Synthesis of new aliphatic diimino-dioximes and diamino-dioximes and their chelate complexes with transitional and radioactive metal: potential applications in medicine

U prvom delu ove teze izvršena je sinteza četiri jedinjenja iz klase diimino-dioksima, čijom redukcijom su dobijena četiri jedinjenja iz klase diamino-dioksima koja do sada nisu bila poznata u literaturi.Sinteza sva četiri diimino-dioksima je izvedena u protičnom rastvaraču (C2H5OH ili CH3OH), uz refluks ili na sobnoj temperaturi, u atmosferi azota i po potrebi u prisustvu katalitičke količine CH3COOH. Sinteza u aprotičnom rastvaraču (benzenu) izvedena je samo za dva diimino-dioksima. Redukcijom odgovarajućeg diimino-dioksima sa NaBH4 u C2H5OHanh, sintetisani su diamino-dioksimi.Jedinjenja su okarakterisana elementarnom analizom, elektronskom apsorpcionom i IR spektroskopijom, 1H i 13C NMR spektroskopijom.Sintetisani diamino-dioksimi grade komplekse sa radioaktivnim izotopom 99mTc. Navedena jedinjenja sadrže četiri atoma azota sa slobodnim parovima elektrona i ponašaju se kao donori elektrona pri građenju koordinativne veze sa 99mTc(V). Zbog navedenog svojstva, ispitivano je da li kompleksi sintetisanih diamino-dioksima sa 99mTc(V) mogu imati primenu u SPECT dijagnostičkoj nuklearnoj medicini. U okviru ove faze istraživanja izvršene su sledeće aktivnosti: obeležavanje diamino-dioksima sa 99mTc(V), određivanje prinosa obeleženih jedinjenja, određivanje stabilnosti nagrađenih kompleksa, određivanje lipofilnosti i proteinskog vezivanja obeleženih jedinjenja i praćenje biološke raspodele (biodistribucije) na eksperimentalnim životinjama.Jedinjenja iz klase diimino-dioksima, lako grade komplekse sa prelaznim metalima, samim tim i sa Cu(II). To je veoma značajno jer bi sintetisana jedinjenja diimino-dioksimske strukture zbog navedenog svojstva mogla biti lako obeležena i radioaktivnim izotopom 64Cu i imati potencijalnu primenu u PET dijagnostičkoj nuklearnoj medicini. Sintetisani su kompleksi jednog odabranog diimino-dioksima i dvovalentnih metala Cu(II),...In this thesis, the synthesis of four compounds from classes of diimine-dioximes have been given, and additionally after their reduction four compounds from classes of diamine-dioximes have been obtained, which have not been so far known in the literature.The synthesis of all four diimine-dioximes have been performed in a protic solvent (CH3OH or C2H5OH), at reflux or at room temperature, under nitrogen atmosphere, and optionally in the presence of a catalytic amount of CH3COOH. The synthesis in an aprotic solvent (benzene) has been performed for only two diimine-dioximes. After reduction of the corresponding diimine-dioximes with NaBH4 in C2H5OHanh, diamine-dioximes have been obtained.All obtained compounds have been characterized by elemental analysis, electronic absorption and IR spectroscopy, 1H and 13C NMR spectroscopy.Synthesized diamino-dioximes form complexes with radioactive isotope 99mTc. They contain four nitrogen atoms with free electron pairs and therefore act as electron donors in coordinating links with 99mTc (V). Because of this property, it have been examined whether the synthesized complexes with diamino-dioximes and 99mTc (V) may be used in the SPECT diagnostic nuclear medicine. For this purposes the following activities have been carried out: the labelling diamino-dioximes with 99mTc (V), the determination of the yield of labeled compounds, the determination of the stability of formed complexes, the determination of lipophilicity and protein binding of labeled compounds and biological monitoring of distribution (biodistribution) in experimental animals.Compounds from the class of diimine-dioximes easily form complexes with transition metals, and therefore with Cu(II). This is very important because the synthesized compounds with diimines-dioxime structure could be easily labeled with radioactive isotope 64Cu and could potentially be used in PET diagnostic nuclear medicine. Complexes..

