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Fe(III) and Mn(II) complexes with condensation product of thiosemicarbazide and 2-acetylthiazole (HL1, (E)-2-(1-(thiazol-2-yl)ethylidene)hydrazine-1-carbothioamide) have been synthesized and characterized by single-crystal X-ray diffraction, IR spectroscopy, and elemental analysis. In both complexes, the thiosemicarbazone ligand is coordinated in deprotonated form through the NNS donor set of atoms. However, while Fe(III) complex is in the doublet ground state with distorted octahedral geometry, the coordination environment around Mn(II) is distorted trigonal-prismatic, and the sextet state is found to be the ground state. DFT calculations were performed to rationalize spin state preferences, and continuous shape measure describes the deviation from ideal six-coordinated polyhedral geometries in the ground and excited states. Antimicrobial activity (against a panel of Gram-negative and Gram-positive bacteria, two yeast, and one fungal strain), brine shrimp assay, and DPPH radical scavenging activity of both complexes were evaluated, and these results relate to the electronic structure of the complexes. This is the peer-reviewed, authors’ version of the article: Stojičkov, M., Zlatar, M., Mazzeo, P. P., Bacchi, A., Radanović, D., Stevanović, N., Jevtović, M., Novaković, I., Anđelković, K., Sladić, D., Čobeljić, B., Gruden, M. (2023). The interplay between spin states, geometries and biological activity of Fe(III) and Mn(II) complexes with thiosemicarbazone. Polyhedron, 237, 116389. [https://doi.org/10.1016/j.poly.2023.116389] The published version: [https://cer.ihtm.bg.ac.rs/handle/123456789/6041] Supplementary information: [https://cer.ihtm.bg.ac.rs/handle/123456789/6043]

In the present work, the α, β-double bond of the aroylacrylic acid phenylamides was suitably modified to optimize the toxicity–antiproliferative activity ratio of the resulting compounds 1 –5 . The phenylamides were modified by Michael’s addition of suitably chosen piperidine-containing fragments: 1-amino-N- benzylpiperidine ( a1 ), 4-benzylpiperidine ( a2 ), and N , N -dimethyl- N -[2-(1-piperazinyl)-ethyl]amine ( a3 ). The compounds exerted micromolar activity toward three cancer cell lines, A549, LoVo, and Skov-3, caus- ing apoptotic cell death. It was shown that the nature of the cyclic amine moiety at position C2 of the compounds is probably the primary determinant of anticancer activity toward tested cell lines and the acute toxicity toward brine shrimp ( Artemia salina ). The majority of compounds revealed the ability to vigorously induce mitochondrial superoxide anion generation in all treated cell lines, which together with cell cycle arrest at the S phase and activation of intrinsic caspase cascade, indicates the possibility that apoptosis was triggered due to irreparable chromosomal damage by acute oxidative stress. Two deriva- tives also exerted significant antibacterial activity with one order of magnitude higher potency than chlo- ramphenicol in most of the investigated bacterial strains. Also, the drug-like properties for all compounds were estimated by available software tools. This is the peer-reviewed version of the article: Vujatović, Tamara B., Vitorović - Todorović, Maja D., Cvijetić, Ilija, Vasović, Tamara, Nikolić, Milan R., Novaković, Irena, Bjelogrlić, Snežana, "Novel derivatives of aroylacrylic acid phenylamides as inducers of apoptosis through the ROS-me diate d pathway in several cancer cell lines" in Journal of Molecular Structure, 1250 (2022):131702, [https://doi.org/10.1016/j.molstruc.2021.131702] The published version: [https://cer.ihtm.bg.ac.rs/handle/123456789/4853]

In this article, cytotoxicity, the mechanisms of cytotoxic activity, genotoxicity, and interaction with DNA and proteins, of two Cu(II) complexes with a salicylaldehyde derivative (4-(diethylamino)salicylaldehyde) and α-diimine (2,2′-bipyridine (bipy) and 1,10-phenanthroline (phen)) are reported. Both Cu(II) complexes performed cytotoxic effects against all tested malignant cell lines. Complexes exerted highest cytotoxicity against HeLa and A375 malignant cell lines. The cytotoxic activity of Cu(II) complex with phen as a α-diimine co-ligand was significantly higher in comparison with cytotoxic activity of Cu(II) complex with bipy. Pretreatment with specific inhibitors of caspase-3, caspase-8 or caspase-9, in order to clear up the mode of cell death triggered by two Cu(II) complexes in HeLa cells, indicated the ability of these complexes to induce apoptosis through activation of target caspases. Cu(II)-phen complex exhibited significant antioxidant activity compared with Cu(II)-bipy complex, and showed a better effect on reducing intracellular ROS levels in HeLa cells. Tested complexes did not display genotoxic potential in human peripheral blood leucocytes, but exhibited an antigenotoxic effect in post-treatment, after H2O2 exposure. The study of the in vitro biological properties regarding their affinity towards CT (calf-thymus) DNA and serum albumins showed that the compounds can intercalate to CT DNA, and bind reversibly and tightly to the albumins. Molecular docking studies of the ability of compounds to bind to biomacromolecules are consistent with in vitro studies. Supplementary material: [https://cherry.chem.bg.ac.rs/handle/123456789/5519]

