Publications by authors named "Bruno Botta"

95 Publications

Exploring the Assembly of Resorc[4]arenes for the Construction of Supramolecular Nano-Aggregates.

Int J Mol Sci 2021 Oct 29;22(21). Epub 2021 Oct 29.

Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Many biologically active compounds feature low solubility in aqueous media and, thus, poor bioavailability. The formation of the host-guest complex by using calixarene-based macrocycles (i.e., resorcinol-derived cyclic oligomers) with a good solubility profile can improve solubilization of hydrophobic drugs. Herein, we explore the ability of resorc[4]arenes to self-assemble in polar solutions, to form supramolecular aggregates, and to promote water-solubility of an isoflavone endowed with anti-cancer activity, namely Glabrescione B (GlaB). Accordingly, we synthesized several architectures featuring a different pattern of substitution on the upper rim including functional groups able to undergo acid dissociation (i.e., carboxyl and hydroxyl groups). The aggregation phenomenon of the amphiphilic resorc[4]arenes has been investigated in a THF/water solution by UV-visible spectroscopy, at different pH values. Based on their ionization properties, we demonstrated that the supramolecular assembly of resorc[4]arene-based systems can be modulated at given pH values, and thus promoting the solubility of GlaB.
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http://dx.doi.org/10.3390/ijms222111785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584166PMC
October 2021

Identification of Effective Anticancer G-Quadruplex-Targeting Chemotypes through the Exploration of a High Diversity Library of Natural Compounds.

Pharmaceutics 2021 Oct 3;13(10). Epub 2021 Oct 3.

Department of Chemical Sciences, University of Naples Federico II (Complesso Universitario di Monte S. Angelo), Via Cintia, 21, 80126 Napoli, Italy.

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand individual natural products was investigated. The combination of molecular docking-based virtual screening and the G4-CPG experimental screening assay proved to be useful to quickly and effectively identify-out of many natural compounds-five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Indeed, the selected ligands proved to specifically interact with G4 structures due to peculiar interaction patterns, while they were unable to firmly bind to a DNA duplex. From biological assays, Chelidonine and Rotenone emerged as the most active compounds of the series against cancer cells, also showing good selectivity over normal cells. Notably, the anticancer activity correlated well with the ability of the two compounds to target telomeric G4s.
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http://dx.doi.org/10.3390/pharmaceutics13101611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537501PMC
October 2021

Editorial: Secondary Metabolites and Peptides as Unique Natural Reservoirs of New Therapeutic Leads for Treatment of Cancer and Microbial Infections.

Front Chem 2021 12;9:748180. Epub 2021 Aug 12.

Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University, Rome, Italy.

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http://dx.doi.org/10.3389/fchem.2021.748180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387627PMC
August 2021

Δ--Tetrahydrocannabinol: Natural Occurrence, Chirality, and Pharmacology.

J Nat Prod 2021 Sep 25;84(9):2502-2510. Epub 2021 Jul 25.

Dipartimento di Scienze del Farmaco, Largo Donegani 2, 28100 Novara, Italy.

The -stereoisomers of Δ-THC [(-)- and (+)-] were identified and quantified in a series of low-THC-containing varieties of registered in Europe as fiber hemp and in research accessions of cannabis. While Δ--THC () occurs in cannabis fiber hemp in the concentration range of (-)-Δ--THC [(-)-], it was undetectable in a sample of high-THC-containing medicinal cannabis. Natural Δ--THC () is scalemic (ca. 80-90% enantiomeric purity), and the absolute configuration of the major enantiomer was established as 6a,10a [(-)-] by chiral chromatographic comparison with a sample available by asymmetric synthesis. The major enantiomer, (-)-Δ--THC [(-)-], was characterized as a partial cannabinoid agonist in vitro and elicited a full tetrad response in mice at 50 mg/kg doses. The current legal discrimination between narcotic and non-narcotic cannabis varieties centers on the contents of "Δ-THC and isomers" and needs therefore revision, or at least a more specific wording, to account for the presence of Δ--THCs [(+)- and (-)-] in cannabis fiber hemp varieties.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00513DOI Listing
September 2021

Neuro-Signals from Gut Microbiota: Perspectives for Brain Glioma.

