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Heterobimetallic complexes as multifunctional tools for cancer theranostics
Letícia Quental1, P. Raposinho1, F. Mendes1, I. Santos1, C. Navarro-Ranninger2, A.
Alvarez-Valdes2, A. Quiroga2, A. Paulo1
1Centro de Ciências e Tecnologias e Nucleares, IST, Universidade de Lisboa, Estrada Nacional
10, 2695-066 Bobadela LRS, Portugal. 2Departamento de Química Inorgánica, Universidad
Autónoma de Madrid, ES-28049 Madrid, Spain.
Keywords: cytotoxic agents, heterobimetallic complexes, platinum, technetium,
rhenium
Metal-based compounds play an important role in the search for more efficient and
innovative anticancer therapeutic tools, namely in the design of cytotoxic metallodrugs,
photosensitizers for photodynamic therapy and radiopharmaceuticals for nuclear imaging or
radionuclide therapy.
In particular, multifunctional metal-based compounds that combine therapeutic and diagnosis
in the same chemical entity may lead to innovative anticancer drugs, within a theranostic
approach to cancer. For this purpose, we have focused on the synthesis, characterization and
general reactivity studies of heterobimetallic complexes containing a trans-chlorido Pt(II)
moiety and a M(I) (M = Re, 99mTc) tricarbonyl core, as described in this contribution. The
rationale for the study of these heterobimetallic complexes stems from the central role of
Pt(II) complexes in the development of cancer chemotherapeutics and from the importance of 99mTc-radiopharmaceuticals for in vivo tumor imaging. [1,2] Moreover, we have also took into
consideration that Re(I) tricarbonyl started to be envisaged more recently as promising
photosensitizers in photodynamic therapy. [2]
Herein, it is reported the synthesis and characterization of these new
heterobimetallicPt(II)/M(I) (M = Re, 99mTc) complexes, as well as their in vitro and in vivo
biological evaluation (cytotoxicity and cell uptake assays in human tumoral cells and
biodistribution in normal mice). We also discuss the relevance of this new family of complexes
for the design of theranostic agents, which can combine both chemo and
photodynamicanticancer therapy while offering the advantage of providing cell and whole
body imaging, based on isostructural optical (Re) and nuclear (99mTc) probes.
Acknowledgments: This work was funded by the Fundação para a Ciência e Tecnologia(FCT), Portugal
(EXCL/QEQ-MED/0233/2012) and by Spanish Ministerio de Economía y Competitividad with the grant
SAF2012-34424. F.Mendes is thankful for the FCT Investigator grant. The research was carried out within
the framework of the European Cooperation COST Action CM1105. The FUP (Fundação das Universidades
Portuguesas) is also acknowledged for “Acção Integrada Portugal-Espanha E 23/12”.
1. Medina et al. (2008). Chemistry&Biodiversity, 5:2090-100.
2. Kitanovicet al. (2014). ChemEur J, 20: 2496-507.
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EXTENDED PROGRAMME
Wednesday 10 June
Session I. Imaging | Carbohydrates Chair: Nick Westwood
09:00-09:15 Opening and Welcome 09:15-10:00 Plenary Lecture 1: Glycoconjugate vaccines: opportunities and
challenges for synthetic oligosaccharides Claney L. Pereira Max Planck Institute, Germany, p. 21
10:00-10:45 Plenary Lecture 2: Molecular imaging probes based on lanthanide complexes Éva Tóth CNRS Orléans, France, p. 22
10:45-11:05 Coffee break 11:05-11:25 Oral 1: Conjugates of metal complexes to Pittsburg compound B
as MRI markers of Aβ-amyloid deposits: in vitro and in vivo studies Carlos Geraldes Universidade Coimbra, Portugal, p. 39
11:25-11:45 Oral 2: Radiometalated L-arginine derivatives for tumor imaging João Correia Instituto Superior Técnico-UL, Portugal, p. 40
11:45-12:05 Oral 3: Rational design of α-helix stabilized Exendin-4 analogues András Perczel Eötvös Loránd University, Hungary, p. 41
12:05-12:25 Oral 4: Molecular recognition of tumor-associated MUC1 peptides by their specific receptors: lectins and antibodies Filipa Marcelo UCIBIO-NOVA, Portugal, p. 42
12:25-12:45 Oral 5: A multi-disciplinary study of the cellulosome assembly Benedita Pinheiro UCIBIO-NOVA, Portugal, p. 43
12:45-14:00 Lunch
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Wednesday 10 June
