Ivica Đilović

Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity

The paper describes synthesis of several novel thiosemicarbazone derivatives. Furthermore, crystal and molecular structure of 4-diethylamino-salicylaldehyde 4-phenylthiosemicarbazone revealed planarity of conjugated aromatic system, which suggested the possibility of DNA binding by intercalation, especially for here studied naphthalene derivatives. However, here presented DNA binding studies excluded this mode of action. Physicochemical and structural properties of novel derivatives were compared with previously studied analogues, taken as reference compounds, revealing distinctive differences. In addition, novel thiosemicarbazone derivatives (1, 2 and 5-8) clearly display stronger antiproliferative activity on five tumor cell lines than the reference compounds 3 and 4, which supports their further investigation as potential antitumor agents.

Dynamic Molecular Recognition in Solid State for Separating Mixtures of Isomeric Dicarboxylic Acids

Molecular recognition emerges from non-covalent interactions and is of paramount importance for understanding of biological processes, ranging from enzymatic activity to DNA base pairing, as well as in the design of functional supramolecular systems, for example, molecular motors, sensors, ion receptors, or systems used in waste management. In the specific area of selective anion binding, numerous anion receptors (hosts) and sensors have been developed. The study of anion binding has traditionally been performed in solution where the host often experiences conformational freedom to form complexes with a wide range of guests. However, selectivity in separation has usually been achieved only upon crystallization, emphasizing the importance of intermolecular interactions in rigid crystal environment which lock the conformation of the host giving rise to its selectivity. In this context, recent advances in chemical reactivity achieved using mechanochemistry indicate that the concepts of supramolecular chemistry, such as templating, may be applicable also to solvent-free reactions. Mechanochemical reactivity can be highly dynamic and has thus far been employed for solid-state differentiation between enantiomers, supramolecular metathesis reactions, and for thermodynamic product selection. Although these reactions show specific interaction patterns between molecules comprising their respective solid phases, the possibility of selective binding and separation of target guest molecules from solid mixtures is, besides the pioneering studies by Etter and Caira, still an unexplored area. Here we focus on recognition and separation of isomeric or geometrically similar dicarboxylic acids (Scheme 1) from either their solid or solution mixtures using principles of supramolecular chemistry. The chosen acids belong to a class of guests of high biological and industrial relevance, and a considerable effort has been put into developing their sensors and receptors. Typically, the receptor for each dicarboxylate had to be meticulously designed because of the specific geometry of each acid molecule and their differing physicochemical properties. The importance of separation of the maleic/fumaric acid (H2mal/H2fum) stereoisomeric pair is not only related to the specific diastereomer recognition, but also arises from their conflicting biochemical behavior and abundant use of H2fum in food and pharmaceutical industry. We show here that the flexible polyamine receptor L (Scheme 1) discriminates among H2mal/H2fum diastereomers, succinic acid (H2suc), and three isomers of benzenedicarboxylic acid, by adapting its conformation and finally forming different solid hydrogenbonded (HB) frameworks. Regardless of whether the recognition takes place in the solid state by milling or by crystallization from solution, the resulting supramolecular complexes are the same and the selectivity bias of L towards the guest acids is fully retained. Milling improved yields to quantitative and almost eliminated the use of solvent. L proved to be an exceptional receptor for H2mal, also on the gram scale, excluding it from solid mixtures with even five other acids or from mixtures where there is a large surplus of a competing acid. Reacting L and H2mal in methanol (MeOH) or ethanol (EtOH) solutions yielded isoskeletal solvated solids, 1a (Table 1 and Section S.2 in the Supporting Information), Scheme 1. Dicarboxylic acids and the polyamine host L. The host binds anions as a cation (HL) resulting from protonation of the central amino group.

