Giovanni Luca Beretta

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Lombardy, Italy

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Publications (66)291.64 Total impact

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    ABSTRACT: Redox-active polymers and carriers are oxidizing nanoagents that can potentially trigger intracellular off-target effects. In the present study, we investigated the occurrence of off-target effects in prostate cancer cells following exposure to redox-active polymer and thin multilayer capsules with different chemical properties. We show that, depending on the intracellular antioxidant capacity, thiol-functionalized poly(methacrylic acid), PMASH triggers cell defense responses/perturbations that result in off-target effects (i.e., induction of autophagy and down-regulation of survivin). Importantly, the conversion of the carboxyl groups of PMASH into the neutral amides of poly(hydroxypropylmetacrylamide) (pHPMASH) nullified the off-target effects and cytotoxicity in tested cell lines. This suggests that the simultaneous action of carboxyl and disulfide groups in PMASH polymer or capsules may play a role in mediating the intracellular off-target effects. Our work provides evidence that the rational design of redox-active carriers for therapeutic-related application should be guided by a careful investigation on potential disturbance of the cellular machineries related to the carrier association.
    Nanoscale 03/2015; DOI:10.1039/c4nr07240e · 6.74 Impact Factor
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    ABSTRACT: The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when it progresses towards the androgen-independent (AIPC) or the castration-resistant (CRPC) forms. Small chemical changes in the structure of non-steroidal AR ligands sensibly detrmine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows obtaining sterically hindered C2-substituted bicalutamide analogs. Biological and theoretical evaluations demonstrate that the C2-substitution with benzyl and phenyl moieties is a new valuable option toward the improvement of the pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide and enzalutamide, displayed very promising in vitro activity in five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed a marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.
    Journal of Medicinal Chemistry 08/2014; 57(17). DOI:10.1021/jm5005122 · 5.48 Impact Factor
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    ABSTRACT: The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds.
    European Journal of Medicinal Chemistry 03/2013; 63C:387-400. DOI:10.1016/j.ejmech.2013.02.022 · 3.43 Impact Factor
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    Giovanni L Beretta, Laura Gatti, Paola Perego, Nadia Zaffaroni
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    ABSTRACT: Poisoning of DNA topoisomerase I is the mechanism by which camptothecins interfere with tumor growth. Although the clinical use of camptothecins has had a significant impact on cancer therapy, de novo or acquired clinical resistance to these drugs is common. Clinical resistance to camptothecins is still a poorly understood phenomenon, likely involving pharmacological and tumor-related factors. Experimental models including yeast and mammalian cell cultures suggest three general mechanisms of camptothecin resistance: i) reduced cellular accumulation of drugs, ii) alteration in the structure/expression of topoisomerase I, and iii) alterations in the cellular response to camptothecin-DNA-ternary complex formation. Some lines of evidence have also suggested links between cellular camptothecin resistance, the existence of a subset of tumor‑initiating cells and miRNA deregulation. In this regard, a better definition of the molecular events clarifying the regulation of tumorigenesis and gene expression might contribute to gain insight into the molecular mechanisms on the basis of camptothecin resistance of tumors and to identify new molecular tools for targeting cancer cells. The relevance of these mechanisms to clinical drug resistance has not yet been completely defined, but their evaluation in clinical specimens should help to define personalized treatments including camptothecins as single agents or in combination with other cytotoxic and target-specific anticancer agents. The present review focuses on the cellular/molecular aspects involved in resistance of tumor cells to camptothecins, including the potential role of cancer stem cells and deregulated miRNAs, and on the approaches proposed for overcoming resistance.
    Current Medicinal Chemistry 01/2013; DOI:10.2174/0929867311320120006 · 3.72 Impact Factor
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    ABSTRACT: Ovarian cancer is the main cause of death from gynaecological malignancies. In spite of the efficacy of platinum-paclitaxel treatment in patients with primary epithelial ovarian carcinoma, platinum-based chemotherapy is not curative and resistance remains one of the most important causes of treatment failure. Although ABC transporters have been implicated in cellular resistance to multiple drugs, the clinical relevance of these efflux pumps is still poorly understood. Thus, we examined the prognostic role of transporters of the MRP family (i.e., ABCC1/MRP1, ABCC4/MRP4) to gain insights into their clinical impacts. A case material of 127 patients with ovarian carcinoma at different stages and histotypes was used. The expression of MRP1 and MRP4 was examined by immunohistochemistry using tissue microarrays in tumor specimens collected at the time of initial surgery expression. We found an association between MRP1 expression and grading, and we observed that MRP4 displayed an unfavourable impact on disease relapse in multivariate analysis (HR = 2.05, 95% CI: 1.01-4.11; P = 0.045). These results suggest that in epithelial ovarian cancer, MRP1 may be a marker for aggressiveness because its expression was associated with tumor grade and support that MRP4 may play an unfavourable role in disease outcome.