The biological activity of Cd compounds has been investigated scarce since Cd has been recognized as a human carcinogen. However, the toxicity of cadmium is comparable to the toxicity of noble metals such as Pt and Pd. The paradigm of metal toxicity has been challenged suggesting that metal toxicity is not a constant property, yet it depends on many factors like the presence of appropriate ligands. Studies on anticancer activity of cadmium complexes showed that the complexation of various ligands resulted in complexes that showed better activities than approved drugs. In the present study, cadmium complexes with biologically potent thiazolyl/selenazoyl-hydrazone ligands have been prepared, and tested for their activity against different types of tumor cell models. The complexation of ligands with Cd(II) resulted in a synergistic effect. The antiproliferative activity study revealed that all complexes are more active compared to 5-fluorouracil and cisplatin. The mechanism of tumor cell growth inhibition reveal that selenium-based compounds induce cell death in T-47D (gland carcinoma) cells through apoptosis via caspase-3/7 activation. Additionally, their pro-apoptotic effect was stronger compared to etoposide and cisplatin. Nuclease activity, detected by gel electrophoresis, may be the possible mechanism of anticancer action of investigated complexes.

Three ruthenium-bipyridine complexes (1–3) carrying acetylpyridine ligand unit were synthesized in methanol via the reaction of [RuCl2(bpy)2] with corresponding acetylpyridine (2-, 3-, and 4-acpy). Obtained complexes were characterized by (1H and 13C) NMR and IR spectroscopy, MS spectrometry, UV‒vis spectrophotometry, and cyclic voltammetry. Their structural characterization revealed bidentate coordination mode for 2-acpy while 3- and 4-acpy acted as monodentate ligands. The electrochemical profile of newly synthesized compounds was investigated by cyclic voltammetry which confirmed their electrochemical activity. Voltammetric responses within the −1.20 < Ep < 1.50 V range of potentials were summarized in two major events: Ru(II)→Ru(III) oxidation spotted at app. ΔEp = 0.65 V and successive reductions of bpy units located from ‒0.79 V to 0.47 V (vs. Ag/AgCl (3 M) electrode). The DNA-binding activity of the complexes was evaluated by both UV‒vis spectrophotometry and cyclic voltammetry indicating DNA-intercalation with a slight contribution of electrostatic interactions. Furthermore, antimicrobial activity was tested against bacterial and fungal strains, for which moderate activity was observed. Assessment of in vitro toxicity against freshly hatched nauplii of Artemia salina as well as radical scavenging capacity was evaluated. The test compounds showed neither toxicity nor antioxidant activity.

In this paper, Cu(II), Mn(II) and Zn(II) complexes with N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL1Cl) were synthesized and characterized by single-crystal X-ray diffraction, IR spectroscopy, elemental analysis and DFT calculations. In all three complexes, a ligand (L1) is coordinated in a deprotonated formally neutral zwitterionic form via NNO donor set atoms. Cu(II) and Zn(II) form mononuclear penta-coordinated complexes [CuL1(N3)(CH3OH)]BF4 and [ZnL1(N3)2], respectively, while Mn(II) forms a binuclear [Mn2L12(μ-1,1-N3)2(N3)2]·2CH3OH complex, with unusual distorted trigonal-prismatic geometry around the metal centers. The antimicrobial activity of these complexes was tested against a panel of Gram-negative and Gram-positive bacteria, two yeasts and one fungal strain. The binuclear Mn(II) complex showed antifungal activity of similar intensity to amphotericin B. Based on the results of the brine shrimp test and DPPH radical scavenging activity, the most active Cu(II) and Mn(II) complexes were selected for evaluation of cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and one normal cell line HaCaT. Both complexes showed significant activity. It should be pointed out that the activity of the Mn(II) complex against the MCF7 breast cancer cell line is only slightly weaker than that of cisplatin, but with selectivity to the tumor cell line in comparison to normal HaCaT cells, which is non-existent in the case of cisplatin. Supporting information: [https://cer.ihtm.bg.ac.rs/handle/123456789/4902] Related crystallographic data (CCDC 2110386): [https://cer.ihtm.bg.ac.rs/handle/123456789/4903] Related crystallographic data (CCDC 2110387): [https://cer.ihtm.bg.ac.rs/handle/123456789/4904] Related crystallographic data (CCDC 2110388): [https://cer.ihtm.bg.ac.rs/handle/123456789/4905]

