Eu

Ch

eM

Sin

Life

Sci

ence

s

Abstracts

Lisbon

2O15

1O-12June

th

117

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.

leticiaquental@ctn.ist.utl.pt

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.

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

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

75

POSTER PRESENTATIONS

76

77

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

78

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

79

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