Publications by authors named "Lorenzo Botta"

50 Publications

Stereoselective Access to Antimelanoma Agents by Hybridization and Dimerization of Dihydroartemisinin and Artesunic acid.

ChemMedChem 2021 Apr 1. Epub 2021 Apr 1.

Department of Biological and Ecological Sciences, Univeristy of Viterbo, Via S.C. De Lellis s.n.c., 01100, Viterbo, Italy.

A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo-controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4-hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC >300 μM) and high antimelanoma activity (IC =0.05 μM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer-type selectivity towards melanoma compared to prostate (PC3) and breast (MDA-MB-231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.
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http://dx.doi.org/10.1002/cmdc.202100196DOI Listing
April 2021

Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection.

Antiviral Res 2021 06 26;190:105064. Epub 2021 Mar 26.

Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address:

COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular proteins hijacked by viruses for their life cycle and develop host-oriented antiviral therapeutics. Here we report the proteomic characterization of host proteins interacting with SARS-CoV-2 Nucleoprotein in infected Vero E6 cells. We identified 24 high-confidence proteins mainly playing a role in RNA metabolism and translation, including RNA helicases and scaffold proteins involved in the formation of stress granules, cytoplasmic aggregates of messenger ribonucleoproteins that accumulate as a result of stress-induced translation arrest. Analysis of stress granules upon SARS-CoV-2 infection showed that these structures are not induced in infected cells, neither eIF2α phosphorylation, an upstream event leading to stress-induced translation inhibition. Notably, we found that G3BP1, a stress granule component that associates with the Nucleoprotein, is required for efficient SARS-CoV-2 replication. Moreover, we showed that the Nucleoprotein-interacting RNA helicase DDX3X colocalizes with viral RNA foci and its inhibition by small molecules or small interfering RNAs significantly reduces viral replication. Altogether, these results indicate that SARS-CoV-2 subverts the stress granule machinery and exploits G3BP1 and DDX3X for its replication cycle, offering groundwork for future development of host-directed therapies.
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http://dx.doi.org/10.1016/j.antiviral.2021.105064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997689PMC
June 2021

Laccase-Catalyzed 1,4-Dioxane-Mediated Synthesis of Belladine -Oxides with Anti-Influenza A Virus Activity.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.

Belladine -oxides active against influenza A virus have been synthetized by a novel laccase-catalyzed 1,4-dioxane-mediated oxidation of aromatic and side-chain modified belladine derivatives. Electron paramagnetic resonance (EPR) analysis confirmed the role of 1,4-dioxane as a co-oxidant. The reaction was chemo-selective, showing a high functional-group compatibility. The novel belladine -oxides were active against influenza A virus, involving the early stage of the virus replication life cycle.
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http://dx.doi.org/10.3390/ijms22031337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866262PMC
January 2021

Production and identification of two antifungal terpenoids from the Posidonia oceanica epiphytic Ascomycota Mariannaea humicola IG100.

Microb Cell Fact 2020 Oct 1;19(1):184. Epub 2020 Oct 1.

Department of Ecological and Biological Sciences, University of Tuscia, Largo Università snc, 01100, Viterbo, Italy.

Background: Marine fungi are an important repository of bioactive molecules with great potential in different technological fields, the annual number of new compounds isolated from marine fungi is impressive and the general trend indicates that it is still on the rise. In this context, the antifungal and antimicrobial activity of the marine strain Mariannaea humicola IG100 was evaluated and two active terpenoids were isolated and characterized.

Methods: Preliminary screening of activity of marine strain IG100 was carried out by agar plug diffusion methods against fungal (Penicillium griseofulvum TSF04) and bacterial (Bacillus pumilus KB66 and Escherichia coli JM109) strains. Subsequently, inhibition tests were done by using the cultural broth and the organic extract (ethyl acetate, EtOAc) by the agar well diffusion methods. The main active fractions were identified and tested for their antifungal activity against P. griseofulvum TSF04 in a 24 wells microplate at different concentrations (1000, 100, 10 and 1.0 µg/mL). Two active compounds were characterized and their relative MIC measured by the broth micro-dilution methods in a 96-well microplate against Aspergillus flavus IG133, P. griseofulvum TSF04, and Trichoderma pleuroticola IG137.