Interest in Cd complexes has been growing in recent years. Cd complexes areconsidered a potential solution in the search for novel antibiotics that can fightantimicrobial resistance. In addition, Cd complexes draw attention to materialchemistry. The main objective of this work was to prepare the firstCd(II) complexes with anionic forms of pyridine-based thiazolyl hydrazone(THs) ligands HLS2[(E)-4-(4-methoxyphenyl)-2-(2-[pyridine-2- ylmethylene]hydrazinyl)thiazole] and HLS3[(E)-2- (2-[pyridine-2-ylmethylene]hydrazinyl)-4-(p- tolyl)thiazole] and perform their structural and spectroscopic characteri-zation, as well as stability in solution and upon heating. Studies related to theirbiological activities and possible electrochromic applications are also beingconducted. Complexes [Cd(HLS2)2](1) and [Cd(HLS3)2](2) have been charac-terized by a single-crystal X-ray diffraction and computational analysis of inter-molecular interactions responsible for their solid-state structures wasperformed. Thermal stability of1and2in the solid-state was analyzed byTGA/MS, where as their solution stability was determined by the spectropho-tometric titration method. Electrochemical andin situUV–Vis spectroelectro- chemical analyses of1and2were carried out to determine redox mechanismsand the influence of the substituents and electrolytes on their redox responses.The antioxidant capacity of both complexes was tested in antioxidant assays, while their antimicrobial activity was tested against five Gram-positive andfour Gram-negative bacteria, as well as against three fungi. The obtainedresults indicate their potent antioxidant capacity. The antimicrobial activity ofinvestigated compounds on almost all tested bacterial strains was strongerthan that of the standard antibiotic erythromycin. The results of docking stud-ies indicate that the minor groove DNA is the possible biological target of1and2.KEYWORDSantimicrobial activity, Cd(II) complex, docking, in situspectroelectrochemistry, thiazolylhydrazonesReceived: 18 July 2022Revised: 14 October 2022Accepted: 20 October 2022DOI: 10.1002/aoc.6942Appl Organomet Chem.2023 ; 37:e6942.wileyonlinelibrary.com/journal/ aoc© 2022 John Wiley & Sons Ltd.1of20https://doi.org/10.1002/aoc.6942

(Thiazolyl-2-yl)hydrazones (THs) are a group of organic compounds containing both hydrazone and 1,3-thiazole pharmacophores present in many approved drugs. They have been investigated greatly in recent years due to potent anticancer, antibacterial, antifungal, antituberculosis, anti-inflammatory, and antiparasitic activities. In this study, one pyridine-based and two quinoline-based, novel THs were synthesized and characterized by elemental analysis, Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). The antimicrobial activity of the compounds was tested against five Gram-positive and five Gram-negative bacteria, as well as against three fungi. The antioxidant capacity of the compounds was tested in six antioxidative assays. The results showed that quinoline-based THs were more active against tested Gram-negative bacteria and fungi strains than pyridine-based compounds. All the compounds showed excellent antioxidative activity comparable to or greater than the used standards (vitamin C and Trolox). Absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were calculated in-silico. Results pointed to promising good pharmacokinetics profiles of investigated compounds, especially 2-quinoline carboxaldehyde-based compound, which can be a lead drug candidate. (Tiazolil-2-il)-hidrazoni (TH) su grupa organskih jedinjenja koja sadrže i hidrazon i 1,3-tiazol farmakofore koje su prisutne u mnogim odobrenim lekovima. Poslednjih godina se u velikoj meri istražuju zbog jakih antikancerogenih, antibakterijskih, antifungalnih, antituberkuloznih, antiinflamatornih i antiparazitskih aktivnosti. U ovoj studiji, sintetisan je jedan novi TH na bazi piridina i dva na bazi hinolina, koji su okarakterisani elementalnom analizom, infracrvenom spektroskopijom sa Furijeovom transformacijom (FTIR) i spektroskopijom nuklearne magnetne rezonancije (NMR). Antimikrobna aktivnost jedinjenja je testirana na pet Gram-pozitivnih i pet Gram-negativnih bakterijskih sojeva, kao i na tri soja gljivica. Šest antioksidativnih testova je korišćeno za određivanje antioksidativnog kapaciteta sintetisanih jedinjenja. Rezultati su pokazali da su TH na bazi hinolina aktivniji prema testiranim Gram-negativnim sojevima bakterija i prema gljivicama, nego jedinjenja na bazi piridina. Sva jedinjenja su pokazala odlično antioksidativno dejstvo, uporedivo ili veće od korišćenih standarda (vitamin C i troloks). Parametri apsorpcije, distribucije, metabolizma, izlučivanja i toksičnosti (ADME) izračunati su in-silico. Rezultati ukazuju na dobre farmakokinetičke profile ispitivanih jedinjenja, posebno jedinjenja na bazi 2-hinolinkarboksaldehida koje ima potencijal da bude kandidat za osnovno jedinjenje (engl. lead compound).