    01/2013; 2013:143202. DOI:10.1155/2013/143202
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    American Journal Of Pathology 10/2012; 181(1):13. · 4.60 Impact Factor
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    ABSTRACT: We report herein the viability of a novel nanoparticles (NPs) conjugated system, namely the attachment, based on ionic and hydrophobic interactions, of different sulfonated organic salts to positively charged poly(methylmethacrylate) (PMMA)-based core-shell nanoparticles (EA0) having an high density of ammonium groups on their shells. In this context three different applications of the sulfonates@EA0 systems have been described. In detail, their ability as cytotoxic drugs and pro-drugs carriers was evaluated in vitro on NCI-H460 cell line and in vivo against human ovarian carcinoma IGROV-1 cells. Besides, 8-hydroxypyrene-1,3,6-trisulfonic acid, trisodium salt (HPTS) was chosen for NPs loading, and its internalization as bioimaging probe was evaluated on Hep G2 cells. Overall, the available data support the interest for these PMMA NPs@sulfonates systems as a promising formulation for theranostic applications. In vivo biological data strongly support the potential value of these core-shell NPs as delivery system for negatively charged drugs or biologically active molecules. Additionally, we have demonstrated the ability of these PMMA core-shell nanoparticles to act as efficient carriers of fluorophores. In principle, thanks to the high PMMA NPs external charge density, sequential and very easy post-loading of different sulfonates is achievable, thus allowing the preparation of nanocarriers either with bi-modal drug delivery behaviour or as theranostic systems.
    Bioorganic & medicinal chemistry 09/2012; 20(22):6640-7. DOI:10.1016/j.bmc.2012.09.023 · 2.82 Impact Factor
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    ABSTRACT: Aim of this work was to carry out an extensive characterization of the Oleoresin (OR) from Copaifera langsdorffii Desf. (Fabaceae), by thermogravimetric analysis (TGA), GC-MS profiling, and molecular mass determination. OR is used in the therapeutic management of several inflammatory affections, i.e. sore throat, urinary, gastric and pulmonary diseases, and to heal skin ulcers wounds. TGA was carried out under N2 from 50 °C to 650 °C by a Perkin Elmer TGA7 Thermogravimetric Analyser. The DTGA thermal curve shows three peaks at 134 °C (22,7%), 248 °C (49,4%), and 371 °C (27,9%), each of them indicative of three main classes of components. Steam distillation of OR gives a volatile fraction (22% of the total), wich when submitted to GC-MS analysis shows a set of sesquiterpene constituents, the main of which were α-bergamotene, α-himachalene, β-caryophillene, β- elemene, cyclosativene, β-selinene, and paraffins. The bulk of these constituents, on the basis of their boiling points and total percentage content, very likely corresponds to the DTGA first peak. The residue was then submitted to derivatization (MeOH/6N HCl) and extracted with n-exhane.The extract, exhamined by GC-MS, exhibited a series of labdanic and labdenoic structures, diterpenoic acids, and diterpenes bearing α-β conjugated dienes, i.e. copalic, pimaric, isopimaric, abietic, daniellic, lambertinic, giberellic acids, the sum of them accounting to a 45% of the OR, close to the amount of the components present in the second TGA fraction. The average molecular weight (Mw) of the post n-exhane residue (≈35% of the total OR, coincident with the value of the last TGA peak), was determined on the OR sample with a multi-angle laser light scattering photometer (MALS, Dawn DSP-F from Wyatt) in off-line batch mode. The solvent used was ethanol at room temperature, the OR sample concentrations ranged from 0.7 mg/ml to 1.5 mg/ml. The MALS data analysis was performed using a conventional Zimm plot (i.e. a double extrapolation to zero angle and to zero concentration). The average molecular mass value was 8835 ± 660 g/mol. The polysaccharidic nature of the polimer (a xiloglucanic structure1) was confirmed by the positive response to the Dubois reaction (phenol/H2SO4) specific for carbohydrates.