Results: Marine strain IG100 presented significant antifungal activity associated with two active compounds, the terpenoids terperstacin 1 and 19-acetyl-4-hydroxydictyodiol 2. Their MIC values were measured for A. flavus (MIC of 7.9 µg/mL and 31.3 µg/mL for 1 and 2, respectively), P. griseofulvum (MIC of 25 µg/mL and 100 µg/mL for 1 and 2, respectively) and T. pleuroticola (MIC > 500 µg/mL and 125 µg/mL for 1 and 2, respectively). They showed a rather good fungistatic effect.

Conclusions: In this study, the first marine strain of M. humicola (IG100) was investigated for the production of bioactive molecules. Strain IG100 produced significant amounts of two bioactive terpenoids, terperstacin 1 and 19-acetyl-4-hydroxydictyodiol 2. The two compounds showed significant antifungal activities against A. flavus IG133, T. pleuroticola IG137 and P. griseofulvum TSF04. Compound 2 was identified for the first time in fungi.
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http://dx.doi.org/10.1186/s12934-020-01445-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528228PMC
October 2020

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned so Far.

Cancers (Basel) 2020 Jun 2;12(6). Epub 2020 Jun 2.

Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression.
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http://dx.doi.org/10.3390/cancers12061448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352436PMC
June 2020

SRC Tyrosine Kinase Inhibitor and X-rays Combined Effect on Glioblastoma Cell Lines.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Normandie University, 14074 Caen, France.

Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at the origin of treatment failure. The aim of this work was to assess the therapeutic potential of a new targeted c-SRC inhibitor molecule, named Si306, in combination with X-rays on the human glioblastoma cell lines, comparing normoxia and hypoxia conditions. For this purpose, the dose modifying factor and oxygen enhancement ratio were calculated to evaluate the Si306 radiosensitizing effect. DNA damage and the repair capability were also studied from the kinetic of γ-H2AX immunodetection. Furthermore, motility processes being supposed to be triggered by hypoxia and irradiation, the role of c-SRC inhibition was also analyzed to evaluate the migration blockage by wound healing assay. Our results showed that inhibition of the c-SRC protein enhances the radiotherapy efficacy both in normoxic and hypoxic conditions. These data open new opportunities for GBM treatment combining radiotherapy with molecularly targeted drugs to overcome radioresistance.
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http://dx.doi.org/10.3390/ijms21113917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312922PMC
May 2020

Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.

ACS Med Chem Lett 2020 May 10;11(5):1035-1040. Epub 2020 Apr 10.

Dipartimento di Biologia, Università di Padova Distaccato presso il "Centro Linceo Beniamino Segre" Accademia Nazionale dei Lincei, Palazzo Corsini, Via della Lungara 10, 00165 Rome, Italy.

Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity . These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236541PMC
May 2020

In Memory of Maurizio Botta: His Vision of Medicinal Chemistry.

ACS Med Chem Lett 2020 May 14;11(5):611. Epub 2020 May 14.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena.

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http://dx.doi.org/10.1021/acsmedchemlett.0c00210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236028PMC
May 2020

Synthesis and Evaluation of Artemisinin-Based Hybrid and Dimer Derivatives as Antimelanoma Agents.

ACS Omega 2020 Jan 27;5(1):243-251. Epub 2019 Dec 27.

Department of Ecological and Biological Sciences, University of Tuscia, via S. C. De Lellis 44, 01100, Viterbo, Italy.

A library of hybrid and dimer compounds based on the natural scaffold of artemisinin was synthesized. These derivatives were obtained by coupling of artemisinin derivatives, artesunate, and dihydroartemisinin with a panel of phytochemical compounds. The novel artemisinin-based hybrids and dimers were evaluated for their anticancer activity on a cervical cancer cell line (HeLa) and on three complementary metastatic melanoma cancer cell lines (SK-MEL3, SK-MEL24, and RPMI-7951). Two hybrid compounds obtained by coupling of artesunate with eugenol and tyrosol, and one of the dimer compounds containing curcumin, emerged as the most active and cancer-selective derivatives.
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http://dx.doi.org/10.1021/acsomega.9b02600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964273PMC
January 2020

Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X.