Cancers (Basel) 2021 Jun 4;13(11). Epub 2021 Jun 4.

IRCCS Neuromed, 86077 Pozzilli, IS, Italy.

Glioblastoma (GBM) is the most aggressive form of glioma tumor in adult brain. Among the numerous factors responsible for GBM cell proliferation and invasion, neurotransmitters such as dopamine, serotonin and glutamate can play key roles. Studies performed in mice housed in germ-free (GF) conditions demonstrated the relevance of the gut-brain axis in a number of physiological and pathological conditions. The gut-brain communication is made possible by vagal/nervous and blood/lymphatic routes and pave the way for reciprocal modulation of functions. The gut microbiota produces and consumes a wide range of molecules, including neurotransmitters (dopamine, norepinephrine, serotonin, gamma-aminobutyric acid [GABA], and glutamate) that reach their cellular targets through the bloodstream. Growing evidence in animals suggests that modulation of these neurotransmitters by the microbiota impacts host neurophysiology and behavior, and affects neural cell progenitors and glial cells, along with having effects on tumor cell growth. In this review we propose a new perspective connecting neurotransmitter modulation by gut microbiota to glioma progression.
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http://dx.doi.org/10.3390/cancers13112810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200200PMC
June 2021

A Multimethodological Characterization of L. Inflorescences from Seven Dioecious Cultivars Grown in Italy: The Effect of Different Harvesting Stages.

Molecules 2021 May 14;26(10). Epub 2021 May 14.

Institute for Biological Systems, Magnetic Resonance Laboratory "Segre-Capitani", CNR, Via Salaria Km 29.300, 00015 Monterotondo, Italy.

The chemical profile of the female inflorescence extracts from seven L. dioecious cultivars (Carmagnola, Fibranova, Eletta Campana, Antal, Tiborszallasi, Kompolti, and Tisza) was monitored at three harvesting stages (4, 14, and 30 September), reaching from the beginning of flowering to end of flowering/beginning of seed formation, using untargeted nuclear magnetic resonance (NMR) and targeted (ultra-high-performance liquid chromatography (UHPLC) and spectrophotometry) analyses. The tetrahydrocannabinol content was always below the legal limits (<0.6%) in all the analyzed samples. The NMR metabolite profile (sugars, organic acids, amino acids, and minor compounds) subjected to principal components analysis (PCA) showed a strong variability according to the harvesting stages: samples harvested in stage I were characterized by a high content of sucrose and myo-inositol, whereas the ones harvested in stage II showed high levels of succinic acid, alanine, valine, isoleucine, phenylalanine, and threonine. Samples harvested in stage III were characterized by high levels of glucose, fructose, choline, trigonelline, malic acid, formic acid, and some amino acids. The ratio between chlorophylls and carotenoids content indicated that all plants grew up exposed to the sun, the Eletta Campana cultivar having the highest pigment amount. Tiborszallasi cultivar showed the highest polyphenol content. The highest antioxidant activity was generally observed in stage II. All these results suggested that the L. inflorescences of each analyzed dioecious hemp cultivar presented a peculiar chemical profile affected by the harvesting stage. This information could be useful for producers and industries to harvest inflorescences in the appropriate stage to obtain samples with a peculiar chemical profile suitable for proper applications.
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http://dx.doi.org/10.3390/molecules26102912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156653PMC
May 2021

Active Components from Prevent HIV-1 Entry by Distinct Mechanisms of Action.

Int J Mol Sci 2021 May 10;22(9). Epub 2021 May 10.

Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg.

is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of , and showed that six bioactive compounds inhibit HIV-1 infection. In the present study, we demonstrate that the six compounds block HIV-1 entry into cells: oleanolic acid, palmitic acid, taxifolin, piceatannol, guibourtinidol-(4α→8)-epiafzelechin, and a novel compound named as cassiabrevone. We report, for the first time, that guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone inhibit HIV-1 entry (IC of 42.47 µM and 30.96 µM, respectively), as well as that piceatannol interacts with cellular membranes. Piceatannol inhibits HIV-1 infection in a dual-chamber assay mimicking the female genital tract, as well as HSV infection, emphasizing its potential as a microbicide. Structure-activity relationships (SAR) showed that pharmacophoric groups of piceatannol are strictly required to inhibit HIV-1 entry. By a ligand-based in silico study, we speculated that piceatannol and norartocarpetin may have a very similar mechanism of action and efficacy because of the highly comparable pharmacophoric and 3D space, while guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone may display a different mechanism. We finally show that cassiabrevone plays a major role of the crude extract of by blocking the binding activity of HIV-1 gp120 and CD4.
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http://dx.doi.org/10.3390/ijms22095052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126241PMC
May 2021

Design and Synthesis of Piperazine-Based Compounds Conjugated to Humanized Ferritin as Delivery System of siRNA in Cancer Cells.

Bioconjug Chem 2021 06 12;32(6):1105-1116. Epub 2021 May 12.

Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), V.le Regina Elena 291, 00161 Rome, Italy.

Gene expression regulation by small interfering RNA (siRNA) holds promise in treating a wide range of diseases through selective gene silencing. However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively charged siRNA duplexes, the internal cavity of "humanized" chimeric Archaeal ferritin (HumAfFt) was specifically decorated with novel cationic piperazine-based compounds (PAs). By coupling these rigid-rod-like amines with thiol-reactive reagents, chemoselective conjugation was efficiently afforded on topologically selected cysteine residues properly located inside HumAfFt. The capability of PAs-HumAfFt to host and deliver siRNA molecules through human transferrin receptor (TfR1), overexpressed in many cancer cells, was explored. These systems allowed siRNA delivery into HeLa, HepG2, and MCF-7 cancer cells with improved silencing effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression with respect to traditional transfection methodologies and provided a promising TfR1-targeting system for multifunctional siRNA delivery to therapeutic applications.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253483PMC
June 2021

Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors.

Chemistry 2021 Jun 4;27(32):8350-8357. Epub 2021 May 4.

Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, 20133, Milan, Italy.

Withanolides constitute a well-known family of plant-based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds.
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http://dx.doi.org/10.1002/chem.202100315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251939PMC
June 2021

Sempervirine inhibits RNA polymerase I transcription independently from p53 in tumor cells.

Cell Death Discov 2020 Oct 28;6(1):111. Epub 2020 Oct 28.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

In the search of small molecules that can target MDM2/p53 pathway in testicular germ cell tumors (TGCTs), we identified sempervirine (2,3,4,13-tetrahydro-1H-benz[g]indolo[2,3-a]quinolizin-6-ium), an alkaloid of Gelsemium sempervirens, that has been previously proposed as an inhibitor of MDM2 that targets p53-wildtype (wt) tumor cells. We found that sempervirine not only affects cell growth of p53-wt cancer cells, but it is also active in p53-mutated and p53-null cells by triggering p53-dependent and independent pathways without affecting non-transformed cells. To understand which mechanism/s could be activated both in p53-wt and -null cells, we found that sempervirine induced nucleolar remodeling and nucleolar stress by reducing protein stability of RPA194, the catalytic subunit of RNA polymerase I, that led to rRNA synthesis inhibition and to MDM2 block. As shown for other cancer cell models, MDM2 inhibition by nucleolar stress downregulated E2F1 protein levels both in p53-wt and p53-null TGCT cells with the concomitant upregulation of unphosphorylated pRb. Finally, we show that sempervirine is able to enter the nucleus and accumulates within the nucleolus where it binds rRNA without causing DNA damage. Our results identify semperivirine as a novel rRNA synthesis inhibitor and indicate this drug as a non-genotoxic anticancer small molecule.
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http://dx.doi.org/10.1038/s41420-020-00345-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595235PMC
October 2020

Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma.

Cancer Lett 2021 02 26;499:220-231. Epub 2020 Nov 26.

