TY - JOUR AU - Kun, Sándor AU - Mathomes, Rachel T. AU - Docsa, Tibor AU - Somsák, László AU - Hayes, Joseph M. TI - Design and Synthesis of 3-(β-d-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential JF - MOLECULES J2 - MOLECULES VL - 28 PY - 2023 IS - 7 PG - 19 SN - 1431-5157 DO - 10.3390/molecules28073005 UR - https://m2.mtmt.hu/api/publication/33762403 ID - 33762403 AB - Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, C-β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion–ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1H-pyrazole (3) and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1H-pyrazole (4) were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed 3 as a moderate inhibitor (IC50 = 565 µM), but 4 displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics—generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while 3 was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion–ion interactions; for 4, the most stable tautomer did not have the His377 backbone C=O interaction and while ion–ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted. LA - English DB - MTMT ER - TY - JOUR AU - Kánya, Nándor AU - Kun, Sándor AU - Somsák, László TI - Glycopyranosylidene-Spiro-Morpholinones: Evaluation of the Synthetic Possibilities Based on Glyculosonamide Derivatives and a New Method for the Construction of the Morpholine Ring JF - MOLECULES J2 - MOLECULES VL - 27 PY - 2022 IS - 22 PG - 18 SN - 1431-5157 DO - 10.3390/molecules27227785 UR - https://m2.mtmt.hu/api/publication/33291682 ID - 33291682 AB - Glycosylidene-spiro-morpholin(on)es are scarcely described skeletons in the literature. In this work, we have systematically explored the synthetic routes towards such morpholinones based on the reactions of O-peracylated hept-2-ulopyranosonamide derivatives of D-gluco and D-galacto configuration. Koenigs–Knorr type glycosylation of 2-chloroethanol, allylic and propargylic alcohols by (glyculosylbromide)onamides furnished the expected glycosides. The 2-chloroethyl glycosides were ring closed to the corresponding spiro-morpholinones by treatment with K2CO3. The (allyl glyculosid)onamides gave diastereomeric mixtures of spiro-5-hydroxymorpholinones by ozonolysis and 5-iodomethylmorpholinones under iodonium ion mediated conditions. The ozonolytic method has not yet been known for the construction of morpholine rings, therefore, it was also extended to O-allyl mandelamide. The 5-hydroxymorpholinones were subjected to oxidation and acid catalyzed elimination reactions to give the corresponding morpholine-3,5-dions and 5,6-didehydro-morpholin-3-ones, respectively. Base induced elimination of the 5-iodomethylmorpholinones gave 5-methyl-2H-1,4-oxazin-3(4H)-ones. O-Acyl protecting groups of all of the above compounds were removed under Zemplén conditions. Some of the D-gluco configured unprotected compounds were tested as inhibitors of glycogen phosphorylase, but showed no significant effect. LA - English DB - MTMT ER - TY - JOUR AU - Tsagkarakou, Anastasia S. AU - Chasapi, Styliani A. AU - Koulas, Symeon M. AU - Tsialtas, Ioannis AU - Kyriakis, Efthimios AU - Drakou, Christina E. AU - Kun, Sándor AU - Somsák, László AU - Spyroulias, Georgios A. AU - Psarra, Anna-Maria G. AU - Leonidas, Demetres D. TI - Structure activity relationship of the binding of p-coumaroyl glucose to glycogen phosphorylase and its effect on hepatic cell metabolic pathways JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS J2 - EJMCR VL - 3 PY - 2021 PG - 11 SN - 2772-4174 DO - 10.1016/j.ejmcr.2021.100011 UR - https://m2.mtmt.hu/api/publication/32549495 ID - 32549495 AB - The binding of p-coumaroyl glucose to glycogen phosphorylase (GP; a pharmaceutical target for the development of antihyperglycaemic drugs) has been studied by kinetics, and X-ray crystallography while its effect to HepG2 cells metabolism has been assessed by NMR metabolomics. p-Coumaroyl glucose is a potent inhibitor of human liver GP with a Ki value of 213 μМ that binds at the active site of the enzyme. Comparative structural analysis with chemically similar GP inhibitors reveals the structural basis of its inhibitory potency. NMR metabolomics analysis revealed that HepG2 cells in the presence of p-coumaroyl glucose actively response to higher glucose uptake from their environment and a display an “insulin-sensitizing’’ state. Furthermore, NMR metabolomics analysis indicates an enhancement of gluconeogenesis towards lipid metabolism and glycerol-derived components. LA - English DB - MTMT ER - TY - JOUR AU - Sipos, Ádám AU - Szennyes, Eszter AU - Hajnal, ÉN AU - Kun, Sándor AU - Szabó, Erzsébet Katalin AU - Uray (Davis), Karen L. AU - Somsák, László AU - Docsa, Tibor AU - Bokor, Éva TI - Dual-target compounds against type 2 Diabetes Mellitus: proof of concept for sodium dependent glucose transporter (SGLT) and glycogen phosphorylase (GP) inhibitors JF - PHARMACEUTICALS J2 - PHARMACEUTICALS-BASE VL - 14 PY - 2021 IS - 4 PG - 27 SN - 1424-8247 DO - 10.3390/ph14040364 UR - https://m2.mtmt.hu/api/publication/31966049 ID - 31966049 AB - A current trend in the quest for new therapies for complex, multifactorial diseases, suchas diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium de-pendent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP)in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type com-pounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucoseanalogue inhibitors exist. The purpose of this study was to identify dual acting compounds whichinhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships ofSGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type com-pounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT.New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods.None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was alsodetermined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methylarene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compoundsinhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitorcompounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor,2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Kiof 31 nM for GP and IC50of 3.5μM forSGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into evenmore efficient dual-target compounds with potential applications in future antidiabetic therapy. LA - English DB - MTMT ER - TY - JOUR AU - Kánya, Nándor AU - Kun, Sándor AU - Batta, Gyula AU - Somsák, László TI - Glycosylation with ulosonates under Mitsunobu conditions: scope and limitations JF - NEW JOURNAL OF CHEMISTRY J2 - NEW J CHEM VL - 44 PY - 2020 IS - 34 SP - 14463 EP - 14476 PG - 14 SN - 1144-0546 DO - 10.1039/d0nj03044a UR - https://m2.mtmt.hu/api/publication/31582694 ID - 31582694 N1 - Funding Agency and Grant Number: Hungarian National Research, Innovation and Development Office [NKFIH PD 121406]; EU - European Regional Development FundEuropean Union (EU) [GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004] Funding text: The research was supported by the Hungarian National Research, Innovation and Development Office (NKFIH PD 121406 to S. K.) and by the EU and co-financed by the European Regional Development Fund under the projects GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004. Dr I. Bajza is thanked for a generous gift of the sialic acid derivative 33. AB - A systematic study was performed by using Mitsunobu conditions (diethyl azodicarboxylate, Ph3P orn-Bu3P in THF or CH3CN) for glycosylations with methyl 3,4,5,7-tetra-O-benzoyl-alpha-d-gluco-hept-2-ulopyranosonate. From a set of 47 O-, N-, S- and C-nucleophiles, phenols andN-hydroxy compounds with a pK(a)of 5-8, phthalimide, benzotriazole, 6-chloropurine, an oxazolidinedione and several tetrazoles with a pK(a)of 4-8, and thiophenol gave the corresponding products in moderate to very good yields, while C-nucleophiles were unreactive. Trihaloacetanilides underwentO-glycosylation to giveO-glycosyl-N-aryl trihaloacetimidates which could not be made by conventionalO-imidoylations. All reactions were highly stereoselective to produce the beta(d) anomers only. With methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d-glycero-d-galacto-2-nonulopyranose)onate phenols and benzotriazole resulted in the expected products, but all other nucleophiles failed to react. While these transformations gave anomeric mixtures in a ratio close to 1 : 1 at room temperature, the alpha-selectivity increased to 92 : 8 at -30 degrees C. Ano-nitrophenyl sialoside was converted to a spiro-benzoxazinone derivative by reduction of the nitro group and subsequent spontaneous ring closure. LA - English DB - MTMT ER - TY - JOUR AU - Kyriakis, Efthimios AU - Karra, Aikaterini G. AU - Papaioannou, Olga AU - Solovou, Theodora AU - Skamnaki, Vassiliki T. AU - Liggri, Panagiota G. V. AU - Zographos, Spyros E. AU - Szennyes, Eszter AU - Bokor, Éva AU - Kun, Sándor AU - Psarra, Anna-Maria G. AU - Somsák, László AU - Leonidas, Demetres D. TI - The architecture of hydrogen and sulfur sigma-hole