Research interest

I. Basics of “crystal engineering”: supramolecular interactions, polymorphy, temperature and pressure

Our research group has a long tradition in both supramolecular chemistry and polymorphy studies. Isostruturality indices were introduced, morphotropy was described, and the first examples of morphotropy induced by supramolecular effects were revealed by our group. Combining all these knowledge we show how to fine tune structural properties by gradual chemical change. We demonstrate how the well balanced spatial and electrostatic forces play role in the arrangement of packing motifs in the crystals. Our research interest is extended on supramolecular interactions of one and multicomponent systems under ambient and non-ambient conditions. Performing crystal engineering, e.g. fine tuning of crystal architecture requires the recognition, understanding and application of supramolecular interactions, crystallographic and in case of occurrence, non-crystallographic symmetries. We focus our work on crystal engineering, supramolecular chemistry of one and more component systems of biologically relevant organic molecules, organometallic compounds and metal coordination complexes.

Ongoing projects:

NKFIH K 124544: „A “crystal engineering” alapjai: szupramolekuláris kölcsönhatások, polimorfia, hőmérséklet és nyomás”

Related publications:

1. Márton Bojtár, András Simon, Petra Bombicz, István Bitter “Expanding the pillararene chemistry: synthesis and application of a 10+1 functionalised pillar[5]arene” Organic Letters(2017) (IF2016: 6.579) 19 (17), 4528–4531 Full text
2. Petra Bombicz „The way from isostructurality to polymorphy. Where are the borders? The role of supramolecular interactions and crystal symmetries.” Crystallography Reviews, 23(2), 118-151 (2017). (IF: 1.600) Full text
3. Klára Aradi, Petra Bombicz, Zoltán Novák “Modular Copper-Catalyzed Synthesis of Chromeno[4,3-b]quinolones with the Utilization of Diaryliodonium Salts” Journal of Organic Chemistry, 81, 920-931, 2016. (IF: 4.849) Full text
4. Resnati G, Boldyreva E, Bombicz P, Kawano M (2015)Supramolecular interactions in the solid state, IUCrJ 2, 675–690 (feature article) (IF: 5.300) Full text
5. Bombicz P*, Gruber T, Fischer C, Weber E, Kálmán A Fine Tuning Of Crystal Architecture By Intermolecular Interactions: Synthon Engineering CrystEngComm16:(18) Pp. 3646-3654. (2014), Invited Paper, Highlight Paper, Cover Page If: 4.034 Full text

II. Crystallization to create solid state molcular associations

Our goal is to obtain and determine the structures of new polymorphic or isostructural crystal forms of small organic molekules, particularly active pharmaceutical ingredients (APIs) by single crystal X-ray diffraction and several thermal analytic methods. It includes the development of laboratory crystallization processes to grow single crystals of one- or two-component systems, clathrates, inclusion complexes and co-crystals. Physico-chemical properties can be gradualy modified e.g. solidity that is related to the formulation, solubility that is connected to bioavailability in human body and stability that infulences the durability.

Ongoing projects:

NKFIH K 100801: „A szupramolekuláris kölcsönhatások szerepe egy- és többkomponensű szilárd fázisú rendszerek felépítésében”

MTA Infrastruktúra pályázatok 2014, 2015, 2016

Related publications

1. Dániel Vajk Horváth, Tamás Holczbauer*, Laura Bereczki, Roberta Palkó, Nóra Veronika May, Tibor Soós, Petra Bombicz“Polymorphism of a porous hydrogen bond assisted ionic organic framework” CrystEngComm (2018) 20, 1779-1782. (Back cover) Full text
2. Dobi Z, Holczbauer T, Soós T (2015)Strain-Driven Direct Cross-Aldol and -Ketol Reactions of Four-Membered Heterocyclic Ketones, Org. Lett., 17 (11),2634–2637 (IF: 6.364) Full text
3. Varga E, Mika LT, Csámpai A, Holczbauer T, Kardosa Gy and Soós T (2015)Mechanistic investigations of a bifunctional squaramide organocatalyst in asymmetric Michael reaction and observation of stereoselective retro-Michael reaction, RSC Adv., 5, 95079–95086 (IF: 3.840) Full text