Evalaution of radioiodination of synthesised meta-iodobenzylguanidine catalyzed by in situ generated Cu(i)

Meta-iodobenzylguanidine (m-IBG) is a biogenic amine precursor, noradrenaline analogue, which is actively taken up by tumors. In tracer amounts, [123/131I]-m-IBG is used as a radiopharmaceutical to target normal and malignant tissues of neuroadrenergic origin for diagnostic scintigraphy, and labeled with higher activities of 131I, it is used for therapy of phenochromocytoma and neuroblastoma. The increased clinical therapeutic use of unlabeled m-IBG at doses of up to 40 mg/m2 emphasizes the need for syntheses and an established quality protocol for this substance that relies on verifiable analytical parameters. Evaluation of radioiodination was necessary to obtain higher labeling yield (we achieved over 90% instead no more than 70%), because isotopic exchange labeling of m-IBG with 131I catalyzed by Cu(I) is much more efficient than with conveniently used ammonium sulphate.Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 200

Factors affecting labelling yield of 111In-DTPA-BSA

Radiolabelling of antibodies depends on a number of factors including the chemical characteristics of the nuclide and the techniques employed for its incorporation into protein. For preliminary research we used model system and investigate the influence of different factors affecting labelling. Obtained results were successfully used for further radiolabelling of antibodies with different trivalent metals.Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 200

Reconstruction of the mandible with an autogenous corticocancellous bone graft and fibrin glue: An animal experiment

This paper reports on an experimental animal study evaluating a method of mandibular reconstruction in dogs using autogenous corticocaneclous bone graft and fibrin glue. Eight animals underwent a resection at the mandibular body and primary reconstruction was carried out using osteosynthesis plates and screws. The defect was bridged with an autogenous particulate bone graft from the anterior iliac crest. To accelerate bone healing, fibrin glue (FG) was mixed with particulate bone graft. The hypothesis of this study was based on the presumption that bone healing, in segmental reconstruction of the dog mandible with a particulate cancellous bone graft mixed with FG, would be successful. All dogs had eventful healing. The histological results were less favorable with regard to bone remodeling than the results obtained in similar experiments with a particulate corticocancellous bone graft

99mTc-hexakis-(2-metoxy-isobutyl-isonitrile) ( 99mTc-MIBI) a new myocardial imaging agent: synthesis of MIBI, optimising conditions for radiolabelling with 99mTc at high radiochemical purity and in vivo behavior

99mTc-MIBI is a promising radiopharmaceutical for myocardial perfusion imaging agent, but it has also shown good results in identifying several types of tumors, such as breast, lung and thyroid cancers. It is a lipophilic, cationic technetium (1) complex. In this paper a complete study on the synthesis of 2-metohy-isobutyl-isonitrile (MIBI) as well as a formulation of a lyophilized kit for labeling with 99mTc is presented. Investigation on effective factors as well as finding out the optimum parameters to obtain the highest labelling efficiency and radiochemical purity of 99mTc-MIBI complex were performed. The radiochemical purity of the labelled preparation was high (>95%). Biodistribution study performed in health male Wistar rats showed satisfactory biokinetics results. 99mTc-MIBI was accumulated in sufficient amount into the hearth tissue for myocardial perfusion imaging. MIBI in kit formulation was found to be stable and also safe for administration.Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 200

The analysis of 2,3-dicarboxypropane-1,1-diphosphonic acid-coated magnetite nanoparticles under an external magnetic field and their radiolabeling for possible theranostic applications

The advances in nanotechnology are directed towards the development of new theranostic agents based on magnetic nanoparticles that can be used for both cancer detection and treatment. In this study, 2,3-dicarboxypropane-1,1-diphosphonic acid-coated magnetite nanoparticles (Fe 3 O 4 -DPD MNPs) were evaluated for their theranostic application using different methods. The magnetic hyperthermia efficiency of the Fe 3 O 4 -DPD MNPs was investigated in saline solution with ionic strengths between 0.05 and 1.0 mol dm −3 . For a better understanding of hyperthermia, the behavior of Fe 3 O 4 -DPD MNPs under a non-alternating magnetic field was studied, and the transparency of the sample was measured. Furthermore, the radiotracer method using the radionuclides 99m Tc and 90 Y was applied as a reliable and powerful method for evaluating the in vivo behavior of a nanoprobe; a high radiolabeling yield (>93%), in vitro and in vivo stability of the radiolabeled nanoparticles and high heating effect were observed, thus paving the way for the possible theranostic applications of Fe 3 O 4 -DPD MNPs.This is the peer-reviewed version of the following article:Perić, M.; Radović, M.; Mirković, M. D.; Nikolić, A. S.; Iskrenović, P.; Janković, D.; Vranješ-Đurić, S. The Analysis of 2,3-Dicarboxypropane-1,1-Diphosphonic Acid-Coated Magnetite Nanoparticles under an External Magnetic Field and Their Radiolabeling for Possible Theranostic Applications. New Journal of Chemistry 2019, 43 (15), 5932–5939. [https://doi.org/10.1039/c8nj06478d]