interactions explain differences in the inhibitory potency of C-beta-D-glucopyranosyl thiazoles, imidazoles and an N-beta-D glucopyranosyl tetrazole for human liver glycogen phosphorylase and offer new insights to structure-based design JF - BIOORGANIC & MEDICINAL CHEMISTRY J2 - BIOORGAN MED CHEM VL - 28 PY - 2020 IS - 1 PG - 10 SN - 0968-0896 DO - 10.1016/j.bmc.2019.115196 UR - https://m2.mtmt.hu/api/publication/31049125 ID - 31049125 N1 - Funding Agency and Grant Number: Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020) [MIS 5002550]; European Union (European Regional Development Fund)European Union (EU); Hellenic State Scholarships Foundation; action "Support of human research resources through doctoral research" - "Operational Programme Education and Lifelong Learning" - European Social Fund (ESF) and National Resources; General Secretariat for Research and Technology (GSRT)Greek Ministry of Development-GSRT; Hellenic Foundation for Research and Innovation (HFRI); National Research, Development and Innovation Office of Hungary [PD121406, FK125067]; EU - European Regional Development FundEuropean Union (EU) [GINOP-2.3.2-15-2016-00008] Funding text: We acknowledge support of this work by the project "The National Research Infrastructures on integrated biology, drug screening efforts and drug target functional characterization - INSPIRED-Thessaly" (MIS 5002550) which is implemented under the Action "Reinforcement of the Research and Innovation Infrastructure", funded by the Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund). E.K., O.P., and T.S. would like to acknowledge financial support from the Hellenic State Scholarships Foundation and the action "Support of human research resources through doctoral research" funded by the "Operational Programme Education and Lifelong Learning" co-funded by the European Social Fund (ESF) and National Resources. A.G.K. would like to acknowledge financial support from General Secretariat for Research and Technology (GSRT) and Hellenic Foundation for Research and Innovation (HFRI). The work was also supported by the National Research, Development and Innovation Office of Hungary (PD121406, FK125067) and by the EU co-financed by the European Regional Development Fund under the project GINOP-2.3.2-15-2016-00008. Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, Larissa, 41500, Greece Department of Organic Chemistry, University of Debrecen, POB 400 Debrecen, H-4002, Hungary Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens, 11635, Greece Export Date: 21 February 2020 CODEN: BMECE Correspondence Address: Psarra, A.-M.G.; Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, Greece; email: ampsarra@bio.uth.gr Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, Larissa, 41500, Greece Department of Organic Chemistry, University of Debrecen, POB 400 Debrecen, H-4002, Hungary Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens, 11635, Greece Export Date: 24 May 2021 CODEN: BMECE Correspondence Address: Psarra, A.-M.G.; Department of Biochemistry and Biotechnology, Biopolis, Greece; email: ampsarra@bio.uth.gr Funding details: FK125067, PD121406 Funding details: GINOP-2.3.2-15-2016-00008 Funding details: Funding details: Funding details: Funding details: Funding details: AB - C-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a K-i value of 3.2 mu M for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 mu M. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur sigma-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent. LA - English DB - MTMT ER - TY - JOUR AU - Kun, Sándor AU - Kánya, Nándor AU - Galó, N. AU - Páhi, A. AU - Mándi, Attila AU - Kurtán, Tibor AU - Makleit, Péter Zoltán AU - Veres, Szilvia AU - Sipos, Ádám AU - Docsa, Tibor AU - Somsák, László TI - Glucopyranosylidene-spiro-benzo[b][1,4]oxazinones and -benzo[b][1,4]thiazinones: synthesis and investigation of their effects on glycogen phosphorylase and plant growth inhibition. JF - JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY J2 - J AGRIC FOOD CHEM VL - 67 PY - 2019 IS - 24 SP - 6884 EP - 6891 PG - 8 SN - 0021-8561 DO - 10.1021/acs.jafc.9b00443 UR - https://m2.mtmt.hu/api/publication/30750491 ID - 30750491 N1 - 30720317 másolata. Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [NKFIH PD121406, PD121020, K120181, K109450]; European Regional Development FundEuropean Union (EU) [GINOP-2.3.2-15-2016-00008] Funding text: This work was supported by the National Research, Development and Innovation Office of Hungary (NKFIH PD121406, PD121020, K120181, and K109450) and also financed by the European Regional Development Fund under the Project GINOP-2.3.2-15-2016-00008. The Governmental Information-Technology Development Agency (KIFU) is thanked for CPU time. AB - Glucopyranosylidene-spiro-benzo[b][1,4]oxazinones were obtained via the corresponding 2-nitrophenyl glycosides obtained by two methods: (a) AgOTf-promoted glycosylation of 2-nitrophenol derivatives by O-perbenzoylated methyl (α-D-gluculopyranosyl bromide)heptonate or (b) Mitsunobu-type reactions of O-perbenzoylated methyl (α-Dgluculopyranose)heptonate with bulky 2-nitrophenols in the presence of diethyl azodicarboxylate (DEAD) and PPh3. Catalytic hydrogenation (H2-Pd/C) or partial reduction (e.g., H2-Pd/C, pyridine) of the 2-nitro groups led to spirobenzo[b][1,4]oxazinones and spiro-benzo[b][1,4]-4-hydroxyoxazinones by spontaneous ring closure of the intermediate 2-aminophenyl or 2-hydroxylamino glycosides, respectively. The analogous 2-aminophenyl thioglycosides, prepared by reactions of O-perbenzoylated methyl (α-D-gluculopyranosyl bromide)heptonate with 2-aminothiophenols, were cyclized in m-xylene at reflux temperature to the corresponding spiro-benzo[b][1,4]thiazinones. O-Debenzoylation was effected by Zempleń transesterification in both series. Spiro-configurations were determined by NMR and electronic circular dichroism timedependent density functional theory (ECD-TDDFT) methods. Inhibition assays with rabbit muscle glycogen phosphorylase b showed (1′R)-spiro{1′,5′-anhydro-D-glucitol-1′,2-benzo[b][1,4]oxazin-3(4H)-one} and (1′R)-spiro{1′,5′-anhydro-D-glucitol-1′,2-benzo[b][1,4]thiazin-3(4H)-one} to be the most efficient inhibitors (27 and 28% inhibition at 625 μM, respectively). Plant growth tests with white mustard and garden cress indicated no effect except for (1′R)-4-hydroxyspiro{1′,5′-anhydro-D-glucitol-1′,2-benzo[b][1,4]oxazin-3(4H)-one} with the latter plant to show modest inhibition of germination (95% relative to control). LA - English DB - MTMT ER - TY - JOUR AU - Barr, Daniel AU - Szennyes, Eszter AU - Bokor, Éva AU - Al-Oanzi, Ziad H. AU - Moffatt, Colin AU - Kun, Sándor AU - Docsa, Tibor AU - Sipos, Ádám AU - Davies, Matthew P. AU - Mathomes, Rachel T. AU - Snape, Timothy J. AU - Agius, Loranne AU - Somsák, László AU - Hayes, Joseph M. TI - Identification of C -β- d -Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies JF - ACS CHEMICAL BIOLOGY J2 - ACS CHEM BIOL VL - 14 PY - 2019 IS - 7 SP - 1460 EP - 1470 PG - 11 SN - 1554-8929 DO - 10.1021/acschembio.9b00172 UR - https://m2.mtmt.hu/api/publication/30739245 ID - 30739245 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [FK125067, PD121406]; EUEuropean Union (EU); European Regional Development FundEuropean Union (EU) [GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004] Funding text: This work was supported by the National Research, Development and Innovation Office of Hungary (Grants FK125067 and PD121406) and the EU cofinanced by the European Regional Development Fund under Projects GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004. School of Physical Sciences and Computing, University of Central Lancashire, Preston, PR1 2HE, United Kingdom Department of Organic Chemistry, University of Debrecen, POB 400, Debrecen, H-4002, Hungary Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom Health and Life Sciences, De Montfort University, Gateway House, Leicester, LE1 9BH, United Kingdom Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, United Kingdom Aljouf University, Medical Laboratory Science, Sakaka, Saudi Arabia Cited By :7 Export Date: 24 May 2021 CODEN: ACBCC Correspondence Address: Agius, L.; Institute of Cellular Medicine, United Kingdom; email: loranne.agius@newcastle.ac.uk Funding details: FK125067, PD121406 Funding details: Funding details: GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004 AB - Several C-beta-D-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (R-P) and Spearman (R-s) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(beta-D-glucopyranosyl)-imidazoles and 2-aryl-4(beta-D-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best K-i values in the low micromolar range (5c = 1.97 mu M; 13b = 4.58 mu M). Ten C-beta-D-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a-c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30-60 mu M). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pK(a) (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form. LA - English DB - MTMT ER - TY - JOUR AU - Körhegyi, Zoltán AU - Rózsa, Dávid AU - Hajdu, István AU - Bodnár, Magdolna AU - Kertész, István AU - Kerekes, Krisztina AU - Kun, Sándor AU - Kollár, József AU - Varga, József AU - Garai, Ildikó AU - Trencsényi, György AU - Borbély, János TI - Synthesis of 68Ga-Labeled Biopolymer-based Nanoparticle Imaging Agents for Positron-emission Tomography JF - ANTICANCER RESEARCH J2 - ANTICANCER RES VL - 39 PY - 2019 IS - 5 SP - 2415 EP - 2427 PG - 13 SN - 0250-7005 DO - 10.21873/anticanres.13359 UR - https://m2.mtmt.hu/api/publication/30655330 ID - 30655330 N1 - 265738 AB - Aim: The purpose of this study was to develop a folate receptor-targeted Ga-68-labeled agent for the detection of cancer cells in mouse models of ovarian cancer by dual positron-emission tomography (PET) and magnetic resonance imaging (MRI). Moreover, we aimed to develop a controlled biopolymer-based chemistry that enables linking metal-binding (here Ga-68) chelators. Materials and Methods: The nanoparticle (NP) agent was created by self-assembling of folic acid-modified polyglutamic acid and chelator-modified chitosan followed by radiolabeling with Ga-68 (III) ions (Ga-68-NODAGA-FA). The structure of modified biopolymers was characterized by spectroscopy. Particle size and mobility were determined. Results: Significant selective binding of NPs was established in vitro using folate receptor-positive KB and - negative MDA-MB-231 cell lines. In vivo tumor uptake of folate-targeted Ga-68(3+)-radiolabeled NPs was tested using subcutaneous tumor-bearing CB17 SCID mice models. PET/MR dual modalities showed high tumor uptake with 6.5 tumor-to-muscle ratio and NP localization. Conclusion: In vivo results supporting the preliminary in vitro tests demonstrated considerably higher Ga-68-NODAGA-FA nanoparticle accumulation in KB tumors than in MDA-MB-231 tumors, thereby confirming the folate receptor-mediated uptake of this novel potential PET imaging agent. LA - English DB - MTMT ER - TY - JOUR AU - Somsák, László AU - Bokor, Éva AU - Juhász, László AU - Kun, Sándor AU - Lázár, László AU - Juhászné Tóth, Éva AU - Vágvölgyiné Tóth, Marietta TI - New syntheses towards C-glycosyl type glycomimetics JF - PURE AND APPLIED CHEMISTRY J2 - PURE APPL CHEM VL - 91 PY - 2019 IS - 7 SP - 1159 EP - 1175 PG - 17 SN - 0033-4545 DO - 10.1515/pac-2019-0208 UR - https://m2.mtmt.hu/api/publication/30647985 ID - 30647985 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [CK-77712, K-109450, PD-105808, PD-121406, FK-125067, FK-128766]; European Regional Development FundEuropean Union (EU) [TAMOP-4.2.4.A/2-11/1-2012-0001, GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004]; University of Debrecen [5N5XBTDDTOMA320]; Alexander von Humboldt Foundation (Germany)Alexander von Humboldt Foundation; EUEuropean Union (EU) Funding text: These works received financial support from the National Research, Development and Innovation Office of Hungary (Grants: CK-77712, K-109450, PD-105808, PD-121406, FK-125067, FK-128766), from the EU co-financed by the European Regional Development Fund under the projects TAMOP-4.2.4.A/2-11/1-2012-0001 'National Excellence Program', GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004, from the University of Debrecen (5N5XBTDDTOMA320) as well as from the Alexander von Humboldt Foundation (Germany). Cited By :3 Export Date: 24 May 2021 CODEN: PACHA Correspondence Address: Somsák, L.; Department of Organic Chemistry, POB 400, Hungary; email: somsak.laszlo@science.unideb.hu Funding details: CK-77712, FK-125067, FK-128766, K-109450, PD-105808, PD-121406 Funding details: Funding details: AB - Glycomimetics are compounds that resemble carbohydrate molecules in their chemical structure and/or biological effect. A large variety of compounds can be designed and synthesized to get glycomimetics, however, C-glycosyl derivatives represent one of the most frequently studied subgroup. In the present survey syntheses of a range of five- and six membered C-glycopyranosyl heterocycles, anhydro-aldimine type compounds, exo-glycals, C-glycosyl styrenes, carbon-sulfur bonded oligosaccharide mimics are described. Some of the C-glycopyranosyl azoles, namely 1,2,4-triazoles and imidazoles belong to the most efficient glucose analog inhibitors of glycogen phosphorylase known to date. Biological studies revealed the therapeutical potential of such inhibitors. Other synthetic derivatives offer versatile possibilities to get further glycomimetics. LA - English DB - MTMT ER -