Session II. Protein Structure and Function Chair: Andrea Mattevi
14:00-14:45 Plenary Lecture 3: Molecular Recognition at Protein Surfaces Ernest Giralt Institute for Research in Biomedicine, Spain, p. 23
14:45-15:15 Invited Lecture 1: Neurometals as modulators of protein aggregation in neurodegenerative diseases Cláudio Gomes Faculty of Sciences-UL, Portugal, p. 31
15:15-15:35 Oral 6: Endogenous inhibitors of amyloid-beta degradation: structural and functional aspects Francesco Bellia Institute of Biostructure and Bioimaging, Italy, p. 44
15:35-15:55 Oral 7: Transmembrane signaling through a bacterial heme transporter Muriel Delepierre Institut Pasteur, France, p. 45
15:55-16:15 Oral 8: Molecular mechanism of Heme-responsive transcriptional regulation in Lactococcus lactis Shigetoshi Aono Okazaki Institute for Integrative Bioscience, Japan, p. 46
16:15-16:45 Coffee break
Session II. Protein Structure and Function Chair: Luc Brunsveld
16:45-17:15 Invited Lecture 2: Computational studies addressed to periplasmic nitrate reductase and formate dehydrogenase. Why similar molecular architectures have very different enzymatic activities? Nuno Cerqueira UCIBIO, Universidade do Porto, Portugal, p. 32
17:15-17:35 Oral 9: Mechanism of iron uptake and transfer from ceruloplasmin to Human serum transferrin Nguyet-Thanh Ha-Duong Université Paris Diderot Sorbonne, France, p. 47
17:35-17:55 Oral 10: Redirecting iron pathways in the ferritin nanocage Caterina Bernacchioni CERM, Italy, p. 48
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Wednesday 10 June
17:55-18:15 Oral 11: Human Cofilin2: towards the comprehension of the molecular mechanism Giulia Di Rocco University of Modena and Reggio Emilia, Italy, p. 49
18:15-18:35 Oral 12: Structural duality in peptides derived from choline binding repeats M. Angeles Jimenez Instituto de Química Física Rocasolano Spain, p. 50
18:35-18:55 Oral 13: Discerning the nature of ionic liquids/protein interactions and their repercussions in protein denaturation Eurico Cabrita UCIBIO-NOVA, Portugal, p. 51
Short Oral Presentations Chair: Maria Manuel Marques
18:55-19:15 Short Oral 1: Structural insights into an unique periplasmic aldehyde oxidoreductase from Escherichia coli Márcia Correia, UCIBIO-NOVA, Portugal, p. 69 P11
Short Oral 2: Marinobacter hydrocarbonoclasticus MreB: a biochemical and structural characterization Rui Almeida UCIBIO-NOVA, Portugal, p. 70
19:15-21:00 Welcome Reception
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Thursday 11 June
Session II. Protein Structure and Function Chair: Muriel Delepierre
09:00-09:45 Plenary Lecture 4: Intrinsically disordered proteins - New advances Peter Tompa Structural Biology Research Center, Belgium, p. 24
09:45-10:15 Invited Lecture 3: AMT Proteins: channels, transporters or sensors? Susana Andrade Albert-Ludwigs University Freiburg, Germany, p. 33
10:15-10:35 Oral 14: The CHAP domain of Twort endolysin specifically targets Staphylococcus aureus Jorge Dias UCIBIO-NOVA, Portugal, p. 52
10:35-10:55 Oral 15: Design and synthesis of selective glycomimetic antagonists of DC-SIGN Anna Bernardi Universita’ degli Studi di Milano, Italy, p. 53
10:55-11:25 Coffee break 11:25-12:40 Poster Session 12:40-14:00 Lunch
Session III. Medicinal Chemistry | Chemical Biology Chair: Antonello Mai
14:00-14:45 Plenary Lecture 5: On the molecular mechanisms of chromatin modification Andrea Mattevi University of Pavia, Italy, p. 25
14:45-15:30 Plenary Lecture 6: Targeting Epigenetic Reader Proteins using Chemical Biology Stuart Conway University of Oxford, UK, p. 26
15:30-16:00 Invited Lecture 4: Novel small molecules with in vitro antitumor activity via inhibition of p53-MDM2 interaction Maria Santos iMed.ULisboa, Portugal, p. 34
16:00-16:20 Oral 17: Chemical biology approaches to elucidate nuclear receptor structural modulation Lucas Brunsveld Technische Universiteit Eindhoven, Netherlands, p. 54
16:20-16:50 Coffee break
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Thursday 11 June
Session III. Medicinal Chemistry | Chemical Biology Chair: Pedro Góis
16:50-17:10 Oral 17: In vitro and in vivo studies in type 2 diabetic GK rats to assess the therapeutic properties of VO(dmpp)2 Margarida Castro University of Coimbra, Portugal, p. 55
