Valeria Costantino

Professor of Organic Chemistry

Name Valeria
Surname Costantino
Institution University of Naples – Federico II
E-Mail valeria.costantino@unina.it
Address Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, via Domenico Montesano 49, 80131 Napoli, Italy
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Valeria Costantino

Member PUBLICATIONS

  • Isolation of Smenopyrone, a Bis-γ-Pyrone Polypropionate from the Caribbean Sponge <i>Smenospongia aurea</i>.

    Publication Date: 17/08/2018 on Marine drugs
    by Esposito G, Teta R, Della Sala G, Pawlik JR, Mangoni A, Costantino V
    DOI: 10.3390/md16080285

    The organic extract of the Caribbean sponge has been shown to contain an array of novel chlorinated secondary metabolites derived from a mixed PKS-NRPS biogenetic route such as the smenamides. In this paper, we report the presence of a biogenetically different compound known as smenopyrone, which is a polypropionate containing two γ-pyrone rings. The structure of smenopyrone including its relative and absolute stereochemistry was determined by spectroscopic analysis (NMR, MS, ECD) and supported by a comparison with model compounds from research studies. Pyrone polypropionates are unprecedented in marine sponges but are commonly found in marine mollusks where their biosynthesis by symbiotic bacteria has been hypothesized and at least in one case demonstrated. Since pyrones have recently been recognized as bacterial signaling molecules, we speculate that smenopyrone could mediate inter-kingdom chemical communication between and its symbiotic bacteria.

  • Smenamide A Analogues. Synthesis and Biological Activity on Multiple Myeloma Cells.

    Publication Date: 13/06/2018 on Marine drugs
    by Caso A, Laurenzana I, Lamorte D, Trino S, Esposito G, Piccialli V, Costantino V
    DOI: 10.3390/md16060206

    Smenamides are an intriguing class of peptide/polyketide molecules of marine origin showing antiproliferative activity against lung cancer Calu-1 cells at nanomolar concentrations through a clear pro-apoptotic mechanism. To probe the role of the activity-determining structural features, the 16--analogue of smenamide A and eight simplified analogues in the 16- series were prepared using a flexible synthetic route. The synthetic analogues were tested on multiple myeloma (MM) cell lines showing that the configuration at C-16 slightly affects the activity, since the 16--derivative is still active at nanomolar concentrations. Interestingly, it was found that the truncated compound , mainly composed of the pyrrolinone terminus, was not active, while compound , essentially lacking the pyrrolinone moiety, was 1000-fold less active than the intact substance and was the most active among all the synthesized compounds.

  • Synthesis and Biological Evaluation of a New Structural Simplified Analogue of cADPR, a Calcium-Mobilizing Secondary Messenger Firstly Isolated from Sea Urchin Eggs.

    Publication Date: 10/03/2018 on Marine drugs
    by D'Errico S, Borbone N, Catalanotti B, Secondo A, Petrozziello T, Piccialli I, Pannaccione A, Costantino V, Mayol L, Piccialli G, Oliviero G
    DOI: 10.3390/md16030089

    Herein, we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the "northern" ribose of cADPR was replaced by a pentyl chain and the pyrophosphate moiety by a phophono-phosphate anhydride. The effect of the presence of the new phosphono-phosphate bridge on the intracellular Ca release induced by cpIPP was assessed in PC12 neuronal cells in comparison with the effect of the pyrophosphate bridge of the structurally related cyclic N1-butylinosine diphosphate analogue (cbIDP), which was previously synthesized in our laboratories, and with that of the linear precursor of cpIPP, which, unexpectedly, revealed to be the only one provided with Ca release properties.

  • Identification and chemical characterization of N acyl-homoserine lactone quorum sensing signals across sponge species and time.