In this work, Pt(II) complexes of previously synthesized steroidal thiosemicarbazones were synthesized and characterized. The ligands and their metal complexes were studied by analytical and spectroscopic data (elemental analysis, IR, 1D NMR and 2D NMR, HSQC, HMBC, NOESY, COSY), the analysis of which enabled complete 1H and 13C assignments of each compound including E and Z isomers. All the synthesized ligands and complexes were screened for their cytotoxic and antimicrobial activity. The results demonstrate that new steroidal thiosemicarbazone complexes were significantly less cytotoxic than corresponding steroidal thiosemicarbazones. Also, complexes show lower antimicrobial activity than the standard drugs, similar to the activity of the starting thiosemicarbazones. Почевши од претходно синтетисаних стероидних тиосемикарбазона, у овом раду су синтетисани и окарактерисани комплекси платине(II). Лиганди и њихови метални комплекси проучавани су аналитичким и спектроскопским методама (елементална анализа, ИЦ, 1D NMR и 2D NMR, HSQC, HMBC, NOESY, COSY). Анализом добијених података омогућена је потпуна 1H и 13C асигнација свих једињења укључујући Е и Z изомере. За синтетисане лиганде, као и њихове комплексе испитивана је цитотоксична и антимикробна активност. Резултати указују на то да нови стероидни тиосемикарбазонски комплекси испољавају значајно нижу цитотоксичност од одговарајућих стероидних тиосемикарбазона. Поред тога, комплекси поседују антимикробну активност сличну активности полазних тиосемикарбазона, a нижу од стандардних лекова

In this work synthesis, characterization and crystal structures of 1, Zn(II) complex ([ZnL1(NCS)2]), with (E)-1-(2-oxo-2-(2-(quinolin-2-ylmethylene)hydrazinyl)ethyl)pyridin-1-ium chloride (HL1Cl) and 2, Bi(III) complex ([BiHL2Cl4] × 1/2CH3OH), with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL2Cl), have been reported. Zn(II) complex possesses a distorted trigonal bipyramidal geometry while surroundings around Bi(III) ion are extended pentagonal bipyramidal. Antimicrobial activity, brine shrimp assay and DPPH radical scavenging activity of both complexes, including previously synthesized complexes with HL2Cl ligand (Zn(II) and Ni(II)) and complexes with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL3Cl) (Zn(II), Cu(II), Cd(II), Co(II), Fe(III), Ni(II)), were evaluated. For the most active complexes, cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and normal cell line HaCaT, as well as generation of reactive oxygen species (ROS), was tested. Supplementary material: [https://cherry.chem.bg.ac.rs/handle/123456789/4675]

Two new Schiff bases derived from L -cysteine and substituted benzaldehyde were synthesized: the compound 1 [2-((2-chlorobenzylidene) amino)-3-mercaptopropanoic acid] and the compound 2 [3-mercapto-2-((2-methoxybenzylidene) amino) propanoic acid]. Their structures were confirmed by experimental FT-IR, NMR (1H, 13C), and theoretical methodology DFT (density functional theory). DFT calculations were based on global chemical reactivity indices calculated using the B3LYP/6–31G*, B3LYP/6–31G**, and B3LYP/6–31+G* theory levels. Experimentally and theoretically obtained values for FT-IR and NMR (1H, 13C) of test compounds showed good agreement. The reactivity descriptors of B3LYP (E, EHOMO, ELUMO, dipole moment, ∆ɛ, μ, η, ω) were calculated to predict the stability of newly synthesized compounds. The microbiological activity of the compounds was tested on several Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, Clostridium sporogenes, Microccocus luteus and Microccocus flavus. The following Gram-negative bacteria were used to test the compounds: Escherichia coli, Pseudomonas aeruginosa Proteus hauseri, Klebsiella pneumoniae, Salmonella enterica subsp. enterica serovar Enteritidis. Also, the activity on the following yeasts was examined: Candida albicans, Saccharomyces cerevisiae and fungal strain Aspergillus brasilliensis. The Schiff base with chlorine in the structure (the compound 1) has the best antimicrobial action against all tested microorganisms. The selected quantum chemical descriptors calculated for the compounds 1 and 2 have a close relationship with the antimicrobial activity.

