Carla Ríos-Luci

Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol

A series of 5-hydroxy-1,4-naphthoquinones analogues was synthesized from juglone (6) and their antiproliferative activity against a representative panel of six human solid tumor cell lines has been investigated. The 2,5-dihydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione (4) and 2,3-dihydro-5-hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione (27) were the most potent antiproliferative agents with GI(50) values of 0.42-8.1 and 0.80-2.2microM, respectively. The results provide insight into the correlation between some structural properties of 5-hydroxynaphthoquinones and their antiproliferative activity.

Antiproliferative activity of novel benzo[b][1,6]naphthyridines in human solid tumor cell lines.

A series of 2-substituted 1,2-dihydro-3-phenyl-1-(trichloromethyl)benzo[b][1,6]naphthyridines were synthesized and their in vitro antiproliferative activities were examined against human solid tumor cell lines and relevant strains of bacteria and Candida. The compounds induced considerably growth inhibition in all cancer cell lines, whilst showed inactive against microbial strains. Furthermore, we found analog 2-ethoxy-1H-pyrano[4,3-b]quinoline as selective inhibitor of microbial strains.

Novel clioquinol and its analogous platinum complexes: importance, role of the halogen substitution and the hydroxyl group of the ligand.

In this communication, we present the synthesis of new platinum complexes based on hydroxyquinoline ligands. We demonstrate the importance and the role of the halogen substitution as well as the chelation, which are essential structural characteristics for finding good cytotoxicities.

β-Lapachone analogs with enhanced antiproliferative activity

In this study, we describe the synthesis of a series of α- and β-lapachone containing hydroxyl or methoxyl groups on the benzene ring, by means of the selective acid promoted cyclization of the appropriate lapachol analog. The evaluation of the antiproliferative activity in human solid tumor cell lines provided 7-hydroxy-β-lapachone as lead with enhanced activity over the parent drug β-lapachone. Cell cycle studies, protein expression experiments, and reactive oxygen species analysis revealed that, similarly to β-lapachone, ROS formation and DNA damage are critical factors in the cellular toxicity of 7-hydroxy-β-lapachone.

Cytotoxic Profile and Peculiar Reactivity with Biomolecules of a Novel "Rule-Breaker" Iodidoplatinum(II) Complex.

Novel and surprising biological properties were disclosed for the platinum(II) complex cis-diiodidodiisopropylamineplatinum(II). Remarkably, this new platinum(II) complex manifests pronounced antiproliferative properties in vitro, in some cases superior to those of cisplatin. A peculiar reactivity with the model protein cytochrome c was indeed highlighted based on the loss of amine ligands and retention of iodides.

Anti-Inflammatory Activity of a Novel Family of Aryl Ureas Compounds in an Endotoxin-Induced Airway Epithelial Cell Injury Model

Background Despite our increased understanding of the mechanisms involved in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), there is no specific pharmacological treatment of proven benefit. We used a novel screening methodology to examine potential anti-inflammatory effects of a small structure-focused library of synthetic carbamate and urea derivatives in a well established cell model of lipopolysaccharide (LPS)-induced ALI/ARDS. Methodology/Principal Findings After a pilot study to develop an in vitro LPS-induced airway epithelial cell injury model, a library of synthetic carbamate and urea derivates was screened against representative panels of human solid tumor cell lines and bacterial and fungal strains. Molecules that were non-cytotoxic and were inactive in terms of antiproliferative and antimicrobial activities were selected to study the effects on LPS-induced inflammatory response in an in vitro cell culture model using A549 human alveolar and BEAS-2B human bronchial cells. These cells were exposed for 18 h to LPS obtained from Escherichia coli, either alone or in combination with the test compounds. The LPS antagonists rhein and emodin were used as reference compounds. The most active compound (CKT0103) was selected as the lead compound and the impact of CKT0103 on pro-inflammatory IL-6 and IL-8 cytokine levels, expression of toll-like receptor-4 (TLR4) and nuclear factor kappa B inhibitor alpha (IκBα) was measured. CKT0103 significantly inhibited the synthesis and release of IL-6 and IL-8 induced by LPS. This suppression was associated with inhibition of TLR4 up-regulation and IκBα down-regulation. Immunocytochemical staining for TLR4 and IκBα supported these findings. Conclusions/Significance Using a novel screening methodology, we identified a compound – CKT0103 – with potent anti-inflammatory effects. These findings suggest that CKT0103 is a potential target for the treatment of the acute phase of sepsis and sepsis-induced ALI/ARDS.

Reactivity and biological properties of a series of cytotoxic PtI2(amine)2 complexes, either cis or trans configured.

Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.

Antiproliferative activity of dmoPTA–Ru(II) complexes against human solid tumor cells

The biological evaluation of new Ru(II) complexes carrying dmoPTA (dmoPTA=3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) ligands is reported. The results on the biological activity revealed that the organometallic complexes are active against all cell lines with GI(50) values in the range 1.1-2.6 μM. When compared to the standard anticancer drug cisplatin, the bimetallic Ru(II) complexes showed a greater activity profile. The cell cycle analysis revealed that the new compounds induced arrest in G(1) phase. Contrary to cisplatin, these Ru(II) complexes do not interact with DNA. This result suggests that DNA might not be the key pharmacological target.

Novel N-sulfonamide trans-platinum complexes: synthesis, reactivity and in vitro evaluation

In this work, we described for the first time the synthesis of trans-N-sulfonamide platinum complexes. The antiproliferative activity (GI50, μM) of these new compounds in human solid tumors cells was compared to cisplatin.

Antiproliferative terpenoids and alkaloids from the roots of Maytenus vitis-idaea and Maytenus spinosa

Investigation of the organic extracts of the roots of Maytenus vitis-idaea and Maytenus spinosa, collected in the province of Salta, Argentina, led to isolation of eighteen compounds belonging to several classes. From M. vitis-idaea, eight methylenequinone celastroids (1-8) were isolated, four of which (4-7) were hitherto unknown. Additionally, from M. spinosa, two known celastroids, a known celastroid dimer (9), three pentacyclic triterpenoids (10-12) and six β-dihydroagarofuran sesquiterpenoid alkaloids (13-18) were identified. Compounds 4-7 were active against six solid tumor cell lines at micromolar concentrations.