Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 72
Filter
1.
Molecules ; 28(21)2023 Nov 04.
Article in English | MEDLINE | ID: mdl-37959843

ABSTRACT

Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes' transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.


Subject(s)
Antioxidants , Neurodegenerative Diseases , Humans , Antioxidants/pharmacology , Antioxidants/metabolism , NF-E2-Related Factor 2/metabolism , Pioglitazone/pharmacology , Oxidative Stress , Neurodegenerative Diseases/metabolism , Monoamine Oxidase/metabolism
2.
Molecules ; 28(17)2023 Aug 29.
Article in English | MEDLINE | ID: mdl-37687158

ABSTRACT

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 µM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 µM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.


Subject(s)
Glioblastoma , Prostatic Neoplasms , Humans , Male , Monoamine Oxidase , Polyamines/pharmacology , Monoamine Oxidase Inhibitors/pharmacology
3.
Molecules ; 27(3)2022 Jan 19.
Article in English | MEDLINE | ID: mdl-35163916

ABSTRACT

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure-activity relationships useful to face the resistance phenotype.


Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Cisplatin/pharmacology , Cisplatin/therapeutic use , Humans , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Platinum/pharmacology , Platinum/therapeutic use
4.
Molecules ; 28(1)2022 Dec 23.
Article in English | MEDLINE | ID: mdl-36615306

ABSTRACT

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N-desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI50 values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B, confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism.


Subject(s)
Antineoplastic Agents , Cannabidiol , Nanoparticles , Humans , Cannabidiol/pharmacology , Antineoplastic Agents/pharmacology , Paclitaxel/pharmacology , Paclitaxel/chemistry , Cell Line, Tumor
5.
Amino Acids ; 52(2): 161-169, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31654209

ABSTRACT

Agmatine (AGM) produces a dual effect on the mitochondrial permeability transition (MPT) mechanism in rat liver mitochondria: at low concentrations, it induces the phenomenon, at high ones, inhibits it. The prevention at high concentrations is evidenced by the significant inhibition of mitochondrial swelling induced by Ca2+ and phosphate; in this condition, AGM both prevents the release of Apoptosis Inducing Factor (AIF) and enhances the release of other pro-apoptotic factors, such as cytochrome c (cyt c) and Smac/DIABLO. As these factors are released without MPT induction, the involvement of mitochondrial outer membrane permeabilization (MOMP) could be hypothesized. Cyclosporin A (CsA), a powerful inhibitor of MPT, enhanced the AGM-mediated inhibition of swelling, and surprisingly, prevented the release of cyt c and Smac/DIABLO. In the presence of Ca2+, AGM also activated the Bcl-2 family protein Bax, a key factor in inducing MOMP, which is inactivated by CsA. Together with the voltage-dependent anion channel (VDAC), Bax forms channels in the outer membrane further supporting the involvement of MOMP in the release of pro-apoptotic factors. In view of the fact that VDAC was inactivated by ruthenium red, which in turn inhibited the release of cyt c, it can be hypothesized that, on the one hand, AGM inhibits MPT induction and, on the other, it selectively permeabilizes the outer membrane via MOMP induction.


Subject(s)
Agmatine/metabolism , Apoptosis Inducing Factor/metabolism , Mitochondrial Membranes/metabolism , Animals , Apoptosis , Apoptosis Inducing Factor/genetics , Calcium/metabolism , Cell Membrane Permeability , Mitochondria, Liver/genetics , Mitochondria, Liver/metabolism , Rats
6.
Molecules ; 25(23)2020 Nov 27.
Article in English | MEDLINE | ID: mdl-33260896