In this article, synthesis, spectral and X-ray structure characterization, antimicrobial activity and Brine shrimp test of two new Cu(II) complexes with a salicylaldehyde derivative have been reported. Complexes [Cu(L)(bipy)]BF4·0.5H2O and [Cu2(L)2(phen)2](BF4)2 were obtained in the reaction of Cu(BF4)2·6H2O, deprotonated 4-(diethylamino)−2-hydroxybenzaldehyde ligand (L) and α-diimine (2,2’-bipyridine or 1,10-phenanthroline). The complex with bipyridine is mononuclear, containing one L and one bipyridine ligand in a distorted square-planar cation with a BF4 − anion and lattice water molecule, whereas the complex with phenanthroline is a dinuclear centrosymmetric dimeric cation, containing two L ligands along with two phenanthroline ligands and BF4 − anions. The coordination geometry of each Cu(II) ion can be described as an elongated square pyramid. MS-ESI spectroscopy indicated that [Cu2(L)2(phen)2](BF4)2 is mononuclear in DMSO solution. In vitro antibacterial and antifungal activity was tested against four Gram-positive, four Gram-negative bacteria and three fungal strains. Complexes showed significantly stronger antibacterial activities than parent ligands. The mononuclear phenanthroline complex in solution showed very good antimicrobial activity, which is comparable to the activity of the standard antibiotic amikacin against all tested bacterial strains. The same complex has better antifungal activity than fluconazole, which was used as a standard. Results of the brine shrimp test indicate that both complexes have good toxicity against Artemia nauplii. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/4026]

Tert-butylquinone (TBQ) and its alkylamino and aralkylamino derivatives are of high interest as a potential antitumor agent. Therefore, it was necessary to investigate if the compounds exert undesirable activities such as interaction with DNA molecule which could result in negative side effects in the case of their use in the diseases treatment. The major aim of this study was to investigate genotoxic potential of TBQ and selected derivatives in an acellular model by using plasmid DNA, in the prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002 and in eukaryotic models by using comet assay in human fetal lung cell line (MRC-5) and human liver cancer cell line (HepG2). Results indicated that in the acellular model TBQ and its derivatives do not interact with plasmid pUC19. In the prokaryotic model, only TBQ exerted weak genotoxic potential and only at highly cytotoxic concentrations. In eukaryotic models, genotoxic potential was detected mainly at the highest concentrations of the tested substances but the effect was lower in both cell lines in comparison with benzo[a]pyrene and etoposide which were used as positive controls. Weak genotoxic potential of tested compounds recommends them as good candidates for further testing in development of new antitumor agents. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

In this study, mutagenic and genotoxic potential of anti-tumor compounds avarol, avarone, and its derivatives 3'-methoxyavarone, 4'-(methylamino)avarone and 3'-(methylamino)avarone was evaluated and compared to cytostatics commonly used in chemotherapy (5-fluorouracil, etoposid, and cisplatin). Mutagenic potential of selected hydroquinone and quinones was assessed in prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002. Genotoxic potential was also assessed in eukaryotic models using comet assay in human fetal lung cell line (MRC-5), human adenocarcinoma epithelial cell line (A549), and in human peripheral blood cells (HPBC). The results indicated that avarol and avarone do not exert mutagenic/genotoxic potential. Among the studied avarone derivatives, mutagenic potential was detected by SOS/umuC test for 3'-(methylamino)avarone, but only after metabolic activation. The results of comet assay indicated that 3'-methoxyavarone and 3'-(methylamino)avarone have a significant impact on the level of DNA damage in the MRC-5 cell line. Genotoxic potential was not observed in A549 cells or HPBC probably due to a different uptake rate for the compounds and lower in metabolism rate within these cells. This is an Accepted Manuscript of an article published by Taylor & Francis in Drug and Chemical Toxicology on 04 Jan 2018, available online: [http://www.tandfonline.com/10.1080/01480545.2017.1413108].

In this paper, the synthesis of fourteen alkylamino and arylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone is described. Branched, cyclic, allylic and benzylic alkylamino/arylamino groups were introduced into the quinone moiety. For all the obtained derivatives, their biological activity and redox properties were studied. The cytotoxic activity of the synthesized derivatives towards multidrug resistant (MDR) human non-small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) was investigated. The antimicrobial activity towards Gram-positive and Gram-negative bacteria, and fungal cultures was determined. Some of the synthesized derivatives showed selectivity for cancer cells, including MDR cells. Regarding their cell death induction potential, the most promising compounds were allylamino derivatives, preferentially triggering apoptosis, with high selectivity for cancer cells, including MDR cells. Several compounds showed promising antimicrobial activity, comparable to those of commercial antibiotic and antimycotic agents.

