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U okviru istraživanja proučavani su N‐heterociklički ligandi i njihovi metalni kompleksi. Provedena je sinteza heterocikličkih spojeva, poput derivata piridina, 2, 2'‐dipiridilamina, benzimidazola i benzotiazola, te njihovih koordinacijskih kompleksa s prijelaznim metalima. Pripravljeni derivati podijeljeni su u šest klasa te im je ispitano biološko djelovanje. Heterobimetalni kompleks konjugata ferocena i 2, 2'‐dipiridilamina s bakrom(II) [Cu(A8c)2](CF3SO3)2 pokazao je selektivno inhibitorno djelovanje na stanice HeLa, MES‐OV, A549 i MDA‐MB‐231 uz povećanje stanične populacije u fazama staničnog ciklusa S i G2/M. Aktivnost 2, 2'‐dipiridilaminskih kompleksa poboljšana je koordinacijom s Re(I), pri čemu je, najizraženiju aktivnost pokazao kompleks [Re(B4a)(CO)3]Cl. Kompleks bis(2, 2'‐ pikolil)aminskog liganda i Ni(II), [Ni(C1)2](NO3)2, pokazao je istaknuto antiproliferativno djelovanje ometajući replikaciju DNK i smanjujući ekspresiju antiapoptotskog markera Bcl‐2. Rutenijevi(II) polusendvič kompleksi konjugata 2‐arilbenzotiazola i 2‐pikolila imali su antiproliferativno djelovanje u submikromolarnom području sa selektivnošću prema PANC1 stanicama. Konjugati acil‐tiourea i benzotiazola te njihovi Ru(II) kompleksi imali su inhibitorno djelovanje u niskom mikromolarnom i nanomolarnom području na stanice H460, MCF‐7, SW 620 i HepG2, s izraženim djelovanjem na staničnoj liniji raka dojke (MCF‐7). Ligand E5c i kompleksi D4aRu, E4cRu i E5cRu odabrani su za daljnja testiranja mehanizma biološkog djelovanja.

Goveđi serumski albumin (BSA) se često koristi kao model proteina za ljudski serumski albumin koji ima važnu ulogu u metabolizmu te postoji značajan interes prema razvoju metoda za njegovu osjetljiva i selektivna. U ovoj publikaciji priredili smo fluorescentne komplekse rutenija čija je fluorescencija ugašena u vodenom mediju, a obnavlja se vezanjem na BSA. Navedeno svojstvo omogućuje korištenje priređenih spojeva kao “Turn‐on“ fluorescentnih senzora za BSA. Isti spojevi su također i bio‐aktivni te pokazuju povećanje svoje toksičnosti prilikom osvjetljavanja, što ih čini potencijalnim kandidatima za fotodinamičku terapiju.

Organometalni spojevi su u pravilu nestabilni i osjetljivi na vodu i kisik, te su stoga rijetko korišteni u biologiji i medicini. Međutim, kemijska veza metala i ugljika, karakteristična za organometalne spojeve, poznata je u prirodi, primjerice kod koenzima vitamina B12 te kod hidrogenaza, koje u aktivnim mjestima sadrže organometalni fragment. U okviru ovog izlaganja bit će predstavljeni organometalni spojevi rutenija i renija istraživani u našem laboratoriju. S jedne strane će biti opisana njihova sinteza i karakterizacija spektroskopskim i kristalografskim instrumentalnim metodama u otopini i u čvrstom stanju. Uz to će biti diskutirana njihova svojstva u biološkom okruženju.

Bovine serum albumin (BSA) is often used as a model protein for human serum albumin, which plays an important role in metabolism.[1] Fluorescence spectroscopy is an attractive method for sensing applications as it is fast, practical, highly sensitive and selective. Ruthenium complexes with organic ligands are widely studied as potential anticancer drugs with some compounds reaching phase II of clinical trials.[2] Continuing our previous work on ruthenium phosphine complexes with anticancer activity, [3] in this paper we describe two ruthenium complexes 1 and 2, both substituted with pyrene – a fluorescent group. Intriguingly, 1 and 2 pyrene emission is completely quenched in water, and mostly reconstituted upon binding to BSA, thus 1 and 2 behaving as switch-on sensors. In addition, the cytotoxicity of the complexes with and without irradiation will be discussed, suggesting their potential use as PTD drugs.