    XXIII Congresso Nazionale della Divisione di Chimica Analitica della Società Chimica Italiana; 09/2012
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    ABSTRACT: Camptothecins are still among the most widely prescribed and effective anticancer drugs. Unfortunately, important drawbacks including water insolubility, lactone instability, reversibility of the drug-target interaction, drug resistance and toxicity are responsible for treatment failure and often require suspension of the drug administration itself. In order to overcome such drawbacks, several options in chemical manipulation of natural camptothecin have been explored, and effective compounds have been identified in a novel series of 7-oxyiminomethyl derivatives. Among the compounds of this series, the hydrophilic derivative namitecan (7 (2-aminoethoxy) iminomethyl camptothecin) has been selected for further development. The relevant features of namitecan are: 1) marked cytotoxic potency - likely related to multiple factors, including i) a potent inhibition of topoisomerase I, ii) a persistent stabilization of the cleavable complex, iii) an increased intracellular accumulation, and iv) a peculiar subcellular localization; 2) enhanced lactone stability and favorable pharmacokinetics; 3) remarkable antitumor efficacy in a large panel of human tumor xenografts (including tumor models relatively resistant to topotecan and irinotecan), particularly on squamous cell carcinomas. The clinical development of namitecan is currently ongoing. Namitecan exhibited an acceptable toxicity profile, with neutropenia being the dose-limiting toxic effect, and clinical benefit was appreciable in patients with different tumor types, particularly bladder and endometrium carcinomas. In this article, we review the relevant features of namitecan, with particular reference to its advantages compared with the two analogues (topotecan and irinotecan) approved for clinical use.
    Current Medicinal Chemistry 06/2012; 19(21):3488-501. · 3.72 Impact Factor
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    ABSTRACT: Tyrosyl-DNA phosphodiesterase 1 (TDP1) plays a unique function as it catalyzes the repair of topoisomerase I-mediated DNA damage. Thus, ovarian carcinoma cell lines exhibiting increased TDP1 levels and resistance to the topoisomerase I poisons campthotecins were used to clarify the role of this enzyme. The camptothecin gimatecan was employed as a tool to inhibit topoisomerase I because it produces a persistent damage. The resistant sublines displayed an increased capability to repair drug-induced single-strand breaks and a reduced amount of drug-induced double-strand breaks, which was enhanced following TDP1 silencing. In loss of function studies using U2-OS cells, we found that TDP1 knockdown did not produce a change in sensitivity to camptothecin, whereas co-silencing of other pathways cooperating with TDP1 in cell response to topoisomerase I poisons indicated that XRCC1 and BRCA1 were major regulators of sensitivity. No change in cellular sensitivity was observed when TDP1 was silenced concomitantly to RAD17, which participates in the stabilization of collapsed replication forks. The expression of dominant-negative PARP1 in cells with reduced expression of TDP1 due to a constitutively expressed TDP1 targeting microRNA did not modulate cell sensitivity to camptothecin. Mild resistance to gimatecan was observed in cells over-expressing TDP1, a feature associated with decreased levels of drug-induced single-strand breaks. In conclusion, since TDP1 alone can account for mild levels of camptothecin resistance, repair of topoisomerase I-mediated DNA damage likely occurs through redundant pathways mainly implicating BRCA1 and XRCC1, but not RAD17 and PARP1. These findings may be relevant to define novel therapeutic strategies.
    Biochemical pharmacology 01/2012; 83(1):27-36. DOI:10.1016/j.bcp.2011.09.021 · 4.25 Impact Factor
  • G L Beretta, V Zuco, P Perego, N Zaffaroni
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    ABSTRACT: DNA topoisomerase I is required for DNA relaxation during a variety of cellular functions. The identification of camptothecins as specific enzyme poisons and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a therapeutic target for cancer. However, several limitations of camptothecins, such as low solubility and stability, high toxicity, and the occurrence of resistance, have encouraged the development of non-camptothecin topoisomerase I inhibitors. Different natural and synthetic compounds (e.g., indolocarbazoles, dibenzonaphthyridine and indenoisoquinoline) have been extensively studied as alternatives to camptothecins and have been proved to be promising therapeutic agents. In this review, we comparatively evaluate the preclinical results obtained with the different non-camptothecin poisons proposed thus far as topoisomerase I inhibitors, with special reference to cellular pharmacology, and discuss the perspective for their use in the clinical setting.