17:10-17:30 Oral 18: Unusual 8-hydroxyquinoline-cyclodextrin conjugates hold promise as antioxidant and antiaggregant chelators Valentina Oliveri Università degli Studi di Catania, Italy, p. 56
17:30-17:50 Oral 19: Novel inorganic chemotherapeutics for cancer treatment Chiara Nardon University of Padova, Italy, p. 57
17:50-18:10 Oral 20: Developing novel chemical tools Nick Westwood University of St. Andrews, UK, p. 58
Short Oral Presentations Chair: Susana Andrade
18:10-18:30 Short Oral 3: NMR studies on the Cd(II) interaction with a three
way junction serving as RNA folding control element Simona Bartova University of Zurich, Switzerland, p. 71
Short Oral 4: Confirmation of the HDV-like secondary structure of the CPEB3 ribozyme in solution and investigation of the role of Mg2+ in folding Kenneth Adea University of Zurich, Switzerland, p. 72
18:30-19:00 Poster Presentation 1: Characterization of trypsin-like serine protease inhibitors by X-ray crystallography and enzymatic assays Hugo Correia UCIBIO-NOVA, Portugal, p. 90 P10
Poster Presentation 2: Novel synthesis methods of peptide-6-amino-D-luciferin conjugates for detection of protease activity Anita Kovács University of Szeged, Hungary, p. 105 P26
Poster Presentation 3: Proline derivatives of different metals: from design and synthesis to preliminary biological studies Leonardo Brustolin University of Padova, Italy, p. 84 P4
Poster Presentation 4: Androgen receptor aggregates in vitro and in a transgenic mouse model of SBMA Bahareh Eftekharzadeh IRB Barcelona, Spain, p. 97 P18
20:00 BUS LEAVES TO THE CONFERENCE DINNER
20:30-23:00 Conference Dinner - Espaço Espelho D'Água
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Friday 12 June
Session IV. Nucleic Acids Chair: Carlos Geraldes
09:00-09:45 Plenary Lecture 7: Functional nucleic acids for RNA ligation and labeling Claudia Höbartner Max Planck Institute, Germany, p. 27
09:45-10:15 Invited Lecture 5: Interaction of metal complexes with DNA: From Z-DNA to photodynamic therapy Bernhard Spingler University of Zurich, Switzerland, p. 35
10:15-10:35 Oral 21: A general strategy to introduce pH-induced allostery in DNA-based receptors to achieve controlled release of ligands Alessandro Porchetta University of Rome, Italy, p. 59
10:35-10:55 Oral 22: RNA mediated RNA recombination: RNA world activity, repair and functionalization Sabine Muller Ernst Moritz Arndt University Greifswald, Germany, p. 60
10:55-11:15 Coffee break
11:15-11:35 Oral 23: Probing G-quadruplex folding and ligand interaction in living cells using NMR spectroscopy Gilmar Salgado Univ. Bordeaux, France, p. 61
11:35-12:45 Poster Session 12:45-14:00 Lunch
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Friday 12 June
Session V. (Nano)Biotechnology Chair: Cristina Silva Pereira
14:00-14:45 Plenary Lecture 8: Synergies between affinity biomimetics and magnetic nanoparticles Cecília Roque UCIBIO-NOVA, Portugal, p. 28
14:45-15:05 Oral 24: Gold-nanobeacons for targeted gene silencing Pedro Baptista UCIBIO-NOVA, Portugal, p. 62
15:05-15:25 Oral 25: Acid-degradable polysaccharide nanoparticles for the delivery of biotherapeutics Peter Wich Johannes Gutenberg-Universität Mainz, Germany, p. 63
15:25-15:45 Oral 26: Gold nanoparticulate systems for new anticancer compounds delivery Alexandra Fernandes UCIBIO-NOVA, Portugal, p. 64
15:45-16:05 Oral 27: Protein-soft nanoparticles association equilibria: recognition and dynamics Michael Assfalg University of Verona, Italy, p. 65
16:05-16:25 Oral 28: Innovative approaches for drug delivery and antiobiotic resistance Luís Branco LAQV-NOVA, Portugal, p. 66
16:25-16:50 Coffee break
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Friday 12 June
Session VI. Short Oral Presentations Chair: Teresa Santos-Silva
16:50-17:10 Short Oral 5: DNA Methyltransferase activity detection using the personal glucose meter Zhigiang Gao National University of Singapore, Singapore, p. 73
Short Oral 6: Characterization of proteins involved in a cell division system of anaerobic bacteria Olga Mestre UCIBIO-NOVA, Portugal, p. 74 P32