An ultrasound-assisted synthesis has been used for the preparation of novel benzothiazole Schiff bases (1–3) as ligands for Zn(II) and Cu(II) metal complexes. In this class of Schiff base ligands, the isolated complexes 1a and 2a appear to be the only ones that have structures which include both the Schiff base ligand and the hydrolysis product 2-aminobenzothiazole in the same complex molecule. The aldehydes formed by Schiff base hydrolysis formed a rare example of a trans isomer in pentacoordinated 2, 4-disubstituted benzaldehyde complexes.

Despite the widespread application of metal complexes with multidentate oxazoline ligands in catalysis, fewer works explore monodentate oxazoline complexes.[1-3] Following our group’s previous work where the choice of metal cations and respective anions affected the structure of the resulting metal complex, [4] nine complexes with varying metal precursors and two similar monodentate oxazoline ligands are reported herein. In particular, zinc(II) and cadmium(II) complexes were found to form tetrahedral structures (type I in Figure 1), while copper(I) and silver(I) formed trigonal structures (types II and III in Figure 1). These compounds were characterized using 1H NMR spectroscopy in solution and single crystal X-ray diffraction.

The stereochemistry of flexible tridentate ligands influences many important properties like stability and reactivity in a chemical or biological environment. Metal coordination with bis-1, 2, 3- triazole ligands is an unexplored area of research in comparison to the structurally related dipicolylamine derivatives. In this work, bis-1, 2, 3-triazole derivatives with unsubstituted N- and O-central donor atoms were prepared using click chemistry by the reaction of aromatic azides with dipropargylamine and dipropargyl ether, respectively. Coordination of transition metals was studied in solution by NMR and UV-Vis spectrometry, along with characterisation in solid-state by single- crystal X-ray crystallography. Our research has shown that these types of ligands prefer formation of ML2 metal complexes. Study of the stereochemical preferences is currently underway as these ligands are able to form cis-, trans-fac or mer-isomers.

Bis-tridentatni metalni kompleksi fleksibilnih liganada [M(A-X-A)2] strukture imaju tri različita geometrijska izomera: mer, trans-fac i cis-fac. [1] Na stabilnost pojedinih izomera utječe niz faktora poput elektronskih i steričkih svojstava liganda, vrsta metalnog iona, mogućnost ostvarivanja nekovalentnih interakcija, vrsta protuiona i drugih. Utjecaji pojedinih faktora na nastanak određenog izomera ML2 kompleksa do danas nisu detaljno istraženi, a razumijevanje tih faktora nam omogućuje dizajn novih kompleksnih spojeva željene geometrije i svojstava. [2, 3] U ovom radu pripravljeni su derivati tridentatnih liganada bis(piridin-2-ilmetil)amina (bpa) i 2, 2'- iminodiacetamida (imda) te njihovi kompleksi s različitim solima Zn(II), Cu(II), Ni(II) i Co(II). Središnji donorski atomi liganada bili su kisik ili sumpor, odnosno -NPh- ili -PPh- skupine. Strukture spojeva u čvrstom stanju karakterizirane su difrakcijom rendgenskih zraka na jediničnom kristalu, a strukture u otopini spektroskopijom NMR. Stehiometrija i stereokemija kompleksa te moguće konformacije supstituenata u ovim sustavima modelirane su pomoću DFT računa kako bi se odredila njihova međusobna relativna stabilnost. Usporedbom eksperimentalnih podataka i DFT računa uočene su preference pojedinih središnjih atoma ka određenim stereoizomerima ML2 kompleksa. Jedan od ciljeva ovog istraživanja bio je odrediti koji čimbenici uzrokuju nastanak cis-fac izomera, koji bi se u slučaju dušika ili fosfora kao središnjeg donorskog atoma, mogli upotrijebiti za dizajn novih selektivnih katalizatora.