III. Structural investigation of bioactive organic molecules and their metal complexes

In diverse fields of clinical practices, metal complexes of small biomolecule are frequently used as bioactive compounds eg. drugs, imaging agents, or chelators. X-ray diffraction method is one of the most powerful technique for the investigation of single crystals of these organic compounds and their complexes. Though crystallographic method can offer detailed and accurate data on the structure of metal-bioligand complexes, it is limited only for solid states. For these bioactive compounds the knowledge of the speciation, and the most plausible chemical forms, in aqueous solution is mandatory. Electron paramagnetic resoncance (EPR) spectroscopy is able to detect paramagnetic metal complexes in solution equilibrium systems. Such a structural comparison obtained at different phases can disclose interesting features of the intramolecular and intermolecular interactions of the complexes, and reveal possible structural transformations which can be crucial both for their biological functions and pharmaceutical formulations.

Ongoing projects

NKFIH K 115762: “Bioligandumok és funkcionális fémkomplexeinek szerkezetmeghatározása szilárd és oldat fázisban”

NKFIH K 124240: “Rákellenes platinafém és tioszemikarbazon komplexek fejlesztése és vizsgálata”

FWO-MTA Mobilitási Pályázat NKM-94/2018

Related publications

1. Ferenc Matyuska, Attila Szorcsik, Nóra V. May, Ágnes Dancs, Éva Kováts, Attila Bényei and Tamás Gajda “Tailoring the local environment around metal ions: solution chemical and structural study of some multidentate tripodal ligands” Dalton Trans., 46, 8626-8642 (2017) (IF:4.029) Full text
2. Eszter Tóth, Nóra V. May, Antal Rockenbauer, Gábor Peintler and Béla Gyurcsik “Exploring the boundaries of direct detection and characterization of labile isomers – a case study of copper(II)–dipeptide systems” Dalton Trans.,46, 8157-8166 (2017) (IF:4.029) Full text
3. Jelena M. Poljarević, Tamás Gál, Nóra V. May, Gabriella Spengler, Orsolya Dömötör, Aleksandar R. Savić, Sanja Grgurić-Šipka, Éva A. Enyedy “Comparative solution equilibrium and structural studies of half-sandwich ruthenium(II)(η6-toluene) complexes of picolinate derivatives” Journal of Inorganic Biochemistry (2018) 181, 74-85.Full text

Cooperations

• All major universities in Hungary (Budapest: BUTE, REU, Szeged Univ., Pannon Univ.) and
• research laboratories from abroad: Austria (Graz), Italy (Parma), Germany (Berlin,Freiberg), USA (El Paso) and the Republic of South Africa (Cape Town).

Educational activities

• Chemistry Doctoral School (Ph.D.), ELTE
• Laboratory thesis projects (B.Sc., M.Sc., TDK)
• Summer technical experience courses

Equipment

• Rigaku R-AXIS RAPID image plate diffractometer,
• X-Stream 2000 low temp unit,
• Enraf-Nonius turbo CAD-4 diffractometer, stereo microscopes,
• Cambridge Structural Database Hung. Affiliated Data Center
• Hot-Stage equipment
• Differencial Scanning Chalorimeter (DSC)

Measurement possibilities

• collection of single crystal diffraction data from organic, metal-organic, inorganic and small protein single crystals in the temperature range of -180 – +60 ^oC degree
• determination of single crystal structures by direct and charge flipping methods, refinement and interpretation of obtained structural forms
• collection of diffraction data of instable crystals
• structural determination of twin crystals and/or crystals with low resolution
• following solid state chemical reactions by crystallization of intermediate molecules
• searching possibilities in the Cambridge Structural Database

Leader

Petra Bombicz

Members

I. Structure, dynamics, and function in proteins

NMR spectroscopy has a unique role in structural biology by providing both structural and dynamic information on biomolecules and their interactions. Its further advantage is that the microscopic atomic-level information obtained by NMR can be related to macroscopically measurable thermodynamic and kinetic parameters. Experiments are performed on biosynthetically produced uniformly ¹⁵N- (MW<7 kDa) or ¹³C/¹⁵N- (MW=7-25 kDa) enriched proteins.