Fourteen mono- and bis-carbohydrazone ligands have been synthesized and characterized. Antioxidant activity of the substances was investigated together with possible (E)/(Z) isomerization, and explained on the most active antioxidant compound 4 in various dimethyl sulphoxide–water mixtures. The addition of water to the system was involved in the formation of hydrated molecules which was confirmed in NMR after the addition of D2O. The ligands were tested in vitro against Gram-positive and Gram-negative bacteria and fungi, and their activity was discussed in relation to the structure of investigated carbohydrazone. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172013]

This paper discusses antioxidative and biological activities of 25 novel amidino substituted benzamides with a variety of heteroaromatic nuclei attached to the benzamide moiety and with a variable number of methoxy or hydroxy substituents. Targeted compounds, bearing either amidino or 2-imidazolinyl substituent, were obtained in the Pinner reaction from cyano precursors. 3D-QSAR models were generated to predict antioxidative activity of the 25 novel aromatic and heteroaromatic benzamide derivatives. The compounds were tested for antioxidative activity using in vitro spectrophotometric assays. Direct validation of 3D-QSAR approach for predicting activities of novel benzamide derivatives was carried out by comparing experimental and computationally predicted antioxidative activity. Experimentally determined activities for all novel compounds were found to be within a standard deviation of error of the models. Following this, structure–activity relationships among the synthesized compounds are discussed. Furthermore, antiproliferative activity in vitro against HeLa cells as well as antibacterial and antifungal activity was tested to confirm the other biological activities of the prepared compounds. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3852] This is the peer-reviewed version of the following article: Sović, I.; Cindrić, M.; Perin, N.; Boček, I.; Novaković, I. T.; Damjanović, A.; Stanojković, T.; Zlatović, M.; Hranjec, M.; Bertoša, B. Biological Potential of Novel Methoxy and Hydroxy Substituted Heteroaromatic Amides Designed as Promising Antioxidative Agents: Synthesis, 3D-QSAR Analysis, and Biological Activity. Chemical Research in Toxicology 2019, 32 (9), 1880. [https://doi.org/10.1021/acs.chemrestox.9b00256]

Eleven new steroidal mono- and bis(semicarbazones)2a–e, 4d and 3a–e have been prepared starting from various 3-oxo-α,β-unsaturated steroids. Mono-semicarbazones 2a–e were further subjected to ethyl chloroacetate in boiling absolute ethanol but, instead of expected intramolecular cyclocondensation reaction products, the new carbazate esters 5a-e were obtained. The structures of all synthesized compounds and identification of each E/Z isomer were deduced by elemental analysis, HRMS, NMR, and IR spectroscopy. Preliminary screening for the cytotoxic activity in vitro of the new compounds has been conducted against three cancer cell lines, K562, Jurkat and HeLa cells. HeLa cells were the most sensitive while K562 cells were the least sensitive to the cytotoxic action of the novel steroid derivatives. Compounds 2e, 3c and 5e were found to have the best but still moderate cytotoxic effects. All tested compounds showed very weak antimicrobial activities. These results demonstrate that the replacement of thioxo group with carbonyl group in steroidal hydrazone derivatives resulted in decrease in their biological activity. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3083] This is peer-reviewed version of the following article: Živković, M. B.; Novaković, I. T.; Matić, I. Z.; Sladić, D. M.; Krstić, N. M. Synthesis and Preliminary Screening for the Biological Activity of Some Steroidal Δ4-Unsaturated Semicarbazone Derivatives. Steroids 2019, 148, 36–46. [https://doi.org/10.1016/j.steroids.2019.04.010]

In this work, synthesis of alkylamino and aralkylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone was described. For all obtained derivatives biological activity was studied. Cytotoxic activity of the synthesized derivatives towards multidrug resistant MDR human non small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) as well as detection of cell death superoxide anion generation were investigated. Antimicrobial activity towards Gram positive and Gram negative bacteria and fungal cultures was determined. The results showed that strong cytotoxic activity toward cancer cells was improved with simple avarone mimetics. Some derivatives were selective towards MDR cancer cells. The most active derivatives induced apoptosis in both cancer cell lines, but not in normal cells. Superoxide production was induced by 2,6-disubstituted compounds in MDR cancer cells and not by less active 2,5-disubstituted compounds and was accompanied by the collapse of the mitochondrial transmembrane potential. Two tert-butylquinone derivatives were particularly selective towards MDR cancer cells. Some tert-butylquinone derivatives exhibited a strong antimicrobial activity. This is the peer-reviewed version of the article: Jeremić, M., Pešić, M., Dinić, J., Bankovic, J., Novaković, I., Šegan, D.,& Sladić, D. (2016). Simple avarone mimetics as selective agents against multidrug resistant cancer cells. European Journal of Medicinal Chemistry, 118, 107-120. [https://doi.org/10.1016/j.ejmech.2016.04.011] Published version: [https://cer.ihtm.bg.ac.rs/handle/123456789/1862] Supplementary material: [https://cer.ihtm.bg.ac.rs/handle/123456789/4580]