Bis-tridentate metal complexes of flexible ligands with [M(A-X-A)2] structure can form three different geometric isomers: mer, trans-fac and cis-fac[1]. Stability of an isomer is influenced by many factors such as electronic and steric properties of the coordinating ligand, type of metal ion, possibility of forming non-covalent interactions, type of anion present and others. The influences of such factors on a formation of a specific isomer of ML2 complex are not fully described. Understanding the isomer preference in said systems is an important starting point in development of new complex compounds with desired form and properties [2, 3]. In this work, derivatives of tridentate ligands bis(2-pyridine-2-ylmethyl)amine (bpa) and 2, 2’- iminodiacetamide (imda) were prepared and their corresponding complexes with different salts of Zn(II), Cu(II), Ni(II) and Co(II). For the central donor atoms oxygen and sulfur were chosen and in the case of nitrogen and phosphorous -NPh- and - PPh- functional groups. The solid-state structures of prepared complexes were characterized by single-crystal X-ray diffraction, while the structures in solution were studied by NMR spectroscopy. The stoichiometry and the stereochemistry of these complexes, together with possible conformations of their substituents, were studied using the (SMD)/M05-2X/6-31+G(d) DTF computational approach to determine their relative stability to each other. Experimental and computational results were compared and preferences of some central donor atoms to form specific isomers of ML2 complexes were observed. One of our goals was to determine which factors lead to formation of cis-fac isomers, which could be in the case of nitrogen or phosphorous as central atoms used in the development of new asymmetric catalysts.

Asymmetric tridentate ligands L (L= acetamide- pyridine) of the type A-B-C, (Figure 1a) enrich the isomerism of bis-tridentate A-B-A ligands [1] to six possible isomers of [M(A-B-C)2] complexes (M=metal, Figure 1b). Ligand L and metal complex [Zn(L)2](BF4)2 have been synthesized and characterized by solution-state NMR (1H and 13C). It is generally known that ligand coordination to the metal atom destroys NMR magnetic equivalences of nuclei near the metal atom, therefore increasing the number of signals in NMR spectra and appearance of hidden J-couplings (Figure 1c). Magnetic equivalences originate from fast nuclei- exchange processes (faster than NMR timescale), due to rotational/inversion motions of molecules in solution. Therefore, the DFT simulation of solution-state NMR spectra is a computational challenge and only recently satisfactory procedures have been suggested [2]. Herein, the conformational space of ligand L and complex [Zn(L)2]2+ has been explored by the CREST program [3]. Ensembles of conformations were optimized on the DFT theory level and free energies were calculated. For conformers with Boltzmann population > 1% the NMR parameters (shifts and J- couplings) have been calculated by the DFT/GIAO theory using the ORCA program [4]. Finally, from differences between measured and calculated NMR data, the most probable isomer of [Zn(L)2]2+ complex in solution is obtained.

Bis-tridentate metal complexes of flexible ligands with [M(A-X-A)2] structure can form three different geometric isomers: mer, trans-fac and cis-fac. Many factors influence the stability of a certain isomer. Important factors to consider are electronic and steric properties of the coordinating ligand, type of central metal ion and counter-ion present, possibilities of forming non-covalent interactions and others. Understanding of the isomer preferences in hereby described systems would give us a head start in the development of new coordination compounds with desired form and properties. Derivatives of tridentate ligands bis(pyridine-2-ylmethyl)amine (bpa) and 2, 2’-iminodiacetamide (imda) were prepared in this work, as well as their corresponding complexes with different Zn(II), Cu(II), Ni(II) and Co(II) salts (Figure 1). Oxygen and sulfur, as well as -NH-, -NPh-, -PH- and -PPhfunctional groups were chosen to occupy a central position in the ligand structure. The stoichiometry and the stereochemistry of these complexes, together with possible conformations of their substituents, were studied using the DTF computational approach to determine their relative stability in solution. The systems in solution were studied by NMR and UV-Vis spectroscopy, while the solid-state structures of prepared complexes, characterized by single-crystal X-ray diffraction, gave us an insight of the isomerism in the solid-state. Experimental and computational results were discussed and preferences of some central donor atoms to form certain isomers of ML2 complexes were shown. One of our goals was to determine which factors lead to formation of cis-fac isomers, which could, in the case of nitrogen or phosphorous as central atoms, be used in the development of new type of selective catalysts.