17:10-18:20 Poster Presentation 5: Effect of pH on the denitrification pathway of Marinobacter hydrocarbonoclasticus and nitrous oxide reductase Cíntia Carreira UCIBIO-NOVA, Portugal, p. 86 P6
Poster Presentation 6: Molybdenum and tungsten: from the membrane transporters to the enzymes Ana Rita Cardoso UCIBIO-NOVA, Portugal, p. 85 P5
Poster Presentation 7: E. coli and Neisseria gonorrhoeae Cytochrome c Peroxidases – Biochemical insights into two distinct oxidative stress enzymes Cláudia Nóbrega UCIBIO-NOVA, Portugal, p. 110 P31
Poster Presentation 8: Targeting aquaglyceroporin-3 with gold(III) anticancer compounds Andreia de Almeida University of Groningen, Netherlands, p. 94 P15
Poster Presentation 9: Structural characterization of VIVO(carrier)2-Protein Adducts – New perspectives on vanadium interactions with lysozyme, trypsin and transferrin Marino Santos UCIBIO-NOVA, Portugal, p. 120 P42
Poster Presentation 10: WW domains as Small scaffolds with novel biotechnological applications Ana Dias UCIBIO-NOVA, Portugal, p. 96 P17
Poster Presentation 11: Rational design of pH-dependent DNA switches to control DNA-based reactions and assembly and disassembly of DNA polymers Andrea Idili University of Rome, Italy, p. 102 P23
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Poster Presentation 12: Interpretation of metalloproteases
function through their internal dynamics: evolution and classification insights Henrique Carvalho UCIBIO-NOVA, Portugal, p. 87 P7
Poster Presentation 13: Nanosystems for MRI cell labeling using magnetism, biopolymers and pH sensitive bio-coatings Susana Palma UCIBIO-NOVA, Portugal, p. 114 P36
Poster Presentation 14: Luminogenic acridinium tests Justyna Czechowska-Kryszk Uniwersytet Gdański, Poland, p. 93 P14
18:20-18:40 Closing Session - Departure
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POSTER PRESENTATIONS
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List of Posters
P1 Hocine Allali Study of the inhibition of 5-lipoxygenase with a new compound of natural origin isolated from Tropaeolum majus L. using molecular modeling tools
P2 Arménio Barbosa New chemical functions on enzymes with computational de novo protein design
P3 Jessica Bevan chemical probes to uncover novel glycosyltransferases in Trypanosoma brucei
P4 PP3
Leonardo Brustolin Proline derivatives of different metals: from design and synthesis to preliminary biological studies
P5 PP6
Rita Otrelo-Cardoso Molybdenum and tungsten: from the membrane transporters to the enzymes
P6 PP5
Cíntia Carreira Effect of pH on the denitrification pathway of Marinobacter
hydrocarbonoclasticus and nitrous oxide reductase P7 PP12
Henrique Carvalho Interpretation of metalloproteases function through their internal dynamics: evolution and classification insights
P8 Kyung-Bin Cho Cyclohexene oxidation by a biomimetic nonheme Fe(IV)O species; combined theoretical and experimental study show that simple C-H activation reactions are not that simple
P9 Mílton Cordeiro Coupling molecular beacons to spectral codification P10 PP1
Hugo Correia Characterization of trypsin-like serine protease inhibitors by X-ray crystallography and enzymatic assays
P11 SO1
Márcia Correia Structural insights into an unique periplasmic aldehyde oxidoreductase from Escherichia coli
P12 Viviana Correia Probing cohesin:dockerin interactions of the bacterial cellulosome using newly developed protein microarrays
P13 Joana Cristóvão Zinc promiscuous binding to immature SOD1 conformers: impact on ALS toxic aggregation
P14 PP14
Justyna Czechowska-Kryszk Luminogenic acridinium tests
P15 PP8
Andreia de Almeida Targeting Aquaglyceroporin-3 with gold(III) anticancer compounds
P16 Matteo de Rosa Characterization of recently identified gelsolin variants leading to novel renal amyloidosis
P17 PP10
Ana Margarida Dias WW domains as small scaffolds with novel biotechnological applications
P18 PP4
Bahareh Eftekharzadeh Androgen receptor aggregates in vitro and in a transgenic mouse model of SBMA
P19 Ana Carina Fernandes In silico design of specific peptidic probes for intravascular molecular imaging of inflammation
P20 Pedro Fernandes Searching for structural determinants in amyloid
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recognition and binding P21 Said Ghalem Synthesis and molecular docking of novel nitrogen-containing
