Publications by authors named "Bruno Mattia Bizzarri"

16 Publications

  • Page 1 of 1

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

ChemMedChem 2021 Jul 7;16(14):2270-2277. Epub 2021 May 7.

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
July 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

Prebiotic Organic Chemistry of Formamide and the Origin of Life in Planetary Conditions: What We Know and What Is the Future.

Int J Mol Sci 2021 Jan 18;22(2). Epub 2021 Jan 18.

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

The goal of prebiotic chemistry is the depiction of molecular evolution events preceding the emergence of life on Earth or elsewhere in the cosmos. Plausible experimental models require geochemical scenarios and robust chemistry. Today we know that the chemical and physical conditions for life to flourish on Earth were at work much earlier than thought, i.e., earlier than 4.4 billion years ago. In recent years, a geochemical model for the first five hundred million years of the history of our planet has been devised that would work as a cradle for life. Serpentinization processes in the Hadean eon affording self-assembled structures and vesicles provides the link between the catalytic properties of the inorganic environment and the impressive chemical potential of formamide to produce complete panels of organic molecules relevant in pre-genetic and pre-metabolic processes. Based on an interdisciplinary approach, we propose basic transformations connecting geochemistry to the chemistry of formamide, and we hint at the possible extension of this perspective to other worlds.
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http://dx.doi.org/10.3390/ijms22020917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831497PMC
January 2021

High-Energy Proton-Beam-Induced Polymerization/Oxygenation of Hydroxynaphthalenes on Meteorites and Nitrogen Transfer from Urea: Modeling Insoluble Organic Matter?

Chemistry 2020 Nov 16;26(65):14919-14928. Epub 2020 Oct 16.

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

Formation and structural modification of oxygenated polycyclic aromatic hydrocarbons (oxyPAHs) by UV irradiation on minerals have recently been proposed as a possible channel of PAH transformation in astrochemical and prebiotic scenarios of possible relevance for the origin of life. Herein, it is demonstrated that high-energy proton-beam irradiation in the presence of various meteorites, including stony iron, achondrite, and chondrite types, promotes the conversion of two representative oxyPAH compounds, 1-naphthol and 1,8-dihydroxynaphthalene, to complex mixtures of oxygenated and oligomeric derivatives. The main identified products include polyhydroxy derivatives, isomeric dimers encompassing benzofuran and benzopyran scaffolds, and, notably, a range of quinones and perylene derivatives. Addition of urea, a prebiotically relevant chemical precursor, expanded the range of identified species to include, among others, quinone diimines. Proton-beam irradiation of oxyPAH modulated by nitrogen-containing compounds such as urea is proposed as a possible contributory mechanism for the formation and processing of insoluble organic matter in meteorites and in prebiotic processes.
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http://dx.doi.org/10.1002/chem.202002318DOI Listing
November 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

Enzyme-Lignin Nanocapsules Are Sustainable Catalysts and Vehicles for the Preparation of Unique Polyvalent Bioinks.

Biomacromolecules 2019 05 10;20(5):1975-1988. Epub 2019 Apr 10.

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

Reactive lignin nanocapsules catalyze a pigmentation reaction to furnish an innovative type of sustainable polyvalent bioink. In this nanodevice, the pigment, vehicle, binder, and additive are included in a single confined spherical space. Bioinks with different shades of color, black, gray, yellow-like, pink-like, and red/brown hues, have been prepared by selecting the reactants and the pigmentation process. Lignin nanocapsules play multiple functions in the support and activation of the enzyme necessary for the synthesis of pigments. Lignin nanocapsules protected the melanin pigment from alkaline and UV-degradation treatment.
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http://dx.doi.org/10.1021/acs.biomac.9b00198DOI Listing
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

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

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

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

A Global Scale Scenario for Prebiotic Chemistry: Silica-Based Self-Assembled Mineral Structures and Formamide.

Biochemistry 2016 05 2;55(19):2806-11. Epub 2016 May 2.

Laboratorio de Estudios Crystalográficos, Instituto Andauz de Ciencias de la Tierra, CSIC-Universidad de Granada , Avenida de las Palmeras 4, E-18100 Armilla, Granada, Spain.