Ten biologically active 2,2,5,5-tetramethyl-9-aryl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives were synthesized and their structures were confirmed by IR, 1H and 13C NMR spectroscopy and mass spectrometry. Synthesized compounds were scanned for their antioxidant, antimicrobial and antiproliferative activity. Antibacterial activity was tested by the diffusion and dilution method against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, while antifungal activity was tested against Candida albicans and Saccharomyces cerevisiae. Antiproliferative activity was tested against HeLa (cervical carcinoma), SW620 (colorectal adenocarcinoma, metastatic), hepatocellular carcinoma (HEpG2), lung carcinoma cells (A549) and mouse embryo fibroblast cell line (3T3). The best antioxidant activity showed compound 2 with two hydroxy groups substituted on phenyl ring in positions 2' and 3'. The best antimicrobial activity of all synthesized compounds showed compound 8, while the best antiproliferative activity showed compound 6. Results signify the importance of xanthene-1,8-dione derivatives as potential antioxidant and antiproliferative agents. This work is licensed under a Creative Commons Attribution 4.0 International License.

Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (1H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R &beta, ) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.

Due to the rise of microbial strains resistant to conventional therapies, there is an urgent need for finding the new antimicrobial chemotypes. Heterocyclic compounds such as thiocarbohydrazones (TCHs) are able to interact with many metalloenzymes essential for microbes, while sulfur atom increases lipophilicity which is generally positively correlated with potency. In this paper, we report antibacterial and antifungal activity of twenty-two TCHs toward eight bacterial and three fungal strains. Furthermore, three alignment independent 3D QSAR models based on descriptors derived from molecular interaction fields (MIFs) are developed in order to rationalize structure-activity relationships for activities of TCHs toward S. aureus, P. aeruginosa and C. albicans. Several structural fragments important for biological activity are recognized in each model, and structural modifications which could lead to increased potency are suggested. Designed structures will be synthesized accordingly and tested toward the same microbial strains in order to obtain more potent derivatives. The supporting information: [https://cer.ihtm.bg.ac.rs/handle/123456789/4480]

A series of new 5H-pyridobenzazepine and pyridobenzothiepine derivatives was synthesized by Pd-catalyzed formation of C-N and C-S bonds. All synthesized compounds were tested for their in vitro antimicrobial activity. The 5H-pyridobenzazepine derivatives showed better antibacterial and antifungal activity than corresponding 5H-dipyridoazepine analogs. Among the synthesized azepines, derivative 8 displayed potent activity against tested bacteria (MIC = 39-78 μg/mL), while azepine 12 showed promising antifungal activity (MIC = 156-313 μg/mL). The synthesized thiepine derivatives exhibited weak antibacterial activity, but showed pronounced antifungal activity. [Projekat Ministarstva nauke Republike Srbije, br. 172008]

The first Co(III) complexes with (1,3-selenazol-2-yl)hydrazones as an unexplored class of ligands were prepared and characterized by NMR spectroscopy and X-ray diffraction analysis. The novel ligands act as NNN tridentate chelators forming octahedral Co(III) complexes. The impact of structural changes on ligands' periphery as well as that of isosteric replacement of sulphur with selenium on the electrochemical and electronic absorption features of complexes are explored. To support the experimental data, density functional theory (DFT) calculations were also conducted. Theoretical NMR chemical shifts, the relative energies and natural bond orbital (NBO) analysis are calculated within the DFT approach, while the singlet excited state energies and HOMO-LUMO energy gap were calculated with time-dependent density functional theory (TD-DFT). The electrophilic f(-) and nucleophilic f(+) Fukui functions are well adapted to find the electrophile and nucleophile centres in the molecules. Both (1,3-selenazol-2-yl)- and (1,3-thiazol-2-yl) hydrazone Co(III) complexes showed potent antimicrobial and antioxidant activity. A significant difference among them was a smaller cytotoxicity of selenium compounds. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3095]