ABSTRACT

The synthesis of a small library of 8-substituted 2-methyl-5,6,7,8-tetrahydroquinoline derivatives is presented. All the compounds were tested for their antiproliferative activity in non-cancer human dermal microvascular endothelial cells (HMEC-1) and cancer cells: human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), human dermal microvascular endothelial cells (HMEC-1), colorectal adenocarcinoma (HT-29), ovarian carcinoma (A2780), and biphasic mesothelioma (MSTO-211H). Compounds 3a, 5a, and 2b, showing significant IC50 values against the whole panel of the selected cells, were further synthesized and tested as pure enantiomers in order to shed light on how their stereochemistry might impact on the related biological effect. The most active compound (R)-5a was able to affect cell cycle phases and to induce mitochondrial membrane depolarization and cellular ROS production in A2780 cells.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Endothelial Cells/drug effects , Mesothelioma/drug therapy , Ovarian Neoplasms/drug therapy , Apoptosis , Cell Cycle , Cell Proliferation , Cells, Cultured , Drug Screening Assays, Antitumor , Female , Humans , Reactive Oxygen Species/metabolism
7.
Photochem Photobiol Sci ; 18(9): 2232-2239, 2019 Sep 01.
Article in English | MEDLINE | ID: mdl-30860541

ABSTRACT

The cytotoxic activity of fluphenazine (FPZ) in combination with UVA light was evaluated on three human tumor cell lines, HeLa, MSTO-211H and A431. The photobiological effect was determined following irradiation treatment in the presence of/or after the removal of incubated FPZ. Under both conditions, FPZ proved to be very effective in killing tumor cells, with GI50 values in the micromolar range. However, when FPZ was present during irradiation, the photocytotoxicity was at least two times higher than that after its removal suggesting the contribution of the drug both outside and inside the cells. The uptake of FPZ was very fast and, after only 15 minutes of incubation, the compound was accumulated inside lysosomes, as evidenced through fluorescence microscopy. FPZ distribution covered also the nucleus and the cytoplasm without significant plasma membrane association. After irradiation, the membrane of lysosomes in which FPZ was accumulated lost its integrity suggesting that the released lysosomal enzymes played an important role in cell death, and mitochondria were damaged as well, following apoptosis. Indeed, cytofluorimetric studies demonstrated that apoptosis was the main mechanism of cell death. Finally, an extremely high production of ROS was found, indicating a significant photodynamic mechanism involved in the photocytotoxic effect of FPZ. Taken together, our data show that FPZ following UVA irradiation behaves as an effective photoantiproliferative compound inducing apoptosis on various human tumor cells.


Subject(s)
Antipsychotic Agents/pharmacology , Apoptosis/drug effects , Fluphenazine/pharmacology , Ultraviolet Rays , Antibodies, Monoclonal/immunology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lysosomes/immunology , Microscopy, Fluorescence , Mitochondria/immunology , Optical Imaging , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured
8.
Int J Mol Sci ; 20(8)2019 Apr 16.
Article in English | MEDLINE | ID: mdl-31014011

ABSTRACT

Annona purpurea, known in Mexico as "cabeza de negro" or "ilama", belongs to the Annonaceae family. Its roots are employed in folk medicine in several regions of Mexico. Taking that information into account, a chemical and biological analysis of the components present in the roots of this species was proposed. Our results demonstrated that the dichloromethane (DCM) extract was exclusively constituted by a mixture of five new acetogenins named annopurpuricins A-E (1-5). These compounds have an aliphatic chain of 37 carbons with a terminal α,ß unsaturated γ-lactone. Compounds 1 and 2 belong to the adjacent bis-THF (tetrahydrofuran) α-monohydroxylated type, while compounds 3 and 4 belong to the adjacent bis-THF α,α'-dihydroxylated type; only compound 5 possesses a bis-epoxide system. Complete structure analysis was carried out by spectroscopy and chemical methods. All compounds were evaluated for their antiproliferative activity on three human tumor cell lines (MSTO-211H, HeLa and HepG2). Compounds 1-4 inhibited significantly the growth of HeLa and HepG2 cells, showing GI50 values in the low/subnanomolar range, while 5 was completely ineffective under the tested conditions. The investigation of the mechanism of action responsible for cytotoxicity revealed for the most interesting compound 1 the ability to block the complex I activity on isolated rat liver mitochondria (RLM).