In this conference paper, an author’s review in the field of bioinorganic chemistry, stereochemistry, homogeneous catalysis and medicinal inorganic chemistry is presented, with particular emphasis on physical chemistry aspects. Within this work, bioconjugates of amino acid containing phosphine or nitrogen ligands were utilized for metal coordination. The metal complexes were extensively characterized by a number of instrumental spectroscopic or crystallographic techniques and by DFT calculations. The metal complexes were used as catalysts in the selective preparation of intermediates in the synthesis of active pharmaceutical ingredients. Special attention was paid to the formation of specific supramolecular artificial secondary structures formed by the amino acid moieties that control the stereochemical outcome of the catalytic reactions. In addition, the metal complexes served as building blocks for supramolecular architectures as well as potent anticancer agents.

In recent years, conjugates of transition metal complexes with amino acids, peptides, nucleic acids and their analogues attract particular attention.In particular, the unique combination of properties of the metal complexes as well as biologically relevant molecules can lead to numerous applications in medicinal chemistry but also in the development of new materials and selective catalysts. As a part of this presentation, recent results from our laboratory will be presented. Rhodium complexes with amide substituted triphenylphospine ligands have been used as catalysts in asymmetric hydrogenation with selectivity up to 97 % e.e. In addition, a double- stranded ferrocene pseudo-peptide exhibiting stimuli responsive chirality inversion triggered by solvent exchange or acid addition will be discussed. Finally, the stereochemistry of bis- tridentate ligand complexes and their potential applications will be included as well.

Bis-tridentate ligand complexes can form three geometric isomers ; mer, trans-fac and cis-fac. For the synthesis of functional complexes incorporating tridentate ligands, understanding the isomer preferences is an important starting point. One way of stabilizing a particular isomer is by non-covalent interactions. In literature, such non-covalent interactions were often found with anions or as π-π interactions in ligands containing aromatic rings. In this work, complexes of tridentate bis(2- pyridine-2-ylmethyl)amine (bpa) and 2, 2'- iminodiacetamide (imda) ligands were prepared with Cu(II) and Zn(II). The ligands have chiral side chains, with amide groups that enable the formation of hydrogen bonds. The solid-state structures were characterized by single-crystal X-ray diffraction, while the structures in solution were studied by NMR, UV-Vis and CD spectroscopy. Several variations were introduced into the ligand structure, such as length of the CH2 linker, orientation of the amide group and type of chiral substituent, in order to construct a ligand suitable for the formation of secondary structures.

Coordination complexes of dipyridylamine (dpa) have shown interesting properties applicable in catalysis and material sciences as well as medicinal chemistry. Our previous study examined the properties and coordination chemistry of triazole-appended dpa derivatives. To expand the knowledge about this type of ligands, ferrocene derivatives of dpa with 1, 2, 3-triazole linker and their Cu(II) complexes were prepared. Dpa-tz ligands prefer formation of metal complexes with trans configuration, while coordination of the 1, 2, 3-triazole group depends on N-1 substitution.

Organometallic and metal-based complexes have been widely used in drug discovery and some of them have entered clinical trials for the treatment of cancer. Design of new chemotherapy agents based on metal complexes is a fast-growing research area in which the biological activity of antitumor agents is based on metal-specific modes of action.1 The ferrocene pharmacophore is often introduced into the structure of drug-like molecules and bioactive hybrids with the aim of improvement of physicochemical properties and potency. In continuation of our research on coordination of mono- and bis-1, 2, 3-triazole derivatives, 2 we have synthesized and characterised ferrocene ligands as well as their Zn(II) and Cu(II) complexes by NMR, IR and UV-Vis spectroscopy and SC- XRD. Cytotoxic activity of N-heterocyclic ferrocene derivatives and their Zn(II) and Cu(II) complexes was evaluated.