Department of Molecular Medicine, University La Sapienza, Roma, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, University La Sapienza, Roma, Italy. Electronic address:

Aberrant activation of the Hedgehog (Hh) pathway leads to the development of several tumors, including medulloblastoma (MB), the most common pediatric brain malignancy. Hh inhibitors acting on GLI1, the final effector of Hh signaling, offer a valuable opportunity to overcome the pitfalls of the existing therapies to treat Hh-driven cancers. In this study, the toxicity, delivery, biodistribution, and anticancer efficacy of Glabrescione B (GlaB), a selective GLI1 inhibitor, were investigated in preclinical models of Hh-dependent MB. To overcome its poor water solubility, GlaB was formulated with a self-assembling amphiphilic polymer forming micelles, called mPEG-cholane. mPEG-cholane/GlaB showed high drug loading and stability, low cytotoxicity, and long permanence in the bloodstream. We found that mPEG-cholane efficiently enhanced the solubility of GlaB, thus avoiding the use of organic solvents. mPEG-cholane/GlaB possesses favorable pharmacokinetics and negligible toxicity. Remarkably, GlaB encapsulated in mPEG-cholane micelles was delivered through the blood-brain barrier and drastically inhibited tumor growth in both allograft and orthotopic models of Hh-dependent MB. Our findings reveal that mPEG-cholane/GlaB is a good candidate for the treatment of Hh-driven tumors and provide relevant implications for the translation of GlaB into clinical practice.
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http://dx.doi.org/10.1016/j.canlet.2020.11.028DOI Listing
February 2021

Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies.

Bioorg Chem 2020 12 12;105:104373. Epub 2020 Oct 12.

Faculty of Sciences, Department of Chemistry, University of Kragujevac, R. Domanovica 12, 34000 Kragujevac, Serbia. Electronic address:

A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD values obtained by the experimental method were found to be in the range from -1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104373DOI Listing
December 2020

Improved identification of phytocannabinoids using a dedicated structure-based workflow.

Talanta 2020 Nov 29;219:121310. Epub 2020 Jun 29.

Department of Chemistry, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy; CNR NANOTEC, Campus Ecotekne, University of Salento, Via Monteroni, 73100, Lecce, Italy.

Phytocannabinoids are a broad class of compounds uniquely synthesized by the various strains of Cannabis sativa. Up to date, most investigation on phytocannabinoids have been addressed to the most abundant species, Δ-tetrahydrocannabinol and cannabidiol, for their well-known wide range of pharmaceutical activities. However, in the recent years a large number of minor constituents have been reported, whose role in cannabis pharmacological effects is of current scientific interest. With the purpose of gaining knowledge on major and minor species and furnishing a strategy for their untargeted analysis, in this study we present an innovative approach for comprehensively identifying phytocannabinoids based on high-resolution mass spectrometry in negative ion mode, which allows discrimination of the various isomeric species. For a faster and more reliable manual validation of the tandem mass spectra of known and still unknown species, an extensive database of phytocannabinoid derivatives was compiled and implemented on Compound Discoverer software for the setup of a dedicated data analysis tool. The method was applied to extracts of the Italian FM-2 medicinal cannabis, resulting in the identification of 121 phytocannabinoids, which is the highest number ever reported in a single analysis. Among those, many known and still unknown unconventional phytocannabinoids have been tentatively identified, another piece in the puzzle of unravelling the many uncharted applications of this matrix.
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http://dx.doi.org/10.1016/j.talanta.2020.121310DOI Listing
November 2020

-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors.

J Org Chem 2020 08 10;85(16):10891-10901. Epub 2020 Aug 10.

Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural -beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an -beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The -beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.
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http://dx.doi.org/10.1021/acs.joc.0c01459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009527PMC
August 2020

Naturally-Occurring Alkaloids of Plant Origin as Potential Antimicrobials against Antibiotic-Resistant Infections.

Molecules 2020 Aug 9;25(16). Epub 2020 Aug 9.

Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Antibiotic resistance is now considered a worldwide problem that puts public health at risk. The onset of bacterial strains resistant to conventional antibiotics and the scarcity of new drugs have prompted scientific research to re-evaluate natural products as molecules with high biological and chemical potential. A class of natural compounds of significant importance is represented by alkaloids derived from higher plants. In this review, we have collected data obtained from various research groups on the antimicrobial activities of these alkaloids against conventional antibiotic-resistant strains. In addition, the structure-function relationship was described and commented on, highlighting the high potential of alkaloids as antimicrobials.
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http://dx.doi.org/10.3390/molecules25163619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466045PMC
August 2020

Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities.

Molecules 2020 Jun 23;25(12). Epub 2020 Jun 23.

Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.

With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model ( grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells.
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http://dx.doi.org/10.3390/molecules25122894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356228PMC
June 2020

The Revaluation of Plant-Derived Terpenes to Fight Antibiotic-Resistant Infections.

Antibiotics (Basel) 2020 Jun 13;9(6). Epub 2020 Jun 13.

Center For Life Nano [email protected], Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.

The discovery of antibiotics has revolutionized the medicine and treatment of microbial infections. However, the current scenario has highlighted the difficulties in marketing new antibiotics and an exponential increase in the appearance of resistant strains. On the other hand, research in the field of drug-discovery has revaluated the potential of natural products as a unique source for new biologically active molecules and scaffolds for the medicinal chemistry. In this review, we first contextualized the worldwide problem of antibiotic resistance and the importance that natural products of plant origin acquire as a source of new lead compounds. We then focused on terpenes and their potential development as antimicrobials, highlighting those studies that showed an activity against conventional antibiotic-resistant strains.
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http://dx.doi.org/10.3390/antibiotics9060325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344648PMC
June 2020

A novel colistin adjuvant identified by virtual screening for ArnT inhibitors.

J Antimicrob Chemother 2020 09;75(9):2564-2572

Department of Sciences, 'Department of Excellence 2018 - 2022', Roma Tre University, Rome, Italy.

Background: Colistin is a last-resort treatment option for many MDR Gram-negative bacteria. The covalent addition of l-aminoarabinose to the lipid A moiety of LPS is the main colistin resistance mechanism in the human pathogen Pseudomonas aeruginosa.

Objectives: Identification (by in silico screening of a chemical library) of potential inhibitors of ArnT, which catalyses the last committed step of lipid A aminoarabinosylation, and their validation in vitro as colistin adjuvants.

Methods: The available ArnT crystal structure was used for a docking-based virtual screening of an in-house library of natural products. The resulting putative ArnT inhibitors were tested in growth inhibition assays using a reference colistin-resistant P. aeruginosa strain. The most promising compound was further characterized for its range of activity, specificity and cytotoxicity. Additionally, the effect of the compound on lipid A aminoarabinosylation was verified by MS analyses of lipid A.

Results: A putative ArnT inhibitor (BBN149) was discovered by molecular docking and demonstrated to specifically potentiate colistin activity in colistin-resistant P. aeruginosa isolates, without relevant effect on colistin-susceptible strains. BBN149 also showed adjuvant activity against colistin-resistant Klebsiella pneumoniae and low toxicity to bronchial epithelial cells. Lipid A aminoarabinosylation was reduced in BBN149-treated cells, although only partially.

Conclusions: This study demonstrates that in silico screening targeting ArnT can successfully identify inhibitors of colistin resistance and provides a promising lead compound for the development of colistin adjuvants for the treatment of MDR bacterial infections.
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http://dx.doi.org/10.1093/jac/dkaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443731PMC
September 2020

Structural Elucidation and Antimicrobial Characterization of Novel Diterpenoids from var. .

ACS Med Chem Lett 2020 May 30;11(5):760-765. Epub 2020 Jan 30.

Department of Biochemical Sciences, Laboratory Affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le Aldo Moro 5 00185, Rome, Italy.

Novel diterpenoids were isolated from the extracts of var. and found to display a selective activity against Gram-positive bacterial strains with negligible cytotoxicity toward human keratinocytes. This study highlighted the role played by the acidic group at C18 of the tetracyclic ent-beyerene scaffold for antibacterial effects and how the length and flexibility of the alkyl chain between the two carbonyl groups are crucial factors to increase the antimicrobial activity of the molecules, supporting the development of natural products from and their derivatives for treatment of microbial infections.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236223PMC
May 2020

Dual SMO/BRAF Inhibition by Flavonolignans from .