Desmotropy, Polymorphism, and Solid-State Proton Transfer: Four Solid Forms of an Aromatic o-Hydroxy Schiff Base

The Schiff base derived from salicylaldehyde and 2-amino-3-hydroxypyridine affords a diversity of solid forms, two polymorphic pairs of the enol-imino (D1 a and D1 b) and keto-amino (D2 a and D2 b) desmotropes. The isolated phases, identified by IR spectroscopy, X-ray crystallography, and (13)C cross-polarization/magnetic angle spinning (CP/MAS) NMR spectroscopy, display essentially planar molecular conformations characterized by strong intramolecular hydrogen bonds of the O-H⋅⋅⋅N (D1) or N-H⋅⋅⋅O (D2) type. A change in the position of the proton within this O⋅⋅⋅H⋅⋅⋅N system is accompanied by substantially different molecular conformations and, subsequently, by divergent supramolecular architectures. The appearance and interconversion conditions for each of the four phases have been established on the basis of a number of solution and solvent-free experiments, and evaluated against the results of computational studies. Solid phases readily convert into the most stable form (D1 a) upon exposure to methanol vapor, heating, or by mechanical treatment, and these transformations are accompanied by a change in the color of the sample. The course of thermally induced transformations has been monitored in detail by means of temperature-resolved powder X-ray diffraction and infrared spectroscopy. Upon dissolution, all forms equilibrate immediately, as confirmed by NMR and UV/Vis spectroscopy in several solvents, with the equilibrium shifted far towards the enol tautomer. This study reveals the significance of peripheral groups in the stabilization of metastable tautomers in the solid state.

Synthesis and biological activity of 4″-O-acyl derivatives of 14- and 15-membered macrolides linked to ω-quinolone-carboxylic unit

The synthesis and antimicrobial activity of a new class of macrolide antibiotics which consist of a macrolide scaffold and a quinolone unit covalently connected by an appropriate linker are described. Optimization of several synthetic steps and structural properties of lead compound 26 are discussed. Promising antibacterial properties of this compound and some of its analogues are reported.

Vanadium-induced formation of thiadiazole and thiazoline compounds. Mononuclear and dinuclear oxovanadium(V) complexes with open-chain and cyclized thiosemicarbazone ligands

Reactions of the salicylaldehyde 4-phenylthiosemicarbazone (H(2)L) with selected vanadium(iv) and vanadium(v) precursors ([VO(acac)(2)], [VO(OAc)(2)], VOSO(4), [V(2)O(4)(acac)(2)]) were investigated under aerobic conditions in different alcohols (methanol, ethanol, propanol). In all examined cases mononuclear alkoxo vanadium(v) complexes [VOL(OR)] (1) (OR = OMe, OEt, OPr) were isolated as major products. On prolonged standing, mother liquids afforded dinuclear vanadium(v) complexes [V(2)O(3)(L(cycl))(2)(OR)(2)] (3) (OR = OMe, OEt, OPr), where L(cycl)(-) represents 1,3,4-thiadiazole ligand, formed by vanadium-induced oxidative cyclization of H(2)L. When [VO(acac)(2)] or [V(2)O(4)(acac)(2)] were used as precursors, in addition to products 1 and 3, a thiazoline derivative HL(acac)(cycl) (2) was isolated. This compound, formed by a reaction between acetylacetone and H(2)L, represented the second type of cyclic product. The products were characterized by IR and NMR spectroscopies, TG analysis, and in some cases by single-crystal X-ray diffraction. To the best of our knowledge, compounds [V(2)O(3)(L(cycl))(2)(OR)(2)] represent the first structurally characterized dinuclear vanadium(v) complexes with a thiadiazole moiety acting as a bridging ligand. Complexes 1 and 3, when dissolved in an appropriate alcohol, underwent substitution of the alkoxo ligand as confirmed by XRPD. The kinetics of reactions in methanolic solutions was qualitatively studied by UV-Vis and ESMS spectrometries. Under the experimental conditions applied, a relatively slow formation of the mononuclear complex [VOL(OMe)] and an even slower formation of the cyclic species 2 were observed, whereas the presence of dinuclear compound [V(2)O(3)(L(cycl))(2)(OMe)(2)] in the reaction mixture could not be detected.

The cocrystal of 4-oxopimelic acid and 4,4′-bipyridine: polymorphism and solid-state transformations

The cocrystal of 4-oxopimelic acid and 4,4′-bipyridine was isolated in two polymorphic forms depending upon the solvent of crystallisation. Polymorphs exhibit hydrogen-bonded chains formed between the carboxyl and pyridine moieties while different packing arrangements of chains result from C–H⋯O interactions. Solid-state synthesis and interconversion conditions were investigated by grinding and thermal methods.