Molecules 2019 Nov 4;24(21). Epub 2019 Nov 4.

Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy.

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.
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http://dx.doi.org/10.3390/molecules24213988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864647PMC
November 2019

L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons.

ACS Med Chem Lett 2019 Apr 9;10(4):431-436. Epub 2019 Jan 9.

Dipartimento di Scienze Ecologiche e Biologiche, Università della Tuscia, Via S. C. De Lellis 44, 01100 Viterbo, Italy.

The oxidative degeneration of dopamine-releasing (DAergic) neurons in the substantia nigra pars compacta (SNc) has attracted much interest in preclinical research, due to its involvement in Parkinson's disease manifestations. Evidence exists on the participation of quinone derivatives in mitochondrial dysfunction, alpha synuclein protein aggregation, and protein degradation. With the aim to investigate the role of L-DOPA-quinone in DAergic neuron functions, we synthesized L-DOPA-quinone by use of 2-iodoxybenzoic acid and measured its activity in recovery from dopamine-mediated firing inhibition of SNc neurons. Noteworthy, L-DOPA-quinone counteracts firing inhibition in SNc DAergic neurons caused by GIRK opening. A possible mechanism to explain the effect of L-DOPA-quinone on GIRK channel has been proposed by computational models. Overall, the study showed the possibility that L-DOPA-quinone stabilizes GIRK in a preopen conformation through formation of a covalent adduct with cysteine-65 on the GIRK2 subunit of the protein.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466524PMC
April 2019

Author Correction: Proton irradiation: a key to the challenge of N-glycosidic bond formation in a prebiotic context.

Sci Rep 2019 Mar 12;9(1):4649. Epub 2019 Mar 12.

Department of Ecological and Biological Sciences, Via S. Camillo de Lellis, University of Tuscia, 01100, Viterbo, Italy.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-40290-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414669PMC
March 2019

Novel broad spectrum virucidal molecules against enveloped viruses.

PLoS One 2018 7;13(12):e0208333. Epub 2018 Dec 7.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.

Viral infections are an important cause of death worldwide. Unfortunately, there is still a lack of antiviral drugs or vaccines for a large number of viruses, and this represents a remarkable challenge particularly for emerging and re-emerging viruses. For this reason, the identification of broad spectrum antiviral compounds provides a valuable opportunity for developing efficient antiviral therapies. Here we report on a class of rhodanine and thiobarbituric derivatives displaying a broad spectrum antiviral activity against seven different enveloped viruses including an HSV-2 acyclovir resistant strain with favorable selectivity indexes. Due to their selective action on enveloped viruses and to their lipid oxidation ability, we hypothesize a mechanism on the viral envelope that affects the fluidity of the lipid bilayer, thus compromising the efficiency of virus-cell fusion and preventing viral entry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6285983PMC
May 2019

Oxidative nucleophilic substitution selectively produces cambinol derivatives with antiproliferative activity on bladder cancer cell lines.

Bioorg Med Chem Lett 2019 01 7;29(1):78-82. Epub 2018 Nov 7.

Department of Biological and Ecological Sciences, University of Tuscia, Largo dell'Università, Viterbo 01100, Italy.

Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol.
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http://dx.doi.org/10.1016/j.bmcl.2018.11.006DOI Listing
January 2019

Tyrosinase-Treated Hydroxytyrosol-Enriched Olive Vegetation Waste with Increased Antioxidant Activity Promotes Autophagy and Inhibits the Inflammatory Response in Human THP-1 Monocytes.

J Agric Food Chem 2018 Nov 7;66(46):12274-12284. Epub 2018 Nov 7.

Department of Ecological and Biological Sciences (DEB) , University of Tuscia , Viterbo , Italy.