    Publication Date: 18/12/2017 on FEMS microbiology ecology
    by Britstein M, Saurav K, Teta R, Sala GD, Bar-Shalom R, Stoppelli N, Zoccarato L, Costantino V, Steindler L
    DOI: 10.1093/femsec/fix182

    Marine sponges form symbiotic relationships with complex microbial communities, yet little is known about the mechanisms by which these microbes regulate their behavior through gene expression. Many bacterial communities regulate gene expression using chemical signaling termed quorum sensing. While a few previous studies have shown presence of N-acyl-homoserine lactones (AHLs) based quorum sensing in marine sponges, the chemical identity of AHL signals has been published for only two sponge species. In this study we screened for AHLs in extracts from 15 sponge species (109 specimens in total) from the Mediterranean and Red Sea, using a wide-range AHL-biosensor. This is the first time that AHL presence was examined over time in sponges. We detected the presence of AHL in 46% of the sponge species, and found that AHL signals differ for certain sponge species in time and across sponge individuals. Furthermore, for the Mediterranean sponge species Sarcotragus fasciculatus, we identified 14 different AHLs. The constant presence of specific AHLs molecules in all specimens, together with varying signaling molecules between the different specimens, make S. fasciculatus a good model to further investigate the function of quorum sensing in sponge-associated bacteria. This study extends the knowledge of AHL-based quorum sensing in marine sponges.

  • Evaluating the Effects of an Organic Extract from the Mediterranean Sponge Geodia cydonium on Human Breast Cancer Cell Lines.

    Publication Date: 09/10/2017 on International journal of molecular sciences
    by Costantini S, Guerriero E, Teta R, Capone F, Caso A, Sorice A, Romano G, Ianora A, Ruocco N, Budillon A, Costantino V, Costantini M
    DOI: 10.3390/ijms18102112

    Marine sponges are an excellent source of bioactive secondary metabolites for pharmacological applications. In the present study, we evaluated the chemistry, cytotoxicity and metabolomics of an organic extract from the Mediterranean marine sponge Geodia cydonium, collected in coastal waters of the Gulf of Naples. We identified an active fraction able to block proliferation of breast cancer cell lines MCF-7, MDA-MB231, and MDA-MB468 and to induce cellular apoptosis, whereas it was inactive on normal breast cells (MCF-10A). Metabolomic studies showed that this active fraction was able to interfere with amino acid metabolism, as well as to modulate glycolysis and glycosphingolipid metabolic pathways. In addition, the evaluation of the cytokinome profile on the polar fractions of three treated breast cancer cell lines (compared to untreated cells) demonstrated that this fraction induced a slight anti-inflammatory effect. Finally, the chemical entities present in this fraction were analyzed by liquid chromatography high resolution mass spectrometry combined with molecular networking.

  • Thermoactinoamide A, an Antibiotic Lipophilic Cyclopeptide from the Icelandic Thermophilic Bacterium Thermoactinomyces vulgaris.

    Publication Date: 22/09/2017 on Journal of natural products
    by Teta R, Marteinsson VT, Longeon A, Klonowski AM, Groben R, Bourguet-Kondracki ML, Costantino V, Mangoni A
    DOI: 10.1021/acs.jnatprod.7b00560

    The thermophilic bacterium Thermoactinomyces vulgaris strain ISCAR 2354, isolated from a coastal hydrothermal vent in Iceland, was shown to contain thermoactinoamide A (1), a new cyclic hexapeptide composed of mixed d and l amino acids, along with five minor analogues (2-6). The structure of 1 was determined by one- and two-dimensional NMR spectroscopy, high-resolution tandem mass spectrometry, and advanced Marfey's analysis of 1 and of the products of its partial hydrolysis. Thermoactinoamide A inhibited the growth of Staphylococcus aureus ATCC 6538 with an MIC value of 35 μM. On the basis of literature data and this work, cyclic hexapeptides with mixed d/l configurations, one aromatic amino acid residue, and a prevalence of lipophilic residues can be seen as a starting point to define a new, easily accessible scaffold in the search for new antibiotic agents.

  • Zeamide, a Glycosylinositol Phosphorylceramide with the Novel Core Arap(1β→6)Ins Motif from the Marine Sponge Svenzea zeai.