Molecular structure and acid/base properties of 1,2-dihydro-1,3,5-triazine derivatives

It is shown that guanidine and its N,N-dimethyl-derivative react with substituted carbodiimides, affording hitherto unknown 1,2-dihydro-1,2,3-triazine derivatives. The structures of three novel compounds of this type and their perchlorate salts were elucidated by spectroscopic (IR, 1H and 13C NMR and 15N solid-state NMR) and X-ray diffraction methods. The acid/base properties were also determined experimentally and by using DFT calculations with the B3LYP functional. The most basic compound was found to be dihydrotriazine 3, the basicity of which with the pKa value of 23.3 is of the same order of magnitude as that of tetramethylguanidine. Acidity measurements revealed that all the compounds studied are very weak acids with pKa values in the range of 25.8–30.8 pKa units in acetonitrile.

Synthesis, NMR and X-ray structure analysis of macrolide aglycons

Macrolide aglycons (E)-9-hydroxyimino-6-O-methylerythronolide A (4), 9a-aza-9-deoxo-9,9-dihydro-9a,11-O-dimethyl-9a-homoerythronolide A (5) and 9a-aza-9-deoxo-9,9-dihydro-9a-homoerythronolide A (6) were prepared by multistep syntheses. A conformational study of these new macrolide aglycons was performed using single crystal X-ray crystallography to gain information about the solid state, while a combination of NMR spectroscopy and molecular modelling was employed to study the solution structures. The crystal structures were found to be stabilised by a complex network of hydrogen bonds and van der Waals interactions. To some extent, the same building motif of infinite molecular chains held together by O–H···O hydrogen bonds was present in the crystal structure of all three compounds. Thorough analysis and comparison of the obtained solid state structures with their solution counterparts showed no significant differences between them, confirming the constrained flexibility of the macrocyclic ring. Moreover, in all three compounds, in both solution and solid state, the macrolactone ring adopts energetically more favoured folded-out conformations.

N-Benzyloxy-1H-benzotriazole-1-carboxamide: a hydrogen-bonded tetramer based upon a rare R(4)4(20) structural motif.

The title compound, C(14)H(12)N(4)O(2), is the first example of a heterocyclic substituted hydroxamic derivative. The asymmetric unit consists of two molecules. The molecules are linked into centrosymmetric R(4)(4)(20) tetramers by four strong hydrogen bonds of the N-H...O and N-H...N types. These tetramers are connected through C-H...O interactions into a three-dimensional network.

Mechanism of Mechanochemical C–H Bond Activation in an Azobenzene Substrate by Pd(II) Catalysts

Mechanism of C-H bond activation by various PdII catalysts under milling conditions has been studied by in situ Raman spectroscopy. Common PdII precursors, that is PdCl2 , [Pd(OAc)2 ]3 , PdCl2 (MeCN)2 and [Pd(MeCN)4 ][BF4 ]2 , have been employed for the activation of one or two C-H bonds in an unsymmetrical azobenzene substrate. The C-H activation was achieved by all used PdII precursors and their reactivity increases in the order [Pd(OAc)2 ]3 <PdCl2 (MeCN)2 <PdCl2 <[Pd(MeCN)4 ][BF4 ]2 . In situ Raman monitoring in combination with stepwise ex situ NMR, IR and PXRD experiments has provided direct probing of the reaction mechanism and kinetics, and revealed how liquids of different acid-base properties and proticity as well as selected solids used as additives modify precursors or intermediates and their reactivity. Reaction intermediates that were isolated and structurally characterized agree with the observed species during reaction. In situ Raman spectroscopy has also enabled the derivation of reaction profiles suggesting an electrophilic process which proceeds via a coordination complex (adduct) undergoing deprotonation by a bound or an external base depending on the used PdII precursor. Slow step of the first palladation for two chloride precursors and [Pd(MeCN)4 ][BF4 ]2 is the C-H bond cleavage whereas palladation using [Pd(OAc)2 ]3 depends primarily on breaking of its trimeric structure by the azobenzene substrate and/or liquid additives.