    Current Medicinal Chemistry 12/2011; 19(8):1238-57. DOI:10.2174/092986712799320529 · 3.72 Impact Factor
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    ABSTRACT: ATP-binding cassette (ABC) transporters are a large family of proteins implicated in physiological cellular functions. Selected components of the family play a well-recognized role in extruding conventional cytotoxic antitumor agents and molecularly targeted drugs from cells. Some lines of evidence also suggest links between transporters and tumor cell survival, in part unrelated to efflux. However, the study of the precise mechanisms regulating the function of drug transporters (e.g., posttranslational modifications such as glycosylation) is still in its infancy. A better definition of the molecular events clarifying the regulation of transporter levels including regulation by microRNAs may contribute to provide new molecular tools to target such a family of transporters. The present review focuses on the biological aspects that implicate ABC transporters in resistance of tumor cells, including cancer stem cells. Molecular analysis of well-known preclinical systems as well as of cancer stem cell models supports the notion that ABC transporters represent amenable targets for modulation of the efficacy of antitumor agents endowed with different molecular features. Recent achievements regarding tumor cell biology are expected to provide a rationale for developing novel inhibitors that target ABC transporters implicated in drug resistance.
    Current Medicinal Chemistry 08/2011; 18(27):4237-49. DOI:10.2174/092986711797189682 · 3.72 Impact Factor
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    ABSTRACT: A novel 5-oxa-6a,8-diazaindeno[2,1-b]phenanthren-7-one scaffold was designed and synthesized as an active analogue of the cytotoxic marine alkaloid Lamellarin D. The design was based on molecular modeling of the site of interaction of Lamellarin D with DNA-topoisomerase I cleavable complex, whereas the synthesis capitalized on a simple Friedel-Crafts cyclization of indole to a β-carbolinone nucleus. The product exhibited topoisomerase I poisoning activity and submicromolar cytotoxicity on human non-small cell lung cancer H460 cell line.
    Bioorganic & medicinal chemistry 08/2011; 19(16):4971-84. DOI:10.1016/j.bmc.2011.06.056 · 2.82 Impact Factor
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    ABSTRACT: The antioxidant constituents of essential oils (EOs) of Rosmarinus officinalis L. (α-pinene chemotype) were isolated at the flowering (A), post-flowering (B), and vegetative stages (C). GC-MS was used to analyze total chemical composition, Folin-Ciocalteau and Prussian blue methods for reducing substances. Radical scavenging capacity (DPPH test, IC(50) 36.78±0.38, 79.69±1.54, 111.94±2.56μL) and anti-lipoperoxidant activity (TBARS, IC(50) 0.42±0.04, 1.20±0.06μL, 4.07±0.05μL) differed widely in the three stages. Antioxidant activity, identified after silica gel fractionation chromatography, was closely related (R(2)=0.9959) to each EO's content of hydroxilated derivatives, (containing alcohols, phenols and 1,8 cineole): 15.26±0.12%, 7.22±0.06%, and 5.09±0.10% in EOs from A, B, and C. Modeling the C, H, O terpenes in a simulated phospholipid bilayer indicated that anti-lipoperoxidant activity depended on the stability and rapidity of their interactions with the membrane bilayer components, and their positioning over its surface.
    Journal of pharmaceutical and biomedical analysis 07/2011; 55(5):1255-64. DOI:10.1016/j.jpba.2011.03.026 · 2.45 Impact Factor
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    ABSTRACT: Novel agents characterized by the scaffold of the atypical retinoid ST1926, but containing different chemical functions (carboxylic or hydroxamic acid), exhibit potent proapoptotic activity. In the present paper, we show that the treatment of the IGROV-1 ovarian cancer cell line with compounds sharing structural features with ST1926 (ST1898, ST3595, ST3056) determines a strong inhibition of proliferation mainly due to apoptotic cell death. In an effort to understand the mechanism of action of these compounds, we performed a proteomics analysis of IGROV-1 total lysates and nuclear extracts. Using this approach, we found that deregulation of calcium homeostasis, oxidative stress, cytoskeleton reorganization, and deregulation of proteasome function may represent important pathways involved in response of IGROV-1 cells to the studied compounds. The most prominent effect was down-regulation of factors involved in protein degradation, an event more marked in cells treated with ST3595. In addition, we identified proteins specifically modulated by each treatment, including prohibitin and cochaperone P23 (ST1898), pre-mRNA splicing factor SF2p32 and clathrin light chain (ST3595), as well as Far upstream element (FUSE) binding protein 1 and DNA-binding protein B (ST3056). By identifying proteins modulated by novel proapoptotic agents, this study provides insights into critical aspects of their mechanism of action.