• identification and mapping of binding sites and interaction surfaces
• structure elucidation
• investigation of internal motions and exchange processes
• residue-level monitoring of unfolding processes
• investigation of membrane peptides in lipid bilyers and membrane mimetics

Ongoing project:

NKFI K 109035: „Investigation of the mechanism of ligand binding in human ileal bile acid-binding protein”, 2014-2018

Related publications:

• G. Horváth, L. Biczók, Z. Majer, M. Kovács, A. Micsonai, J. Kardos, O. Tőke (2017) Structural insight into a partially unfolded state preceding aggregation in an intracellular lipid-binding protein. FEBS Journal, 284:3637-3661.
• Horváth, Á. Bencsura, Á. Simon Á, G. P. Tochtrop, G. T. DeKoster, D. F. Covey, D. P. Cistola, O. Tőke (2016) Structural determinants of ligand binding in the ternary complex of human ileal bile acid-binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR, FEBS Journal, 283:541-555.
• Horváth, O. Egyed, O. Tőke (2014) Temperature dependence of backbone dynamics in human ileal bile acid-binding protein: Implications for the mechanism of ligand binding. Biochemistry, 53:5186-5198.
• Horváth, P. Király, G. Tárkányi, O. Tőke (2012) Internal motions and exchange processes in human ileal bile acid-binding protein as studied by backbone ¹⁵N NMR spectroscopy, Biochemistry, 51:1848-1861.
• Tőke, Z. Banoczi, P. Király, R. Heinzmann, J. Burck, A. S. Ulrich, F. Hudecz (2011) A kinked antimicrobial peptide from Bombina maxima. I. Three-dimensional structure determined by NMR in membrane-mimicking environments, Eur. Biophys. J. 40:447-462.

II. Polymeric systems

NMR spectroscopy is a powerful tool for the study of polymeric systems. The combination of solution- and solid-state NMR techniques are used to elucidate the structure of synthetic/natural polymers and to investigate the various intra- and intermolecular interactions giving rise to their macroscopic characteristics. Systematic studies of host-guest interactions between macromolecules and various biologically active compounds are directed at the development of controlled drug delivery systems.

• investigation of chemical modifications in synthetis/natural polymers
• polymer molecular weight analysis (DOSY NMR)
• structural characterization of polymeric systems in the solid state
• study of intra-/intermolecular interactions of polymers in the solid state
• morphological characterization of polymeric systems with an active substance

Ongoing project:

NKFI K 115939: „Intermolecular interactions in regulated substance delivery systems”, 2015-2019

Related publications:

• Szabó, B. Berke, K. László, Z. Osváth, A. Domján (2017) Non-covalent interactions between poly(N-isopropylacrylamide) and small aromatic probe molecules studied by NMR spectroscopy. European Polymer Journal 93:750-760.
• Domján, E. Geissler, K. László (2010) Phenol-polymer proximity in a thermoresponsive gel determined by solid-state ¹H-¹H CRAMPS NMR spectroscopy, Soft Matter, 6:247-249.
• Domján, C. Fodor, S. Kovács, T. Marek, B. Iván, K. Süvegh (2012) Anomalous swelling behavior of poly(N-vinylimidazole)-l-poly(tetrahydrofuran) amphiphilic conetwork in water studied by solid-state NMR and positron annihilation lifetime spectroscopy, Macromolecules, 45:7557-7565.
• Domján, E. Manek, E. Geissler, K. László (2013) Host–Guest Interactions in Poly(N-isopropylacrylamide) Hydrogel Seen by One- and Two-Dimensional ¹H CRAMPS Solid-State NMR Spectroscopy, Macromolecules, 46:3118-3124.
• Nikowitz, A. Domján, K. Pintye-Hódi, G. Regdon Jr, (2016) Multivariate calibration of the degree of crystallinity in intact pellets by X-ray powder diffraction, International Journal of Pharmaceutics, 502:107-116.