Treatment of olive vegetation waste with tyrosinase immobilized on multiwalled carbon nanotubes increased the antioxidant activity as a consequence of the conversion of phenols to corresponding catechol derivatives, as evaluated by DPPH, Comet assay, and micronucleus analyses. During this transformation, 4-hydroxyphenethyl alcohol (tyrosol) was quantitatively converted to bioactive 3,4-dihydroxyphenethyl alcohol (hydroxytyrosol). The hydroxytyrosol-enriched olive vegetation waste also promoted autophagy and inhibited the inflammatory response in human THP-1 monocytes.
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http://dx.doi.org/10.1021/acs.jafc.8b03630DOI Listing
November 2018

Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors.

Molecules 2018 Sep 17;23(9). Epub 2018 Sep 17.

Department of Pharmacy, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy.

Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed ICs in the nanomolar range, with 2⁻130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds and showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB.
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http://dx.doi.org/10.3390/molecules23092369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225123PMC
September 2018

Layer-by-Layer Preparation of Microcapsules and Nanocapsules of Mixed Polyphenols with High Antioxidant and UV-Shielding Properties.

Biomacromolecules 2018 09 16;19(9):3883-3893. Epub 2018 Aug 16.

Department of Ecology and Biology , University of Tuscia , Via S. Camillo de Lellis , Viterbo , Italy , 01100.

Microcapsules and nanocapsules based on the contemporary presence of sulfonate lignin and tannic acid have been prepared by the layer-by-layer procedure, using MnCO or organosolv lignin as core templates, and polydiallyldimethylammonium chloride or chitosan as positive charged supporting layers. Nanocapsules and microcapsules of mixed polyphenols showed antioxidant activity, UV-shielding properties, and electrochemical responsiveness, higher than that in homopolymer nanocapsule counterparts and of the native polyphenols, suggesting the presence of synergistic effects between the two components. The presence of UV-visible bathochromic shift suggested the formation of J-aggregates characterized by an orientation of the adjacent phenolic rings parallel to the longitudinal direction of the layer, with a head-to-tail like arrangement. Moreover, nanocapsules of mixed polyphenols showed an aggregation state higher than that observed in references, the specific morphology of their surface being dependent on the structural arrangement of the different components.
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http://dx.doi.org/10.1021/acs.biomac.8b01006DOI Listing
September 2018

Laccase-Mediated Enhancement of the Antioxidant Activity of Propolis and Poplar Bud Exudates.

ACS Omega 2017 Jun 6;2(6):2515-2523. Epub 2017 Jun 6.

Department of Biological and Ecological Sciences, University of Tuscia, Via S. Camillo de Lellis snc, I-01100 Viterbo, Italy.

The treatment of propolis and poplar bud exudates with laccase from and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical increased the antioxidant activity, as evaluated by the 2,2'-diphenyl picrylhydrazyl (DPPH)- and -butyl-OOH-induced DNA breakage comet assay analyses. The effect was highest for shorter reaction times. Propolis showed the highest antioxidant activity in the DPPH test, whereas poplar bud exudates were more active in reducing the -butyl-OOH-induced lesions in the Chinese hamster ovary cell line. Even if the concentration of polyphenols decreased during the oxidation, the formation of low-molecular-weight phenols phloroglucinol (1,3,5-trihydroxy benzene), hydroquinone (1,4-dihydroxy benzene), and catechol (1,2-dihydroxy benzene), characterized by the radical-scavenging activity, can account for the observed increase in the antioxidant activity.
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http://dx.doi.org/10.1021/acsomega.7b00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044900PMC
June 2017

Iodoxybenzoic Acid Supported on Multi Walled Carbon Nanotubes as Biomimetic Environmental Friendly Oxidative Systems for the Oxidation of Alcohols to Aldehydes.

Nanomaterials (Basel) 2018 Jul 10;8(7). Epub 2018 Jul 10.

Department of Ecology and Biology, University of Tuscia, Largo dell'Università, 01100 Viterbo (VT), Italy.