Antioxidants (Basel) 2020 May 5;9(5). Epub 2020 May 5.

Department of QSAR and Molecular Modelling, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

Silymarin is the standardized extract from the fruits of (L.) Gaertn., a well-known hepatoprotectant and antioxidant. Recently, bioactive compounds of silymarin, i.e., silybins and their 2,3-dehydro derivatives, have been shown to exert anticancer activities, yet with unclear mechanisms. This study combines in silico and in vitro methods to reveal the potential interactions of optically pure silybins and dehydrosilybins with novel protein targets. The shape and chemical similarity with approved drugs were evaluated in silico, and the potential for interaction with the Hedgehog pathway receptor Smoothened (SMO) and BRAF kinase was confirmed by molecular docking. In vitro studies on SMO and BRAF V600E kinase activity and in BRAF V600E A-375 human melanoma cell lines were further performed to examine their effects on these proteins and cancer cell lines and to corroborate computational predictions. Our in silico results direct to new potential targets of silymarin constituents as dual inhibitors of BRAF and SMO, two major targets in anticancer therapy. The experimental studies confirm that BRAF kinase and SMO may be involved in mechanisms of anticancer activities, demonstrating dose-dependent profiles, with dehydrosilybins showing stronger effects than silybins. The results of this work outline the dual SMO/BRAF effect of flavonolignans from Silybum marianum with potential clinical significance. Our approach can be applied to other natural products to reveal their potential targets and mechanism of action.
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http://dx.doi.org/10.3390/antiox9050384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278695PMC
May 2020

L. Inflorescences from Monoecious Cultivars Grown in Central Italy: An Untargeted Chemical Characterization from Early Flowering to Ripening.

Molecules 2020 Apr 20;25(8). Epub 2020 Apr 20.

Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

The chemical composition of the inflorescences from four L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and -cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.
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http://dx.doi.org/10.3390/molecules25081908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221798PMC
April 2020

Site-Directed Antibody Immobilization by Resorc[4]arene-Based Immunosensors.

Chemistry 2020 Jul 25;26(38):8400-8406. Epub 2020 Jun 25.

Department of Chemistry and Technology of Drugs, Department of Excellence 2018-2022, Sapienza University of Rome, P.le Aldo Moro 5, 00185, Rome, Italy.

One of the main problems in the development of immunosensors is to overcome the complexity of binding antibodies to the sensor surface. Most immobilizing methods lead to a random orientation of antibodies with a lower binding site density and immunoaffinity. In order to control the orientation of antibody immobilization, several resorc[4]arene derivatives were designed and synthesized. After the spectroscopic characterization of resorc[4]arene self-assembled monolayers (SAMs) onto gold films, the surface coverage and the orientation of insulin antibody (Ab-Ins) were assessed by a surface plasmon resonance (SPR) technique and compared with a random immobilization method. Experimental results combined with theoretical studies confirmed the dipole-dipole interaction as an important factor in antibody orientation and demonstrated the importance of the upper rim functionalization of resorcarenes. Accordingly, resorcarene 5 showed a major binding force towards Ab-Ins thanks to the H-bond interactions with the amine protein groups. Based on these findings, the resorcarene-based immunosensor is a powerful system with improved sensitivity providing new insight into sensor development.
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http://dx.doi.org/10.1002/chem.202000989DOI Listing
July 2020

Hedgehog signaling pathway inhibitors: an updated patent review (2015-present).

Expert Opin Ther Pat 2020 Apr 19;30(4):235-250. Epub 2020 Feb 19.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy.