    Publication Date: 01/09/2017 on Molecules (Basel, Switzerland)
    by Della Sala G, Teta R, Esposito G, Pawlik JR, Mangoni A, Costantino V
    DOI: 10.3390/molecules22091455

    Glycosylinositol phosphorylceramides (GIPCs) show a great structural diversity, but all share a small number of core structures, with a glucosamine, a mannose, or a glucuronic acid as the first sugar linked to the inositol. The Caribbean sponge Svenzea zeai was shown to consistently contain zeamide (1), the first example of a new class of GIPCs, in which the inositol is glycosylated by a d-arabinose. The structure of zeamide was determined by spectroscopic analysis (NMR, MS, ECD) and microscale chemical degradation. The 6-O-β-d-arabinopyranosyl-myo-inositol (d-Arap(1β→6)Ins) core motif of zeamide is unprecedented not only among GIPCs, but also in any natural glycoconjugate.

  • Studies toward the Synthesis of Smenamide A, an Antiproliferative Metabolite from <i>Smenospongia aurea</i>: Total Synthesis of <i>ent</i>-Smenamide A and 16-<i>epi</i>-Smenamide A.

    Publication Date: 30/04/2017 on ACS omega
    by Caso A, Mangoni A, Piccialli G, Costantino V, Piccialli V
    DOI: 10.1021/acsomega.7b00095

    A chiral pool protocol toward the synthesis of the smenamide family of natural products is described. Two stereoisomers of smenamide A, namely, -smenamide A and 16--smenamide A were synthesized with a 2.6 and 2.5% overall yield, respectively. Their carboxylic acid moieties were assembled starting from -citronellene via two Wittig reactions and a Grignard process. Its coupling with either ()- or ()-dolapyrrolidinone, synthesized from Boc-l-Phe and Boc-d-Phe, respectively, was accomplished by using the Andrus protocol. This work also established the previously unknown relative and absolute configurations of smenamide A.

  • Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation.

    Publication Date: 03/03/2017 on Marine drugs
    by Schirmeister T, Oli S, Wu H, Della Sala G, Costantino V, Seo EJ, Efferth T
    DOI: 10.3390/md15030063

    The 6-epimer of the plakortide H acid (1), along with the endoperoxides plakortide E (2), plakortin (3), and dihydroplakortin (4) have been isolated from a sample of the Caribbean sponge Plakortis halichondrioides. To perform a comparative study on the cytotoxicity towards the drug-sensitive leukemia CCRF-CEM cell line and its multi-drug resistant subline CEM/ADR5000, the acid of plakortin, namely plakortic acid (5), as well as the esters plakortide E methyl ester (6) and 6-epi-plakortide H (7) were synthesized by hydrolysis and Steglich esterification, respectively. The data obtained showed that the acids (1, 2, 5) exhibited potent cytotoxicity towards both cell lines, whereas the esters showed no activity (6, 7) or weaker activity (3, 4) compared to their corresponding acids. Plakortic acid (5) was the most promising derivative with half maximal inhibitory concentration (IC50) values of ca. 0.20 µM for both cell lines.

  • Plakofuranolactone as a Quorum Quenching Agent from the Indonesian Sponge Plakortis cf. lita.

    Publication Date: 28/02/2017 on Marine drugs
    by Costantino V, Della Sala G, Saurav K, Teta R, Bar-Shalom R, Mangoni A, Steindler L
    DOI: 10.3390/md15030059

    There is an urgent need for novel strategies to fight drug resistance and multi-drug resistance. As an alternative to the classic antibiotic therapy, attenuation of the bacteria virulence affecting their Quorum sensing (QS) system is a promising approach. Quorum sensing (QS) is a genetic regulation system that allows bacteria to communicate with each other and coordinate group behaviors. A new γ-lactone that is capable of inhibiting the LasI/R QS system, plakofuranolactone (1), was discovered in the extract of the marine sponge Plakortis cf. lita, and its structure, including absolute configuration, was determined by NMR spectroscopy, MS spectrometry, and quantum-mechanical prediction of optical rotation. The quorum quenching activity of plakofuranolactone was evaluated using reporter gene assays for long- and short-chain signals (E. coli pSB1075, E. coli pSB401, and C. violeaceum CV026) and was confirmed by measuring the total protease activity (a virulence factor which is under control of the LasI/R system) of the wild-type P. aeruginosa PAO1. Further research will be pursued to assess the potential of plakofuranolactone as a new antivirulence lead compound and a chemical tool to increase the knowledge in this field.