Iodoxybenzoic acid (IBX) supported multi walled carbon nanotube (MWCNT) derivatives have been prepared as easily recyclable solid reagents. These compounds have been shown to be able to mimic the alcohol dehydrogenases and monooxygenases promoted oxidation of aromatic alcohols to corresponding aldehydes. Their reactivity was found to be dependent on the degree of functionalization of MWCNTs as well as from the chemical properties of the spacers used to bind IBX on the surface of the support. Au-decorated MWCNTs and the presence of longer spacers resulted in the optimal experimental conditions. A high conversion of the substrates and yield of desired products were obtained.
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http://dx.doi.org/10.3390/nano8070516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071043PMC
July 2018

Silica Metal Oxide Vesicles Catalyze Comprehensive Prebiotic Chemistry.

Chemistry 2018 Jun 14;24(32):8126-8132. Epub 2018 May 14.

Laboratorio de Estudios Cristalográficos, Instituto Andaluz de Ciencias de la, Tierra, Consejo Superior de Investigaciones Científicas-Universidad de, Granada, Avenida de las Palmeras 4, Armilla, Granada, 18100, Spain.

It has recently been demonstrated that mineral self-assembled structures catalyzing prebiotic chemical reactions may form in natural waters derived from serpentinization, a geological process widespread in the early stages of Earth-like planets. We have synthesized self-assembled membranes by mixing microdrops of metal solutions with alkaline silicate solutions in the presence of formamide (NH CHO), a single-carbon molecule, at 80 °C. We found that these bilayer membranes, made of amorphous silica and metal oxide/hydroxide nanocrystals, catalyze the condensation of formamide, yielding the four nucleobases of RNA, three amino acids and, several carboxylic acids in a single-pot experiment. Besides manganese, iron and magnesium, two abundant elements in the earliest Earth crust that are key in serpentinization reactions, are enough to produce all these biochemical compounds. These results suggest that the transition from inorganic geochemistry to prebiotic organic chemistry is common on a universal scale and, most probably, occurred earlier than ever thought for our planet.
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http://dx.doi.org/10.1002/chem.201706162DOI Listing
June 2018

Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors.

Eur J Med Chem 2018 Apr 2;150:491-505. Epub 2018 Mar 2.

Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy. Electronic address:

It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC.
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http://dx.doi.org/10.1016/j.ejmech.2018.02.080DOI Listing
April 2018

The Prevailing Catalytic Role of Meteorites in Formamide Prebiotic Processes.

Life (Basel) 2018 Feb 22;8(1). Epub 2018 Feb 22.

Biological and Ecological Department, University of Tuscia, 01100 Viterbo, Italy.

Meteorites are consensually considered to be involved in the origin of life on this Planet for several functions and at different levels: (i) as providers of impact energy during their passage through the atmosphere; (ii) as agents of geodynamics, intended both as starters of the Earth's tectonics and as activators of local hydrothermal systems upon their fall; (iii) as sources of organic materials, at varying levels of limited complexity; and (iv) as catalysts. The consensus about the relevance of these functions differs. We focus on the catalytic activities of the various types of meteorites in reactions relevant for prebiotic chemistry. Formamide was selected as the chemical precursor and various sources of energy were analyzed. The results show that all the meteorites and all the different energy sources tested actively afford complex mixtures of biologically-relevant compounds, indicating the robustness of the formamide-based prebiotic chemistry involved. Although in some cases the yields of products are quite small, the diversity of the detected compounds of biochemical significance underlines the prebiotic importance of meteorite-catalyzed condensation of formamide.
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http://dx.doi.org/10.3390/life8010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871938PMC
February 2018

Regioselective IBX-Mediated Synthesis of Coumarin Derivatives with Antioxidant and Anti-influenza Activities.

J Nat Prod 2017 12 13;80(12):3247-3254. Epub 2017 Dec 13.

Department of Ecology and Biology, University of Tuscia , Via C. De Lellis, Viterbo, 01100, Italy.

Different catechol and pyrogallol derivatives have been synthesized by oxidation of coumarins with 2-iodoxybenzoic acid (IBX) in DMSO at 25 °C. A high regioselectivity was observed in accordance with the stability order of the incipient carbocation or radical benzylic-like intermediate. The oxidation was also effective in water under heterogeneous conditions by using IBX supported on polystyrene. The new derivatives showed improved antioxidant effects in the DPPH test and inhibitory activity against the influenza A/PR8/H1N1 virus. These data represent a new entry for highly oxidized coumarins showing an antiviral activity possibly based on the control of the intracellular redox value.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00665DOI Listing
December 2017

Proton irradiation: a key to the challenge of N-glycosidic bond formation in a prebiotic context.