In this presentation, several examples or artificial catalytic systems have benn presented, including well defined supramolecular metal complexes with chiral amino acids or amides, that can serve as selective catalysts of asymmetric reactions. 1. S. I. Kirin, H.-B. Kraatz, N. Metzler-Nolte: Chem. Soc. Rev. 2006, 35, 348-354. 2. Z. Kokan, B. Kovačević, Z. Štefanić, P. Tzvetkova, S. I. Kirin: Chem. Commun. 2018, 54, 2094-2097. 3. S. Opačak, Z. Kokan, Z. Glasovac, B. Perić, S. I. Kirin: Eur. J. Org. Chem. 2019, 2115- 2128.

U ovom osvrtu predstavljen je rad na EU strukturnom projektu CAT Pharma.

Ferrocene compounds have attracted significant interest as biologically active derivatives. Introduction of the ferrocene moiety in drug-like molecules improves the physicochemical properties and stability of drug candidates, while the transition metals coordinated to biologically active ligands participate in metal-specific processes which enhance drug delivery and biological activity. As part of our research of ferrocene derivatives and their transition metal complexes, we have prepared dipicolylamine, iminodiacetamide and bis-triazole derivatives connected to ferrocene through an ethylenediamine linker. The conjugates were used as ligands in the synthesis of Zn(II), Ni(II) and Cu(II) metal complexes. The stoichiometry and stereochemistry of the obtained complexes were examined by NMR and UV-Vis spectroscopy. We have obtained two crystal structures of metal complexes with bis-triazole ligands and one with an iminodiacetamide ligand. Investigation of antitumor activity is in progress.

Ferrocene represents a significant pharmacophore in medicinal chemistry along with its derivatives being important ligands in coordination chemistry. Click chemistry involves a set of widely applicable stereospecific reactions with high yield and without unwanted side reactions. The copper-catalysed azide–alkyne cycloaddition (CuAAC) reaction represents a simple approach to the synthesis and fine-tuning the properties of 1, 2, 3-triazole ligands. Our goal was to prepare novel mono- and bis- ferrocenyl derivatives connected to an aromatic amine through a 1, 2, 3- triazolyl linker. Conjugates of ferrocene and heterocycles were prepared by CuAAC reactions of propargylated aromatic amines and ferrocene azides. Conjugates of ferrocene and heterocycles were used as ligands in the synthesis of Zn(II) and Cu(II) metal complexes and the stoichiometry and stereochemistry of the obtained complexes was examined. The structures of the newly synthesized derivatives were confirmed by 1H and 13C NMR spectroscopy. The spectroscopic properties of the obtained complexes were investigated by NMR, UV- Vis and IR spectroscopy. Crystal structures of several Cu(II) complexes containing mono- and bis- ferrocenyl ligands were determined by single- crystal X-ray diffraction.

One of the main concerns of drug development is the transfer through the cell membrane, and even further, through the nuclear membrane via protein transduction domains, a class of diverse peptides that can target intracellular proteins [1]. In our previous work it was shown that attaching metal complexes to a protein transduction domain does facilitate the transport to the cell nucleus [2]. In this communication, oxazoline amino acid bioconjugates 1-3 were prepared, containing none, one or two amino acid strands, Figure 1. The bioconjugates were characterized by NMR and IR spectroscopy and MS spectrometry. Initial synthetic studies with several inorganic or organometallic precursors will be reported. The metallated model compounds that show the best results will be chosen for further investigation with longer amino acid strands.

The diketopiperazines have been steadily attracting researchers’ attention in pharmaceutical chemistry due to their potential biological effects. Electrospray ionization mass spectrometry (ESI MS) is known to be a versatile analytical technique for detection of very low concentrations of various diketopiperazines in different samples. Hence, we characterized our p-disubstituted phenyldiketopiperazines 1 ( R = H ), 2 ( R = NO2 ) and 3 ( R = -N(CH3) ) by ESI MS. We have shown that the majority of the fragment ions in the ESI mass spectra originated from reactions initiated by one of the nitrogen atoms of the piperazine ring.