Examinando por Autor "Navas, Francisco"

Mostrando 1 - 8 de 8

Enhanced Cytotoxicity and Reactivity of a Novel Platinum(IV) Family with DNA-Targeting Naphthalimide Ligands
(American Chemical Society, 2017-05-10) Navas, Francisco; Mendes, Filipa; Santos, Isabel; Navarro-Ranninger, Carmen; Cabrera, Silvia; Gómez Quiroga, Adoración
Pt(IV) complexes are known as prodrugs that can potentially overcome cisplatin limitations by slowing down its reactivity, and once reduced, act as the corresponding Pt(II) drugs. We report a new approach towards trans Pt(IV) complexes, conceived to afford nonconventional active trans Pt(II) complexes with dual targeting properties. The reduction of the complexes has been studied in the presence of ascorbic acid and glutathione, showing that different species are formed in the process. The interaction with DNA after reduction has been also studied and correlated to the formation of Pt(II) species. The cytotoxicity profile of the Pt(IV) complexes corroborated the rationale behind this approach.
Increasing DNA reactivity and in vitro antitumor activity of trans diiodido Pt(II) complexes with UVA light
(Elsevier Sciencie Inc., 2015-07-21) Navas, Francisco; Perfhal, Stefanie; Garino, Claudio; Salassa, Luca; Novakova, Olga; Navarro-Ranninger, Carmen; Bednarski, Patrick J.; Malina, Jaroslav; Gómez Quiroga, Adoración
Trans diiodido platinum(II) complexes bearing the same as well as different aliphatic amines (mixed-amines) have interesting biological activity; cytotoxicity and interactions with some important biological models have already been demonstrated. Herein we described the interaction of such compounds with ct-DNA, supercoiled and linearized plasmid DNA and 5-GMP. Interestingly, UV irradiation of these compounds results in an increase in reactivity towards DNA and 5-GMP in such model systems. Additionally, the cytotoxicity of the trans-Pt(II) complexes towards human cancer cells is noticeably increased when treatment is combined for 90 min with UVA-irradiation. With this work we provide evidence that trans diiodido compounds can be activated by UVlight over relatively short treatment times.
Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery
(MDPI (Multidisciplinary Digital Publishing Institute), 2021-07-26) Martínez Erro, Samuel; Navas, Francisco; Romaní Cubells, Eva; Fernández García, Paloma; Morales, Victoria; Sanz, Raúl; García Muñoz, Rafael Á.
Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.
L‑arginine‑containing mesoporous silica nanoparticles embedded in dental adhesive (Arg@MSN@DAdh) for targeting cariogenic bacteria
(BioMed Central, 2022-12-01) López Ruíz, Marta; Navas, Francisco; Fernández García, Paloma; Martínez Erro, Samuel; Fuentes, María Victoria; Giráldez, isabeI; Ceballos, Laura; Ferrer Luque, Carmen María; Ruíz Linares, Matilde; Morales, Victoria; Sanz, Raúl; García Muñoz, Rafael Á.
Dental caries is the major biofilm-mediated oral disease in the world. The main treatment to restore caries lesions consists of the use of adhesive resin composites due to their good properties. However, the progressive degradation of the adhesive in the medium term makes possible the proliferation of cariogenic bacteria allowing secondary caries to emerge. In this study, a dental adhesive incorporating a drug delivery system based on L-arginine-containing mesoporous silica nanoparticles (MSNs) was used to release this essential amino acid as a source of basicity to neutralize the harmful acidic conditions that mediate the development of dental secondary caries. The in vitro and bacterial culture experiments proved that L-arginine was released in a sustained way from MSNs and diffused out from the dental adhesive, effectively contributing to the reduction of the bacterial strains Streptococcus mutans and Lactobacillus casei. Furthermore, the mechanical and bonding properties of the dental adhesive did not change significantly after the incorporation of L-arginine-containing MSNs. These results are yielding glimmers of promise for the costeffective prevention of secondary caries.
Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bisorganosilane Ligands in Axial Positions
(American Chemical Society, 2024-04-09) Navas, Francisco; Chocarro Calvo, Ana; Iglesias Hernández, Patricia; Fernández García, Paloma; Morales, Victoria; García Martínez, José Manuel; Sanz, Raúl; De la Vieja, Antonio; García Jiménez, Custodia; García Muñoz, Rafael Á.
We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-[3-(triethoxysilyl)propylcarbamate]- platinum(IV) (Pt(IV)-biSi-1) and cis-dichloro(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)- biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.
Reactions of a tetranuclear Pt-thiosemicarbazone complex with model proteins
(Elsevier Sciencie Inc., 2018-01-10) Marzo, Tiziano; Navas, Francisco; Cirri, Damiano; Merlino, Antonello; Ferraro, Giarita; Messori, Luigi; Gómez Quiroga, Adoración
The tetranuclear Pt complex (PtL)4 (where L2− is the anion derived from para-isopropyl thiosemicarbazone) was first described in A.G. Quiroga et al., J. Med. Chem. 41, 1998, 1399–1408. (PtL)4 manifests antiproliferative properties toward various cancer cell lines being a promising anticancer drug candidate. Yet, details of its reactivity with biomolecules have not been elucidated. To this end, we investigated the reactions of (PtL)4 with a few model proteins, i.e. bovine pancreatic ribonuclease (RNase A), cytochrome c (Cyt c) and hen egg white lysozyme (Lysozyme), through electrospray ionization mass spectrometry and other biophysical methods. A rich reactivity of (PtL)4 with the above-mentioned model proteins is observed, leading to the formation of numerous metallodrug-protein adducts. The tetranuclear complex breaks down and various fragments bind proteins up to high metal/protein ratios; this typically results into very complicated mass spectral patterns. However, some of the main mass peaks could be assigned in the case of the Lysozyme adduct. In addition, crystallographic data were obtained for the (PtL)4/Lysozyme and (PtL)4/RNase A adducts pointing at His side chains as the primary binding sites for monometallic Pt fragments. Notably, a few selected features of the interactions observed in the (PtL)4/protein adducts were reproduced by reacting (PtL)4 with a small molecule, i.e. N-methylimidazole. In conclusion, the present study confirms the prodrug nature of the tetraplatinum complex, clarifies one possible pathway for its activation through cluster disassembly and allows initial identification of adducts formed with a representative protein.
Using phosphine ligands with a biological role to modulate reactivity in novel platinum complexes
(Royal Society, 2018-02-21) Echeverri, Marcelo; Álvarez Valdés, Amparo; Navas, Francisco; Perles, Josefina; Sánchez Pérez, Isabel; Gómez Quiroga, Adoración
Three platinum complexes with cis and trans configuration cis-[Pt(TCEP)2Cl2], cis-[Pt(tmTCEP)2Cl2] and trans- [Pt(TCEP)2Cl2], where TCEP is tris(2-carboxyethyl)phosphine, have been synthesized and fully characterized by usual techniques including single-crystal X-ray diffraction for trans-[Pt(TCEP)2Cl2] and cis-[Pt(tmTCEP)2Cl2]. Here, we also report on an esterification process of TCEP, which takes place in the presence of alcohols, leading to a platinum complex coordinated to an ester tmTCEP (2-methoxycarbonylethyl phosphine) ligand. The stability in solution of the three compounds and their interaction with biological models such as DNA (pBR322 and calf thymus DNA) and proteins (lysozyme and RNase) have also been studied.
Versatile Route to trans-Platinum(II) Complexes via Manipulation of a Coordinated 3‑(Pyridin-3-yl)propanoic Acid Ligand
(American Chemical Society, 2019-04-12) Cabrera, Silvia; Navas, Francisco; Matesanz, Ana I.; Maroto, Marta; Riedel, Tina; Dyson, Paul J.; Gómez Quiroga, Adoración
We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.