Sci Rep 2017 11 7;7(1):14709. Epub 2017 Nov 7.

Department of Ecological and Biological Sciences, Via S. Camillo de Lellis, University of Tuscia, 01100, Viterbo, Italy.

The formation of nucleosides in abiotic conditions is a major hurdle in origin-of-life studies. We have determined the pathway of a general reaction leading to the one-pot synthesis of ribo- and 2'-deoxy-ribonucleosides from sugars and purine nucleobases under proton irradiation in the presence of a chondrite meteorite. These conditions simulate the presumptive conditions in space or on an early Earth fluxed by slow protons from the solar wind, potentially mimicking a plausible prebiotic scenario. The reaction (i) requires neither pre-activated precursors nor intermediate purification/concentration steps, (ii) is based on a defined radical mechanism, and (iii) is characterized by stereoselectivity, regioselectivity and (poly)glycosylation. The yield is enhanced by formamide and meteorite relative to the control reaction.
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http://dx.doi.org/10.1038/s41598-017-15392-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677017PMC
November 2017

Drug repurposing approaches to fight Dengue virus infection and related diseases.

Front Biosci (Landmark Ed) 2018 Jan 1;23:997-1019. Epub 2018 Jan 1.

Department of Food and Drug, University of Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy,

Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of Dengue Virus (DENV), namely DENV1-4 and is currently considered the most important arthropod-born viral disease in the world. An effective antiviral therapy to treat Dengue Virus infection is still missing and a number of replicative cycle inhibitors are currently under study. Considering the rapid spreading of DENV and the common timeframe required for bringing a new drug on the market, the repurposing of approved drugs used for different diseases to identify novel inhibitors of this pathogen represents an attractive approach for a rapid therapeutic intervention. Herein, we will describe the most recent drug repurposing approaches to fight DENV infection and their implications in antiviral drug-discovery.
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http://dx.doi.org/10.2741/4630DOI Listing
January 2018

Advances in biotechnological synthetic applications of carbon nanostructured systems.

J Mater Chem B 2017 Aug 27;5(32):6490-6510. Epub 2017 Jun 27.

Department of Biological and Ecological Sciences (DEB), University of Tuscia, Via S. Camillo de Lellis snc, 01100 Viterbo, Italy.

In the last few years carbon nanostructures have been applied for the immobilization of enzymes and biomimetic organo-metallic species useful for biotechnological applications. The nature of the support and the method of immobilization are responsible for the stability, reactivity and selectivity of the system. In this review, we focus on the recent advances in the use of carbon nanostructures, carbon nanotubes, carbon nanorods, fullerene and graphene for the preparation of biocatalytic and biomimetic systems and for their application in the development of green chemical processes.
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http://dx.doi.org/10.1039/c7tb00764gDOI Listing
August 2017

Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer.

J Med Chem 2017 09 22;60(17):7447-7458. Epub 2017 Aug 22.

DiSTABiF, Università della Campania "Luigi Vanvitelli" , Via Vivaldi 43, 81100 Caserta, Italy.

Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an "in silico drug repurposing" approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00794DOI Listing
September 2017

Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment.

J Med Chem 2017 05 1;60(9):3626-3635. Epub 2017 May 1.

DiSTABiF, University of Campania Luigi Vanvitelli , 81100 Caserta, Italy.

G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells, and has an antiproliferative effect in BRCA2 deficient tumor cells.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01563DOI Listing
May 2017

One drug for two targets: Biological evaluation of antiretroviral agents endowed with antiproliferative activity.

Bioorg Med Chem Lett 2017 06 1;27(11):2502-2505. Epub 2017 Apr 1.

Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain.

AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.
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http://dx.doi.org/10.1016/j.bmcl.2017.03.097DOI Listing
June 2017

Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma.

Eur J Med Chem 2017 Feb 19;127:369-378. Epub 2016 Dec 19.

Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy. Electronic address:

In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC value of 7.1 μM.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.036DOI Listing
February 2017