Glucosomes: Magnetically induced controlled release of glucose modified liposomes

Novel methods of cancer therapy are constantly being investigated since the current approach heavily relies on the use of non-specific and toxic chemotherapy agents. Ideally, a drug used for cancer therapy would specifically target tumor sites or rather bind specifically with cancer cells. The way to achieve this is by targeting cancer cell specific receptors or receptors present in abnormally high counts at the surface. Rapid proliferation of cancer cells is fueled by large amounts of energy that is in turn produced by abnormal glucose uptake. Because of this high energy/glucose demand, cancer cells exhibit an abnormally high glucose receptor (GLUTs) count on their surface, compared to normal, healthy cells. We have utilized this glucose dependency to create glucose modified liposomes (Glucosomes) that are specifically bound by cancer cells. Glucosomes can be used to transport different substances, either hydrophilic or hydrophobic, and can therefore deliver any type of drug to cancer cells, increasing its efficiency. Another important aspect to consider is the controlled release of the drug being transported in order to maximize therapeutic efficiency. Controlled release can be achieved by utilizing different internal or external influences. In our study, we have used standard Fe3O4 magnetic nanoparticles to load glucosomes and induce their controlled opening via an external magnetic field. By applying an external magnetic field, the magnetic nanoparticles start heating up and transferring this thermal energy to the surrounding lipid bilayer, causing its perturbation and opening of the glucosome. Our study has found that controlled release can be achieved with high efficiency while the chemical stability of the Fe3O4 nanoparticles stays practically intact. Using EPR spectroscopy, we have shown that Fe3O4 nanoparticles remain trapped within the lipid bilayer and are essentially protected from oxidation that would diminish their magnetic properties. Since magnetic Fe3O4 nanoparticles are lodged well within the lipid bilayer no thermal damage can be caused to the drug being transported within the glucosome bilayer, making this a viable controlled release cancer targeting drug delivery system.Twentieth Young Researchers’ Conference - Materials Science and Engineering: Program and the Book of Abstracts; November 30 – December 2, 2022, Belgrade, Serbi

Influence of the weak interaction on the structure of metallocycle in binuclear copper(II) complex

The structure of binuclear Cu(II) complex containing double oximato bridges was determined by the single-crystal X-ray diffraction analysis. Copper is five-coordinated with perchlorato anion present at the borderline of semi-coordination. Comparison with the structurally related diiminedioxime Cu(II) complexes revealed the influence of the weak Cu···O(perchlorate) interaction on the geometry of the metallocycle

Synthesis and characterization of a new diaminodioxime, a potential ligand for 99mTc radiopharmaceuticals

This paper reports synthesis of a new diaminodioxime ligand, derivative of hexamethylpropyleneamine oxime (HM-PAO). The 99mTc(V)-d,l-HM-PAO complex is well-known radiopharmaceutical for regional blood flow imaging. The structure of the new ligand was investigated by elemental analysis, IR, 1H and 13C NMR. Complexation studies with 99mTc were carried out using stannous chloride as the reducing agent. The complex was characterized by paper chromatography and thin-layer chromatography. It was obtained in high yield when the reactions were carried out at pH=9. Also, it was found that the complex was stable up to 4 h

Supplementary data for article : Lozo, J.; Mirkovic, N.; O’Connor, P. M.; Malesevic, M.; Miljkovic, M.; Polović, N.; Jovcic, B.; Cotter, P. D.; Kojić, M. O. Lactolisterin BU, a Novel Class II Broad-Spectrum Bacteriocin from Lactococcus Lactis Subsp Lactis Bv. Diacetylactis BGBU1-4. Applied and Environmental Microbiology 2017, 83 (21). https://doi.org/10.1128/AEM.01519-17

Supplementary material for: [ https://doi.org/10.1128/AEM.01519-17]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2541