bisphosphonates as potential antitumor agents P22 Blanca González Human cancer cell lines proliferation is inhibited by
isopolyoxomolibdates P23 PP11
Andrea Idili Rational design of pH-dependent DNA swicthes to control DNA-based reactions and assembly and disassembly of DNA polymers
P24 Ioana Ionuţ Antimicrobial activity and lipophilicity evaluation of some synthetic flavones
P25 Lina Juknaitė Ionic liquid-functionalized mineral particles as innovative agents in protein crystal nucleation and optimization
P26 PP2
Anita Kovács Novel synthesis methods of peptide-6-amino-D-luciferin conjugates for detection of protease activity
P27 Sophie Laine Potential MRI contrast agent for enzymatic detection P28 Francisco Leisico Structural characterization of Nitric Oxide Synthase
Interaction with Imaging Probes P29 Joana Lourenço Reactivity and antimicrobial activity of a diterpene from
Plectranthus Ornatus P30 Paula Medeiros Effect of dietary phytochemicals in cancer: Raman
microspectroscopy studies in Human breast cancer cells P31 PP7
Cláudia Nóbrega E. coli and Neisseria gonorrhoeae cytochrome c peroxidases – Biochemical insights into two distinct oxidative stress enzymes
P32 SO6
Olga Mestre Characterization of proteins involved in a cell division system of anaerobic bacteria
P33 Smaranda Oniga Synthesis, antimicrobial and anti-biofilm activity of some new chalcones and pyrazolines bearing a thiazolyl scaffold
P34 Elif Özcan The investigation of hydrolytic degradation of new hexakis(methyl glycinato) cyclotriphosphazene and octakis(methyl glycinato) cyclotetraphosphazene
P35 Aurora Pacini Synthesis and characterization of metal complexes as NO donors
P36 PP13
Susana Palma Nanosystems for MRI cell labeling using magnetism, biopolymers and pH sensitive bio-coatings
P37 Sofia Pauleta Mo-Cu metal cluster formation and binding in an Orange Protein isolated from Desulfovibrio gigas
P38 Valentina Pirota α-Synuclein quenches the copper(II) oxidation of the catecholic substrates
P39 Letícia Quental Heterobimetallic complexes as multifunctional tools for cancer theranostics
P40 Susana Ramos Biochemical characterization of cytochrome c552 and the electron transfer subunit of Nitric Oxide Reductase from Marinobacter
hydrocarbonoclasticus
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P41 Sven Range Optimizing the continuous synthesis and performing a biological
study of antibacterial effects of a silver-doped calcium phosphate ceramic P42 PP9
Marino Santos Structural characterization of VIVO(carrier)2-protein adducts – New perspectives on vanadium interactions with Lysozyme, Trypsin and Transferrin
P43 Sofia Soares Studies on the interaction of ovalbumin with phenolic compounds
P44 Anca-Daniela Stana Synthesis of new 5-arylidene-thiazoline-4-ones with antimicrobial activity
P45 Gabor K. Tóth Application of native chemical ligation (NCL) for the synthesis of multiple disulfide containing polypeptides
P46 Barbara Valdes Synthesis of biocompatible polyurethanes: in vitro and physicochemicalcharacterization
P47 Graziella Vecchio Metal-chelating polymer based on cyclodextrin and 8-hydroxyquinoline
P48 Beata Zadykowicz New luminogenic molecules used as luminogenic fragments of indicators and labels
Posters from the Local Organizing Committee
P49 Maria Manuel Marques LAQV, NOVA Strategies towards bacterial peptidoglycan Involved in cellular recognition
P50 Joana Pais & Rúben Rodrigues ITQB, NOVA Development of bactericidal biomaterials through mimesis of plant defensive interfaces
P51 Roberta Paterna Pharmacy Faculty, Lisbon University Efficient EDA addition and ring-expansion reaction of isatins catalyzed by a DBU/Rh(II) metal-organo system: on route to the synthesis of viridicatin alkaloids
P52 Rute Nunes & António Neca UCIBIO, NOVA Characterization of proteins from the ORP system - An essential role in anaerobic bacteria to be discovered
P53 Elisabeth Pires UCIBIO, NOVA Mapping the cohesin-dockerin interactions responsible for the Cellulosome assembly using X-Ray crystallography
P54 Cátia Silva UCIBIO, NOVA Structural and kinetic characterization of a trypsin inhibitor: a derivate of boronic acid