Subject(s)
Acetogenins/chemistry , Annona/chemistry , Plant Roots/chemistry , Acetogenins/isolation & purification , Acetogenins/pharmacology , Animals , Annona/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Magnetic Resonance Spectroscopy , Membrane Potential, Mitochondrial/drug effects , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Molecular Conformation , Plant Roots/metabolism , Rats
9.
Biochem Biophys Res Commun ; 479(1): 48-53, 2016 10 07.
Article in English | MEDLINE | ID: mdl-27613098

ABSTRACT

Microtubule (MT) dynamic behaviour is an attractive drug target for chemotherapy, whose regulation by MT-stabilizing and destabilizing agents has been fruitfully applied in treating several types of cancers. MT-stabilizing agents are also emerging as potential remedies for neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, although single-target drugs are not expected to fully cure these complex pathologies. Drug combination often displays enhanced efficacy with respect to mono-therapies. In particular, MT-targeting bivalent compounds (MTBCs) represent a promising class of molecules; however, surprisingly, the majority of MTBCs reported so far exhibit equal if not less efficacy than their building monomers. In order to shed light on MTBCs poor performance, we characterised through a set of complementary approaches thiocolchine (TH) and two bivalent TH-homodimers as prototype molecules. First, the binding affinities of these three molecules were assessed, then we obtained the crystallographic structure of a tubulin-TH complex. The binding affinities were interpreted in light of structural data and of molecular dynamics simulations. Finally, their effects on MT cytoskeleton and cell survival were validated on HeLa cells. The ensemble of these data provides chemical and structural considerations on how a successful rational design of MTBCs should be conceived.


Subject(s)
Antineoplastic Agents/metabolism , Drug Design , Microtubules/metabolism , Tubulin Modulators/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding, Competitive , Cell Proliferation/drug effects , Crystallography, X-Ray , Depsipeptides/chemistry , Depsipeptides/metabolism , Depsipeptides/pharmacology , Dimerization , HeLa Cells , Humans , Microscopy, Fluorescence , Microtubules/chemistry , Models, Molecular , Molecular Structure , Protein Binding , Protein Domains , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology
10.
Amino Acids ; 48(10): 2327-37, 2016 10.
Article in English | MEDLINE | ID: mdl-27255894

ABSTRACT

Spermine, besides to be transported in mitochondria by an energy dependent electrophoretic mechanism, can be also released by two different mechanisms. The first one is induced in deenergizing conditions by FCCP or antimycin A and it is mediated by an electroneutral exchange spermine protons. The second one takes place in energizing conditions during the activity of the adenine nucleotide translocase and is mediated by an electroneutral symport mechanism involving the efflux in co-transport of spermine and phosphate and the exchange of exogenous ADP with endogenous ATP. The triggering of this mechanism permits an alternating cycling of spermine across the mitochondrial membrane, that is spermine is transported or released by energized mitochondria in the absence or presence of ATP synthesis, respectively. The physiological implications of this cycling of spermine are related to the induction or prevention of mitochondrial permeability transition and, consequently, on apoptosis or its prevention.


Subject(s)
Apoptosis , Mitochondria, Liver/metabolism , Mitochondrial ADP, ATP Translocases/metabolism , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/metabolism , Spermine/metabolism , Animals , Antimycin A/pharmacology , Biological Transport, Active/drug effects , Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology , Male , Rats , Rats, Wistar
11.
Bioorg Med Chem Lett ; 26(20): 4875-4878, 2016 10 15.
Article in English | MEDLINE | ID: mdl-27665377

ABSTRACT

An unpredicted condensation of naphthylamine with two molecules of ethyl propiolate yields directly carbethoxy benzoquinoline in high yield. Some benzoquinoline carboxamide derivatives with protonatable side chains were then synthesized and evaluated for antiproliferative activity on human tumor cell lines. The most active compound (7a) demonstrated to intercalate into DNA and to inhibit the relaxation activity mediated by topoisomerase II.