: Hedgehog (Hh) signaling plays a pivotal role in tissue development and stemness, and its deregulation is found in many different tumors. Several efforts have been devoted to discovery of Hh inhibitors, including three drugs approved by the Food and Drug Administration (FDA), targeting the upstream receptor smoothened (SMO). However, SMO mutations or SMO-independent Hh pathway activation raise the need for novel Hh inhibitors.: This review describes Hh inhibitors with anticancer potential patented in the period 2015-present.: Despite the initial enthusiasm in SMO antagonists, drug-resistant mutations, and SMO-independent Hh activation limited their clinical application. A growing number of therapeutic strategies are currently focusing on downstream Hh effectors (i.e. glioma-associate oncogenes (GLI) proteins) or other signaling pathways related to Hh, in addition to drug repositioning. Given the heterogenic nature of cancers, a terrific clinical impact is expected by multi-targeting approaches able to modulate simultaneously SMO and GLI, and/or additional targets that act as regulators of Hh signaling. It is expected that these alternative strategies might be investigated in clinical trials in the next years against a wide variety of tumor types, and that they provide improved outcomes compared to current SMO antagonists or other single-agent anticancer drugs.
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http://dx.doi.org/10.1080/13543776.2020.1730327DOI Listing
April 2020

The Pictet-Spengler Reaction Updates Its Habits.

Molecules 2020 Jan 19;25(2). Epub 2020 Jan 19.

Center for Life Nano [email protected], Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011-2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed -acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.
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http://dx.doi.org/10.3390/molecules25020414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024544PMC
January 2020

In Memory of Maurizio Botta: His Contribution to the Development of Computer-Aided Drug Design.

J Chem Inf Model 2019 12 5;59(12):4961-4967. Epub 2019 Dec 5.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 Siena , Italy.

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http://dx.doi.org/10.1021/acs.jcim.9b01043DOI Listing
December 2019

Statins interfere with the attachment of mtDNA to the inner mitochondrial membrane.

J Enzyme Inhib Med Chem 2020 Dec;35(1):129-137

Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy.

The 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme of the mevalonate pathway for the synthesis of cholesterol in mammals (ergosterol in fungi), is inhibited by statins, a class of cholesterol lowering drugs. Indeed, statins are in a wide medical use, yet statins treatment could induce side effects as hepatotoxicity and myopathy in patients. We used as a model to investigate the effects of statins on mitochondria. We demonstrate that statins are active in by lowering the ergosterol content in cells and interfering with the attachment of mitochondrial DNA to the inner mitochondrial membrane. Experiments on murine myoblasts confirmed these results in mammals. We propose that the instability of mitochondrial DNA is an early indirect target of statins.
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http://dx.doi.org/10.1080/14756366.2019.1687461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844431PMC
December 2020

A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth.

Cancers (Basel) 2019 Oct 9;11(10). Epub 2019 Oct 9.

Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.

Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound , which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition.
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http://dx.doi.org/10.3390/cancers11101518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826940PMC
October 2019

Nigritanine as a New Potential Antimicrobial Alkaloid for the Treatment of -Induced Infections.

Toxins (Basel) 2019 09 1;11(9). Epub 2019 Sep 1.

Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy.

is a major human pathogen causing a wide range of nosocomial infections including pulmonary, urinary, and skin infections. Notably, the emergence of bacterial strains resistant to conventional antibiotics has prompted researchers to find new compounds capable of killing these pathogens. Nature is undoubtedly an invaluable source of bioactive molecules characterized by an ample chemical diversity. They can act as unique platform providing new scaffolds for further chemical modifications in order to obtain compounds with optimized biological activity. A class of natural compounds with a variety of biological activities is represented by alkaloids, important secondary metabolites produced by a large number of organisms including bacteria, fungi, plants, and animals. In this work, starting from the screening of 39 alkaloids retrieved from a unique library, we identified a heterodimer -carboline alkaloid, nigritanine, with a potent anti- action. Nigritanine, isolated from , was characterized for its antimicrobial activity against a reference and three clinical isolates of Its potential cytotoxicity was also evaluated at short and long term against mammalian red blood cells and human keratinocytes, respectively. Nigritanine showed a remarkable antimicrobial activity (minimum inhibitory concentration of 128 µM) without being toxic in vitro to both tested cells. The analysis of the antibacterial activity related to the nigritanine scaffold furnished new insights in the structure-activity relationships (SARs) of -carboline, confirming that dimerization improves its antibacterial activity. Taking into account these interesting results, nigritanine can be considered as a promising candidate for the development of new antimicrobial molecules for the treatment of -induced infections.
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http://dx.doi.org/10.3390/toxins11090511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783983PMC
September 2019

Severity of urinary incontinence is associated with prevalence of sexual dysfunction.

