The interaction of the Pt(II) complexes with DNA was studied by several techniques: circular dichroism, electrophoresis on agarose gel and atomic force microscopy (AFM). These studies showed differences in the degree of interaction between both enantiomers and DNA (calf thymus DNA and plasmid pBR322 DNA). The cytotoxicity of enantiomers 1 and 2 against the HL-60 cell line was studied by in vitro tests of antiproliferative activity, incubating during both 24 h and 72 h. An important difference of activity was found between both enantiomers regarding the IC50 data at 24 h of incubation. Thus, complex 1 showed to be much more active than its enantiomer 2.
ChemBioChem, Oct 13, 2005
The synthesis and chemical characterization of two new trans platinum complexes, trans‐[PtCl2NH3(... more The synthesis and chemical characterization of two new trans platinum complexes, trans‐[PtCl2NH3(4‐hydroxymethylpyridine)] (1) and trans‐[PtCl4NH3(4‐hydroxymethylpyridine)] (2) are described. Their ability to interact with 5′‐GMP by themselves and in the presence of reducing agents in the case of trans‐[PtCl4NH3(4‐hydroxymethylpyridine)] were tested. Circular dichroism, electrophoretic mobility in agarose gel, and atomic force microscopy studies showed that the interaction of complex 1 with DNA is stronger than that of complex 2. Cytotoxicity tests against HL‐60 tumor cells also showed higher activity for trans‐[PtCl2NH3(4‐hydroxymethylpyridine)] than for trans‐[PtCl4NH3(4‐hydroxymethylpyridine)]. Complex 1 presents similar behavior to cisplatin, but with a lower IC50 at 24 h. Complex 1 also showed high apoptosis induction.
Inorganic Chemistry, Feb 17, 2021
Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold an... more Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold and bearing varying aromatic substituents (-H,-Cl,-Br) have been synthesized and characterized. The experimental and computational data obtained suggest that all three complexes exist in dimeric form in the solid state and adopt 2 the same conformation. MS and EPR results indicate that the dimeric structure coexists with the monomeric form in solution upon solvent (DMSO and water) coordination. The three synthesized Cu(II) complexes exhibit high potentiality as ROS generators, with the Cu(II)/Cu(I) redox potential inside the biological redox window, and thus being able to biologically undergo Cu(II)/Cu(I) redox cycling. The formation of ROS is one of the most promising reported cell-death mechanisms for metal complexes to offer an inherent selectivity to cancer cells. In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblasts cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 µM in HeLa cells, which is in the range of cisplatin and improved respect to carboplatin), hence placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds.
Biomaterials Science, 2019
A novel chemical approach integrating the benefits of nanoparticles with the versatility of coord... more A novel chemical approach integrating the benefits of nanoparticles with the versatility of coordination chemistry is reported here to increase the effectiveness of well-known HIV antiretroviral drugs. The novelty of our approach is illustrated using a catechol ligand tethered to the known antiretroviral AZT as a consitutive building block of the nanoparticles. The resulting nanoscale coordination polymers ensure good encapsulation yields and equivalent antiretroviral activity while significantly diminishing its cytotoxicity. Moreover, this novel family of nanoparticles also offer: i) long lasting drug release dissimilar inside and outside the cells depending on pH, ii) triggering in the presence of esterases, activating in an on-off manner the antiviral activity, thanks to a proper chemical design of the ligand and iii) improved colloidal stabilities and cellular uptakes (up to 50 fold increase). The presence of the iron nodes also adds multifunctionality as possible contrast agents. The present study demonstrates the suitability of NCPs bearing pharmacologically active ligands as an alternative to conventional antiretroviral treatments.
Cancers, Oct 10, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Chemico-Biological Interactions, Jun 1, 2019
Aldehyde dehydrogenases (ALDHs) are enzymes catalyzing the NAD(P)+-dependent oxidation of aldehyd... more Aldehyde dehydrogenases (ALDHs) are enzymes catalyzing the NAD(P)+-dependent oxidation of aldehydes to their corresponding carboxylic acids. High ALDH activity has been related to some important features of cancer stem cells. ALDH1A enzymes, involved in the retinoic acid signaling pathway, are promising drug targets for cancer therapy, and the design of selective ALDH1A inhibitors has a growing pharmacological interest. In the present work, two already known compounds (DEAB and WIN 18,446) and novel thiazolidinedione and pyrimido quinoline acetic acid derivatives (compounds 5a and 64, formerly described as aldo-keto reductase inhibitors) were tested as inhibitors of the ALDH1A enzymes (namely, ALDH1A1, ALDH1A2 and ALDH1A3) as a first step to develop some potential drugs for cancer therapy. The inhibitory capacity of these compounds against the ALDH1A activity was characterized in vitro by using purified recombinant proteins. The IC50 values of each compound were determined indicating that the most potent inhibitors against ALDH1A1, ALDH1A2 and ALDH1A3 were DEAB, WIN 18,446 and compound 64, respectively. Type of inhibition and Ki values were determined for DEAB against ALDH1A1 (competitive, Ki = 0.13 μM) and compound 64 against ALDH1A3 (non-competitive, Ki = 1.77 μM). The effect of these inhibitors on A549 human lung cancer cell viability was assessed, being compound 64 the only inhibitor showing an important reduction of cell survival. We also tested the effect of the ALDH substrate, retinaldehyde, which was cytotoxic above 10 μM. This toxicity was enhanced in the presence of DEAB. Both DEAB and compound 64 were able to inhibit the ALDH1A activity in A549 cells. The current work suggests that, by blocking ALDH activity, drug inactivation may be avoided. Thus these results may be relevant to design novel combination therapies to fight cancer cell chemoresistance, using both enzyme inhibitors and chemotherapeutic agents.