    Journal of Proteome Research 03/2011; 10(3):1191-207. DOI:10.1021/pr100963n · 5.06 Impact Factor
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    ABSTRACT: We previously reported that the G-quadruplex (G4) ligand RHPS4 potentiates the antitumor activity of camptothecins both in vitro and in tumor xenografts. The present study aims at investigating the mechanisms involved in this specific drug interaction. Combination index test was used to evaluate the interaction between G4 ligands and standard or novel Topo I inhibitors. Chromatin immunoprecipitation was performed to study the presence at telomeres of various types of topisomerase, while immunolabeling experiments were performed to measure the activation of DNA damage both in vitro and in tumor xenografts. We report that integration of the Topo I inhibitor SN-38, but not the Topo II poison doxorubicin with telomere-based therapy is strongly effective and the sequence of drug administration is critical in determining the synergistic interaction, impairing the cell ability to recover from drug-induced cytotoxicity. The synergistic effect of this combination was also observed by using novel camptothecins and, more interestingly, mice treated with ST1481/RHPS4 combination showed an inhibition and delay of tumor growth as well as an increased survival. The study of the mechanism(s) revealed that treatment with G4 ligands increased Topo I at the telomeres and the functional relevance of this observation was directly assessed by showing that standard and novel camptothecins stabilized DNA damage both in vitro and in xenografts. Our results demonstrate an outstanding efficacy of Topo I inhibitors/G4 ligands combination, which likely reflects an enhanced and persistent activation of DNA damage response as a critical determinant of the therapeutic improvement.
    Clinical Cancer Research 02/2011; 17(8):2227-36. DOI:10.1158/1078-0432.CCR-10-3033 · 8.19 Impact Factor
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    ABSTRACT: In an effort to decrease the toxicity and improve the stability of the E-ring of camptothecin, new analogues with an ‘inverted’ lactone ring were designed and synthesised. The compounds retained a good cytotoxic activity on human non-small lung cancer cells H-460.
    Tetrahedron Letters 12/2010; 51(50):6489-6492. DOI:10.1016/j.tetlet.2010.09.130 · 2.39 Impact Factor
  • EJC Supplements 11/2010; 8(7):103-104. DOI:10.1016/S1359-6349(10)72030-9 · 2.71 Impact Factor
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    ABSTRACT: Herein, we study the nanomechanical characteristics of single DNA molecules in the presence of DNA binders, including intercalating agents (ethidium bromide and doxorubicin), a minor groove binder (netropsin) and a typical alkylating damaging agent (cisplatin). We have used magnetic tweezers manipulation techniques, which allow us to measure the contour and persistence lengths together with the bending and torsional properties of DNA. For each drug, the specific variations of the nanomechanical properties induced in the DNA have been compared. We observed that the presence of drugs causes a specific variation in the DNA extension, a shift in the natural twist and a modification of bending dependence on the imposed twist. By introducing a naive model, we have justified an anomalous correlation of torsion data observed in the presence of intercalators. Finally, a data analysis criterion for discriminating between different molecular interactions among DNA and drugs has been suggested.
    Nucleic Acids Research 11/2010; 38(20):7089-99. DOI:10.1093/nar/gkq597 · 8.81 Impact Factor
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    ABSTRACT: The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I-mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a-thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I-DNA cleavable complex. These effects were prominent for thio-SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.
    ChemMedChem 11/2010; 5(12):2006-15. DOI:10.1002/cmdc.201000369 · 3.05 Impact Factor

Publication Stats

798 Citations
291.64 Total Impact Points


  • 2006–2014
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      • Dipartimento di Oncologia Sperimentale e Medicina Molecolare
      Milano, Lombardy, Italy
  • 2004–2013
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
  • 2001–2011
    • University of Milan
      • • Faculty of Pharmacy
      • • Department of AgriFood Molecular Sciences
      Milano, Lombardy, Italy
  • 2008
    • National Research Council
      • Laboratory of Gas Chemistry
      Roma, Latium, Italy
    • Sigma Tau Pharmaceuticals
      GAI, Maryland, United States
  • 1999–2008
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      Meldola, Emilia-Romagna, Italy
  • 2005
    • Istituto Oncologico Veneto
      Padua, Veneto, Italy