Subject(s)
Alkynes/chemistry , Amines/chemistry , Propionates/chemistry , Quinolines/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Quinolines/chemistry
12.
Bioorg Med Chem ; 24(13): 2929-2937, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27179449

ABSTRACT

Some new platinum(II) complexes have been prepared, of general formula trans-[PtCl2(PPh3){NH(Bu)CH2Ar}], where the dimension of the Ar residue in the secondary amines has been varied from small phenyl to large pyrenyl group. The obtained complexes, tested in vitro towards a panel of human tumor cell lines showed an interesting antiproliferative effect on both cisplatin-sensitive and -resistant cells. For the most cytotoxic derivative 2a the investigation on the mechanism of action highlighted the ability to induce apoptosis on resistant cells and interestingly, to inhibit the catalytic activity of topoisomerase II.


Subject(s)
Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Amines/chemistry , Amines/pharmacology , Amines/toxicity , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Flow Cytometry , HeLa Cells , Humans , Ligands , Magnetic Resonance Spectroscopy , Organoplatinum Compounds/toxicity , Structure-Activity Relationship
13.
Photochem Photobiol Sci ; 14(11): 2074-86, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26415515

ABSTRACT

Some 4,8-dimethyl-3-psoralenacetic acids were synthesized and studied. All the designed psoralenacetic acids bear alkyl or cycloalkyl substituents at the furan ring. These psoralenacetic acids were shown to be a novel class of psoralen derivatives characterized by an interesting photobiological profile. The carboxylic group at the 3 position, useful to confer hydrophilic properties, appears to be detrimental to the classical intercalation into DNA, likely because of repulsive interactions with the negative surface of the macromolecule. Nevertheless, the new derivatives possess a notable photoantiproliferative activity, due to a peculiar mechanism of action consisting of a decarboxylation step before exerting their photobiological activity. The most active compound 2 is able to induce a noteworthy photocytotoxic effect, with GI50 values being submicromolar on human tumor cell lines and no effect in the dark. The involvement of DNA photoaddition after UVA light-mediated decarboxylation and ROS formation is responsible for its biological activity, as demonstrated comparing the activity profile of the decarboxylated analogue. However, other biological targets seem to be involved in the photooxidative damage, such as proteins. Compound 2 could thus be considered as a prodrug, inactive without UVA light but activated upon specific irradiation, thus preventing unselective side effects and opening new perspectives on agents useful in photochemotherapy.


Subject(s)
Acetates/pharmacology , Furocoumarins/pharmacology , Photosensitizing Agents/pharmacology , Acetates/chemistry , Animals , Cattle , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Furocoumarins/chemistry , HeLa Cells , Humans , Molecular Structure , Oxidation-Reduction , Photolysis , Photosensitizing Agents/chemistry , Phototrophic Processes , Reactive Oxygen Species/metabolism , Serum Albumin, Bovine/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured , Ultraviolet Rays
14.
Amino Acids ; 46(3): 671-9, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24043461

ABSTRACT

The polyamine spermine is transported into the mitochondrial matrix by an electrophoretic mechanism having as driving force the negative electrical membrane potential (ΔΨ). The presence of phosphate increases spermine uptake by reducing ΔpH and enhancing ΔΨ. The transport system is a specific uniporter constituted by a protein channel exhibiting two asymmetric energy barriers with the spermine binding site located in the energy well between the two barriers. Although spermine transport is electrophoretic in origin, its accumulation does not follow the Nernst equation for the presence of an efflux pathway. Spermine efflux may be induced by different agents, such as FCCP, antimycin A and mersalyl, able to completely or partially reduce the ΔΨ value and, consequently, suppress or weaken the force necessary to maintain spermine in the matrix. However this efflux may also take place in normal conditions when the electrophoretic accumulation of the polycationic polyamine induces a sufficient drop in ΔΨ able to trigger the efflux pathway. The release of the polyamine is most probably electroneutral in origin and can take place in exchange with protons or in symport with phosphate anion. The activity of both the uptake and efflux pathways induces a continuous cycling of spermine across the mitochondrial membrane, the rate of which may be prominent in imposing the concentrations of spermine in the inner and outer compartment. Thus, this event has a significant role on mitochondrial permeability transition modulation and consequently on the triggering of intrinsic apoptosis.