The pathway from simple abiotically made organic compounds to the molecular bricks of life, as we know it, is unknown. The most efficient geological abiotic route to organic compounds results from the aqueous dissolution of olivine, a reaction known as serpentinization (Sleep, N.H., et al. (2004) Proc. Natl. Acad. Sci. USA 101, 12818-12822). In addition to molecular hydrogen and a reducing environment, serpentinization reactions lead to high-pH alkaline brines that can become easily enriched in silica. Under these chemical conditions, the formation of self-assembled nanocrystalline mineral composites, namely silica/carbonate biomorphs and metal silicate hydrate (MSH) tubular membranes (silica gardens), is unavoidable (Kellermeier, M., et al. In Methods in Enzymology, Research Methods in Biomineralization Science (De Yoreo, J., Ed.) Vol. 532, pp 225-256, Academic Press, Burlington, MA). The osmotically driven membranous structures have remarkable catalytic properties that could be operating in the reducing organic-rich chemical pot in which they form. Among one-carbon compounds, formamide (NH2CHO) has been shown to trigger the formation of complex prebiotic molecules under mineral-driven catalytic conditions (Saladino, R., et al. (2001) Biorganic & Medicinal Chemistry, 9, 1249-1253), proton irradiation (Saladino, R., et al. (2015) Proc. Natl. Acad. Sci. USA, 112, 2746-2755), and laser-induced dielectric breakdown (Ferus, M., et al. (2015) Proc Natl Acad Sci USA, 112, 657-662). Here, we show that MSH membranes are catalysts for the condensation of NH2CHO, yielding prebiotically relevant compounds, including carboxylic acids, amino acids, and nucleobases. Membranes formed by the reaction of alkaline (pH 12) sodium silicate solutions with MgSO4 and Fe2(SO4)3·9H2O show the highest efficiency, while reactions with CuCl2·2H2O, ZnCl2, FeCl2·4H2O, and MnCl2·4H2O showed lower reactivities. The collections of compounds forming inside and outside the tubular membrane are clearly specific, demonstrating that the mineral self-assembled membranes at the same time create space compartmentalization and selective catalysis of the synthesis of relevant compounds. Rather than requiring odd local conditions, the prebiotic organic chemistry scenario for the origin of life appears to be common at a universal scale and, most probably, earlier than ever thought for our planet.
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http://dx.doi.org/10.1021/acs.biochem.6b00255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872262PMC
May 2016

Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family.

J Med Chem 2016 Mar 8;59(6):2747-59. Epub 2016 Mar 8.

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

Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01979DOI Listing
March 2016

Carbon nanotubes supported tyrosinase in the synthesis of lipophilic hydroxytyrosol and dihydrocaffeoyl catechols with antiviral activity against DNA and RNA viruses.

Bioorg Med Chem 2015 Sep 30;23(17):5345-51. Epub 2015 Jul 30.

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

Hydroxytyrosol and dihydrocaffeoyl catechols with lipophilic properties have been synthesized in high yield using tyrosinase immobilized on multi-walled carbon nanotubes by the Layer-by-Layer technique. All synthesized catechols were evaluated against a large panel of DNA and RNA viruses, including Poliovirus type 1, Echovirus type 9, Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Coxsackievirus type B3 (Cox B3), Adenovirus type 2 and type 5 and Cytomegalovirus (CMV). A significant antiviral activity was observed in the inhibition of HSV-1, HSV-2, Cox B3 and CMV. The mechanism of action of the most active dihydrocaffeoyl derivative was investigated against a model of HSV-1 infection.
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http://dx.doi.org/10.1016/j.bmc.2015.07.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125559PMC
September 2015

Current Advances in L-DOPA and DOPA-Peptidomimetics: Chemistry, Applications and Biological Activity.

Curr Med Chem 2015 ;22(36):4138-65

Dipartimento di Ecologia e Biologia, University of Tuscia, Via S. Camillo de Lellis snc, 01100 Viterbo Italy.

L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L-DOPA) is a natural constituent of animal and plant tissue derived from post-translational modification of the amino acid tyrosine. L-DOPA is modified during metabolism to catecholamine neurotransmitters, noradrenaline and adrenaline, which are characterized by different biological activities. L-DOPA has been the first drug of choice in the therapy of Parkinson's disease that is a progressive neurodegenerative disorder involving the loss of dopaminergic neurons of substantia nigra pars compacta. The social and economic impact of these diseases is very high due to the progressive aging of the population. This review focuses on the biological effect of LDOPA, as well as on the synthesis of L-DOPA derivatives and their application in central nervous system diseases. Among them, L-DOPA-containing peptides (L-DOPA-Pep) show important biological and pharmacological activities. For example, L-DOPA analogues of the alpha-factor interact with models of the G protein-coupled receptor, inhibit the oxidation of low-density lipoproteins, and are used for improving L-DOPA absorption in long-term treatment of Parkinson's disease and as skin moisturizer in cosmetic compositions. Moreover, L-DOPA residues in proteins provide reactive tools for the preparation of adhesives and coatings materials. Usually, L-DOPA-Pep is prepared by traditional liquid or solid state procedures starting from simple amino acids. Recently, selective side-chain modifications of pre-formed peptides have also been reported both for linear and branched peptides. Here, we describe the recent advances in the synthesis of L-DOPA and dopa-peptidomimetics and their biological and pharmacological activities, focusing the attention on new synthetic procedures and biological mechanism of actions.
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http://dx.doi.org/10.2174/0929867322666150625095748DOI Listing
September 2016
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