Inorganic Chemistry, Jul 1, 2008
The new complexes [Pd(dmba)( N10-9AA)(PPh 3)]ClO 4 ( 1), [Pt(dmba)( N9-9AA)(PPh 3)]ClO 4 ( 2), [P... more The new complexes [Pd(dmba)( N10-9AA)(PPh 3)]ClO 4 ( 1), [Pt(dmba)( N9-9AA)(PPh 3)]ClO 4 ( 2), [Pd(dmba)( N10-9AA)Cl] ( 3), and [Pd(C 6F 5)( N10-9AA)(PPh 3)Cl] ( 4) (9-AA = 9-aminoacridine; dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl) have been prepared. The crystal structures have been established by X-ray diffraction. In complex 2, an anagostic C-H...Pt interaction is observed. All complexes are luminescent in the solid state at room temperature, showing important differences between the palladium and platinum complexes. Complex 2 shows two structured emission bands at high and low energies in the solid state, and the lifetimes are in agreement with excited states of triplet parentage. Density functional theory and time-dependent density functional theory calculations for complex 2 have been done. Values of IC 50 were also calculated for the new complexes 1- 4 against the tumor cell line HL-60. All of the new complexes were more active than cisplatin (up to 30-fold in some cases). The DNA adduct formation of the new complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the complexes on plasmid DNA pB R322 were also obtained.
Tercera Época, Nov 1, 2014
LIST OF ABBREVIATIONS ACE Angiotensin-converting enzyme APR Aggregation prone region CCP Cytosoli... more LIST OF ABBREVIATIONS ACE Angiotensin-converting enzyme APR Aggregation prone region CCP Cytosolic carboxypeptidase CD Catalytic domain COFRADIC COmbined FRActional DIagonal Chromatography CP Carboxypeptidase CPs Carboxypeptidases CPAs A-type carboxypeptidases CPA1 Carboxypeptidase A1 CPA2 Carboxypeptidase A2 CPA3 Carboxypeptidase A3 CPA4 Carboxypeptidase A4 CPA6 Carboxypeptidase A6 CPB Carboxypeptidase B CPU Carboxypeptidase U Opioid Pro-enkephalyn (PENK), pro-opiomelanocortin (POMC) Vasopresin/Oxitocin Vasopresin (AVP), Oxytocin (OXT) CCK/Gastrin Gastrin (GAST), Cholecystokinin (CCK) Oxitocin Somatostatin (SST), Cortistatin (CST) F and Y amide Neuropetide FF (NPFF), Neuropeptide Y (NPY) Calcitonin Calcitonin (CALCA), Adrenomedullin (ADM) Natriuretic Factor Atrial natriuretic factor (NPPA), Brain natriuretic factor (NPPB) Bombesin like Gastrin releasing peptide (GRP), Neuromedin B (NMB) Endotelin Endotelin 1-3 (END 1-3) Glucagon/Secretin Glucagon (CGC), Secretin (SCT), Vasoactive intestinal peptide (VIP) CRH Corticotropin releasing hormone (CRH), Urocortin (UCN), Urotensin (VTS) Kinin Pre-protachykinin A and B (TAC 1 y TAC 3) Neuromedin Neuromedin S (NMS), Neuromedin U (NMU) Tensins / Kinins Angiotensin (AGT), Neurotensin (NTS) Granins Chromogranin A (CHGA), Chromogranin B (CHGB), Secretogranin (SCG) Motilin Motilin (MLN), Ghrelin (GHRL)
The synthesis, full characterization, photochemical properties, and cytotoxic activity toward cis... more The synthesis, full characterization, photochemical properties, and cytotoxic activity toward cisplatin-resistant cancer cell lines of new semisquaraine-type Pt(II) complexes are presented. The synthesis of eight semisquaraine-type ligands has been carried out by means of an innovative, straightforward methodology. A thorough structural NMR and X-ray diffraction analysis of the new ligands and complexes has been done. Density functional theory calculations have allowed to assign the trans configuration of the platinum center. Through the structural modification of the ligands, it has been possible to synthesize some complexes, which have turned out to be photoactive at wavelengths that allow their activation in cell cultures and, importantly, two of them show remarkable solubility in biological media. Photodegradation processes have been studied in depth, including the structural identification of photoproducts, thus justifying the changes observed after irradiation. From biological assessment, complexes C7 and C8 have been demonstrated to behave as promising photoactivatable compounds in the assayed cancer cell lines. Upon photoactivation, both complexes are capable of inducing a higher cytotoxic effect on the tested cells compared with nonphotoactivated compounds. Among the observed results, it is remarkable to note that C7 showed a PI > 50 in HeLa cells, and C8 showed a PI > 40 in A2780 cells, being also effective over cisplatin-resistant A2780cis cells (PI = 7 and PI = 4, respectively). The mechanism of action of these complexes has been studied, revealing that these photoactivated platinum complexes would actually present a combined mode of action, a therapeutically potential advantage.
Oficina Española de Patentes y Marcas, Jul 20, 2015