Subject(s)
Mitochondrial Membranes/metabolism , Spermine/metabolism , Mitochondrial Membranes/chemistry , Spermine/chemistry
15.
Bioorg Med Chem ; 21(22): 6965-72, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24095013

ABSTRACT

A convenient synthetic route and the characterization of complexes trans-[PtCl2(L)(PPh3)] (L=Et2NH (2), (PhCH2)2NH (3), (HOCH2CH2)2NH) (4) are reported. The antiproliferative activity was evaluated on three human tumor cell lines. The investigation on the mechanism of action highlighted for the most active complex 4 the capacity to affect mitochondrial functions. In particular, both the induction of the mitochondrial permeability transition phenomenon and an aspecific membrane damage occurred, depending on concentration.


Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/chemical synthesis , Mitochondria/drug effects , Platinum/chemistry , Platinum/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , HeLa Cells , Humans , Isomerism , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Phosphines/chemistry
16.
Bioorg Med Chem ; 21(14): 4120-31, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23735829

ABSTRACT

A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines. The estrogen like properties of the novel compounds were compared with those of the untreated controls using an estrogen responsive element-based (ERE) luciferase reporter assay and compared to 17ß-estradiol (E2). Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerases I and II was assayed.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Tamoxifen/chemical synthesis , Tamoxifen/pharmacology , Antineoplastic Agents/chemistry , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Endometrial Neoplasms/drug therapy , Female , Humans , Molecular Structure , Receptors, Estrogen/metabolism , Tamoxifen/chemistry
17.
Bioorg Med Chem ; 21(22): 6920-8, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24103429

ABSTRACT

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results.


Subject(s)
DNA Topoisomerases, Type I/chemistry , Quinazolines/chemistry , Sirtuins/antagonists & inhibitors , Topoisomerase I Inhibitors/chemistry , Alkaloids/chemistry , Binding Sites , Carbolines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/metabolism , Enzyme Activation/drug effects , Hep G2 Cells , Humans , MCF-7 Cells , Molecular Docking Simulation , Protein Structure, Tertiary , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Sirtuins/metabolism , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology
18.
Pharmaceuticals (Basel) ; 16(5)2023 May 09.
Article in English | MEDLINE | ID: mdl-37242505

ABSTRACT

A potent nontoxic antitumor drug, 2-hydroxyoleic acid (6, 2OHOA) used for membrane lipid therapy, was selected as a self-assembly inducer due to its ability to form nanoparticles (NPs) in water. For this purpose, it was conjugated with a series of anticancer drugs through a disulfide-containing linker to enhance cell penetration and to secure drug release inside the cell. The antiproliferative evaluation of the synthesized NP formulations against three human tumor cell lines (biphasic mesothelioma MSTO-211H, colorectal adenocarcinoma HT-29, and glioblastoma LN-229) showed that nanoassemblies 16-22a,bNPs exhibit antiproliferative activity at micromolar and submicromolar concentrations. Furthermore, the ability of the disulfide-containing linker to promote cellular effects was confirmed for most nanoformulations. Finally, 17bNP induced intracellular ROS increase in glioblastoma LN-229 cells similarly to free drug 8, and such elevated production was decreased by pretreatment with the antioxidant N-acetylcysteine. Also, nanoformulations 18bNP and 21bNP confirmed the mechanism of action of the free drugs.