Int Urogynecol J 2020 08 28;31(8):1669-1674. Epub 2019 Aug 28.

University of Campinas (UNICAMP), School of Medicine, Campinas, Brazil.

Introduction And Hypothesis: Urinary incontinence (UI) affects overall health-related and sexual quality of life (QoL) in women. There is no consensus on the impact of severity and type of UI on the prevalence of sexual dysfunction (DS). The aim of this study was to evaluate the association between types and severity of UI and DS.

Methods: A cross-sectional study of women with UI.

Inclusion Criteria: women complaining of UI and > 18 years old. Women with a history of previous treatment for UI, recurrent urinary tract infections, renal lithiasis, previous radiation therapy or pelvic organ prolapse above stage 2 in the Pelvic Organ Prolapse Quantification (POP-Q) system were excluded. Clinical and epidemiological data were collected, and the following questionnaires were applied: ICIQ-SF, ICIQ-OAB, King's Health Questionnaire (KHQ) and Female Sexual Function Index (FSFI).

Results: Concerning the type of UI, the majority of women had MUI (69.1%) and 56.8% reported having coital UI. The mean score was 20.81 ± 8.45 in the FSFI questionnaire. There was a prevalence of SD in 71.6% of women, with no difference in types of UI (p = 0.753) and loss during sexual intercourse (p = 0.217). There was a correlation between severity of UI (ICIQ-SF) and arousal (r = -0.26; p = 0.008), lubrication (r = -0.25; p = 0.009), orgasm (r = -0.25; p = 0.009), pain (r = -0.26; p = 0.007) and total (r = -0.28; p = 0.004) domain scores.

Conclusions: There is a high prevalence of SD in women with urinary incontinence, irrespective of the type of UI and urine leakage during sexual intercourse. However, the greater the severity of UI is, the worse the sexuality questionnaire scores.
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http://dx.doi.org/10.1007/s00192-019-04092-8DOI Listing
August 2020

H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma.

Cell Commun Signal 2019 08 28;17(1):108. Epub 2019 Aug 28.

IRCCS Neuromed, Pozzilli, IS, Italy.

Background: Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (GlaB) has been recently identified as the first direct inhibitor of Gli1, the downstream effector of the pathway.

Methods: We established the overexpression of Gli1 in murine glioma cells (GL261) and GlaB effect on cell viability. We used H-nuclear magnetic resonance (NMR) metabolomic approach to obtain informative metabolic snapshots of GL261 cells acquired at different time points during GlaB treatment. The activation of AMP activated protein Kinase (AMPK) induced by GlaB was established by western blot. After the orthotopic GL261 cells injection in the right striatum of C57BL6 mice and the intranasal (IN) GlaB/mPEG-Cholane treatment, the tumor growth was evaluated. The High Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS) was used to quantify GlaB in brain extracts of treated mice.

Results: We found that GlaB affected the growth of murine glioma cells both in vitro and in vivo animal model. Using an untargeted H-NMR metabolomic approach, we found that GlaB stimulated the glycolytic metabolism in glioma, increasing lactate production. The high glycolytic rate could in part support the cytotoxic effects of GlaB, since the simultaneous blockade of lactate efflux with α-cyano-4-hydroxycinnamic acid (ACCA) affected glioma cell growth. According to the metabolomic data, we found that GlaB increased the phosphorylation of AMPK, a cellular energy sensor involved in the anabolic-to-catabolic transition.

Conclusions: Our results indicate that GlaB inhibits glioma cell growth and exacerbates Warburg effect, increasing lactate production. In addition, the simultaneous blockade of Gli1 and lactate efflux amplifies the anti-tumor effect in vivo, providing new potential therapeutic strategy for this brain tumor.
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http://dx.doi.org/10.1186/s12964-019-0421-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712882PMC
August 2019
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