III. Applications in organic chemistry and material sciences

Structure determination of natural and synthetic compounds, conformational analysis, NMR spectroscopic investigation of reaction mechanisms, self-association processes, elucidation of the structural background of unusual mechanistic and optical properties. In addition to the commonly used one- and two-dimensional NMR measurements, diffusion and relaxation NMR experiments are carried out to characterize molecular interactions and dynamic processes, Besides the routinely performed ¹H, ¹³C, ¹⁵N, ³¹P experiments, ¹⁹F and exotic nuclei such as ¹⁰B/¹¹B, ²⁹Si, ²⁰⁷Pb can also be investigated.

Related publications:

• É. Dorkó, M. Szabó, B. Kótai, I. Pápai, A. Domján, T. Soós (2017) Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls. Angewandte Chemie – International Edition 56:9512-9516.
• Palko, O. Egyed, TA. Rokob, P. Bombicz, Z. Riedl, G. Hajós (2015) Transformation of zwitterionic pyridine derivatives to a spiro-fused ring system: Azoniabenzo[de]fluorine. Synthesis and mechanistic rationalization. J. Org. Chem. 80:174-179.
• Takács, I. Nagy, P. Bombicz, O. Egyed, K. Jemnitz, Z. Riedl, J. Molnár, L. Amaral, G.Hajós, G. (2012) Selective hydroboration of dieneamines. Formation of hydroxyalkylphenothiazines as MDR modulators, Bioorganic and Medicinal Chemistry 20:4258-4270.
• Baranyai, G.Marsi, C. Jobbágy, A. Domján, L. Olah, A. Deák (2015) Mechano-induced reversible colour and luminescence switching of a gold(I)-diphosphine complex. Dalton Trans. 44:13455-13459.
• Á. Gyömöre, M.Bakos, T.Földes, I.Pápai, Domján, T. Soós (2015) Moisture-Tolerant Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones. ACS Catalysis 5:5366-5372.

Cooperations

• RCNS HAS, IOF, Organocatalysis Research Group
• RCNS HAS IE, Protein Interaction Group
• RCNS HAS, IE, Signal Transduction and Functional Genomics Research Group
• RCNS HAS, IE, Cell Architecture Research Group
• RCNS HAS, IMEC, Polymer Physics Research Group
• RCNS HAS, IMEC, Polymer Chemistry Research Group
• RCNS HAS, IMEC, Biological Nanochemistry Research Group
• Biological Research Centre, Szeged and Research Institute of Chemical and Process Engineering, University of Pannonia
• Eötvös University, Department of Organic Chemistry; HAS-ELTE Peptide Research Group
• Eötvös University, Department of Biochemistry, Protein Folding and Amyloid Group
• Eötvös University, Department of Biochemistry, Motor Enzymology Research Group
• Department of Physical Chemistry and Materials Science, Budapest University of Technology and Economics
• Department of Pharmaceutical Technology, University of Szeged
• University of Debrecen, Department of Organic Chemistry
• Karlsruhe Institute of Technology, Germany
• Washington University School of Medicine, St. Louis, USA

Educational activities

• Chemistry & Biology Doctoral School (Ph.D.), ELTE
• Laboratory thesis projects (M.Sc.)
• Summer technical experience courses

Equipments

Varian NMR System(R), 600 MHz, narrow bore spectrometer, 40 channel shims, five RF channels with pulse shaping, DirectDrive(R) technology, 100W and 800W ¹H amplifiers, Performa IV. triaxial XYZ pulsed field gradient (PFG) unit, solid-state accessories (CP/MAS), low-gamma option, ¹H¹³C{¹⁵N-³¹P}-XYZ indirect detection triple tunable probe with triaxial gradient, HFC-Z indirect detection triple probe, HCN-Z indirect detection triple probe, ¹⁵N-³¹P{¹H-¹⁹F} direct detection dual broadband gradient probe, 3.2mm and 6mm HXY Varian/Chemagnetics triple tunable T3 MAS probes, temperature preconditioning unit.

Varian NMR System(R), 400 MHz, narrow bore spectrometer, two RF channels, DirectDrive(R) technology, pulsed field gradient (PFG) unit, AutoX 5mm direct detection dual broadband gradient probe, solid-state accessories (CP/MAS), 4.0mm HX Varian/Chemagnetics T3 MAS probe, temperature preconditioning unit.

Leader

Orsolya Tőke

Members

Leader

Pál Szabó

Members