19.
Mod Pathol ; 25(1): 86-99, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21983934

ABSTRACT

Epithelial-mesenchymal transition is a physiopathological process by which epithelial cells acquire mesenchymal shape and properties. Malignant mesothelioma is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter being associated to worse prognosis, thus suggesting a role of epithelial-mesenchymal transition in this dual phenotype. We studied 109 malignant mesotheliomas (58 epithelioid, 26 sarcomatoid, and 25 biphasic) by immunohistochemistry and qRT-PCR analysis, and demonstrated a substantial switch from epithelial markers (E-cadherin, ß-catenin, and cytokeratins 5/6) to mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin, Snail, Slug, Twist, ZEB1, ZEB2, S100A4, MMP2, and MMP9) through epithelioid to biphasic and sarcomatoid histotypes. In agreement with these findings, the ectopic expression of miR-205 (a repressor of ZEB1 and ZEB2 expression) in MeT-5A (mesothelial cell line), H2452 (an epithelioid malignant mesothelioma cell line) and MSTO-211H (a biphasic malignant mesothelioma cell line) not only induced a significant reduction of ZEB1 and ZEB2 and a consequent up-regulation of E-cadherin gene expression, but also inhibited migration and invasion. Moreover, miR-205 was significantly down-regulated in biphasic and sarcomatoid histotypes (qRT-PCR and in situ hybridization analyses). Collectively, our findings indicate that epithelial-mesenchymal transition has a significant part in the morphological features of malignant mesothelioma. In particular, miR-205 down-regulation correlated significantly with both a mesenchymal phenotype and a more aggressive behavior.


Subject(s)
Epithelial-Mesenchymal Transition , Mesothelioma/pathology , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Genotype , Humans , Immunohistochemistry , In Situ Hybridization , Male , Mesothelioma/genetics , Mesothelioma/metabolism , Mesothelioma/mortality , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Neoplasm Invasiveness , Phenotype , Prognosis , Proportional Hazards Models , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Time Factors , Transfection
20.
Chemistry ; 18(45): 14464-72, 2012 Nov 05.
Article in English | MEDLINE | ID: mdl-23012112

ABSTRACT

Hereby we present the synthesis of several ruthenium(II) and ruthenium(III) dithiocarbamato complexes. Proceeding from the Na[trans-Ru(III)(dmso)(2)Cl(4)] (2) and cis-[Ru(II)(dmso)(4)Cl(2)] (3) precursors, the diamagnetic, mixed-ligand [Ru(II)L(2)(dmso)(2)] complexes 4 and 5, the paramagnetic, neutral [Ru(III)L(3)] monomers 6 and 7, the antiferromagnetically coupled ionic α-[Ru(III)(2)L(5)]Cl complexes 8 and 9 as well as the ß-[Ru(III)(2)L(5)]Cl dinuclear species 10 and 11 (L = dimethyl- (DMDT) and pyrrolidinedithiocarbamate (PDT)) were obtained. All the compounds were fully characterised by elemental analysis as well as (1)H NMR and FTIR spectroscopy. Moreover, for the first time the crystal structures of the dinuclear ß-[Ru(III)(2)(dmdt)(5)]BF(4)⋅CHCl(3)⋅CH(3)CN and of the novel [Ru(II)L(2)(dmso)(2)] complexes were also determined and discussed. For both the mono- and dinuclear Ru(II) and Ru(III) complexes the central metal atoms assume a distorted octahedral geometry. Furthermore, in vitro cytotoxicity of the complexes has been evaluated on non-small-cell lung cancer (NSCLC) NCI-H1975 cells. All the mono- and dinuclear Ru(III) dithiocarbamato compounds (i.e., complexes 6-10) show interesting cytotoxic activity, up to one order of magnitude higher with respect to cisplatin. Otherwise, no significant antiproliferative effect for either the precursors 2 and 3 or the Ru(II) complexes 4 and 5 has been observed.


Subject(s)
Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Ruthenium/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/therapeutic use , Coordination Complexes/toxicity , Crystallography, X-Ray , Humans , Lung Neoplasms/drug therapy , Molecular Conformation , Organometallic Compounds/chemistry , Organometallic Compounds/therapeutic use , Organometallic Compounds/toxicity
SELECTION OF CITATIONS
SEARCH DETAIL