The synthesis and cytotoxic activities determination of new steroidal mono- and bis(thiazolidin-4-ones) 4a-f and 5a-f have been performed. Their anticancer action was also evaluated in comparison to previously synthesized and reported corresponding steroidal thiosemicarbazones. All compounds were obtained as stereoisomeric mixtures with different configuration (E or Z) in the hydrazone moiety at the C-3 position. After several consecutive crystallizations diastereomerically pure major (5)-isomers of mono-thiazolidin-4-ones were isolated. The structure and stereochemistry of 2,4-thiazolidinedione,2-[(17-oxoandrost-4-en-3-ylidene)hydrazone] were confirmed by X-ray analysis. A pathway for the formation of thiazolidin-4-one ring was proposed. The steroid thiazolidinone derivatives examined in this study exerted selective concentration-dependent cytotoxic activities on six tested malignant cell lines. Ten out of twelve examined compounds exhibited strong cytotoxic effects on K562 cells (IC50 values from 8.5 mu M to 14.9 mu M), eight on HeLa cells (IC50 values ranging from 8.9 mu M to 15.1 mu M) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC50 values from 12.7 mu M to 25.6 mu M) than cisplatin (21.5 mu M) which served as a positive control. Eight of these ten compounds showed high selectivity in the cytotoxic action against HeLa and K562 cancer cell lines when compared with normal human fibroblasts MRC-5 and normal human PBMC. The study of mechanisms of the anticancer activity of the two selected compounds, mono- and bis(thiazolidin-4-one) derivatives of 19-norandrost-4-ene-3,17-dione 4a and 5a, revealed that both of these compounds induced apoptosis in HeLa cells through extrinsic and intrinsic signalling pathways. Treatment of EA.hy926 cells with sub-toxic concentrations of these compounds led to the inhibition of cell connecting and sprouting, and tube formation. The synthesized compounds exhibited poor antioxidant activity. This is the peer-reviewed version of the following article: Živković, M. B.; Matić, I. Z.; Rodić, M. V.; Novaković, I. T.; Krivokuća, A. M.; Sladić, D. M.; Krstić, N. M. Anticancer Potential of New Steroidal Thiazolidin-4-One Derivatives. Mechanisms of Cytotoxic Action and Effects on Angiogenesis in Vitro. Journal of Steroid Biochemistry and Molecular Biology 2017, 174, 72–85. [https://doi.org/10.1016/j.jsbmb.2017.07.031] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3192]

The interactions of avarone, a quinone from the marine sponge Dysideaavara, and the methylamino derivatives of avarone ( 2 ), 3′-(methylamino)avarone ( 3 ) and 4′-(methylamino)avarone ( 4 ) with calf thymus DNA (CT-DNA) were studied. Agarose gel electrophoreticanalysis showed that binding of the quinones quenched fluorescence of ethidium bromide (EB). The extent of fluorescence quenching of intercalator EB by competitive displacement from EB–CT-DNA system and of groove binder Hoechst 33258 (H) from H–CT-DNA system with the quinones was analyzed by fluorescence spectroscopy. The obtained results demonstrated that the quinones reduced binding of both the intercalator EB and the minor groove binder H, indicating possible degradation of DNA. The substituent on the quinone moiety determined the extent of DNA damaging effect of the quinone, which was the most extensive with 3′-(methylamino)avarone and the least extensive with its regioisomer 4′-(methylamino)avarone. The results were confirmed by the observed hyperchromic effects in UV–visible spectra measured after interactions of the derivatives with CT-DNA.

A series of new steroidal mono- and bis(thiosemicarbazones) (2a-e and 3a-e) and corresponding mono- and bis(1,3,4-thiadiazolines) (4a-e and 5a-e) was synthesized, characterized and evaluated for their anticancer activity. Detailed NMR analysis of the mono-and bis(thiosemicarbazones) revealed the presence of two stereoisomers (Z and E) with different configurations in the hydrazone moiety at the C-3 position, where the substituents on the C(3)]=N double bond in the main isomers adopted the E configuration. The configurations at C-3 and C-17 in thiadiazolines 4a-e and 5a-e were deduced by detailed NMR analysis as well as by the examination of Dreiding molecular models and X-ray analysis of 3-thiadiazoline 4a, which confirmed the structure and absolute configuration at C-3. The synthesized compounds were tested against six cancer cell lines (HeLa, K562, MDA-MB-361, MDA-MB-453, LS174 and A549), the normal human cell line MRC-5 and peripheral blood mononuclear cells (PBMC) isolated from healthy donors. The best activity was exhibited by 3-thiosemicarbazones 2a, 2b, 2c and 2e and 3,17-bis(thiadiazolines) 5a and 5d. Examination of the mechanisms of cytotoxicity on cervical adenocarcinoma HeLa cells revealed the pro-apoptotic action of these compounds, which triggered both extrinsic and intrinsic apoptotic pathways. These compounds also showed the ability to decrease angiogenesis in vitro. In addition, 3,17-bis(thiadiazolines) 5a and 5d showed high selectivity in anticancer activity against all the examined malignant cell lines. Compound 5a displayed prominent anticancer potential. The tested compounds showed poor antimicrobial activity. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3645]

The reactions of 17 alpha-hydroxyprogesterone with Lawesson's reagent (LR) in toluene, CH2Cl2 and/or CCl4 gave, depending on the duration of the reaction, two diastereoisomeric androst-4-en-17-spiro-1,3,2-oxathiaphospholane-2-sulfide pairs 2a,b and 3a,b in approximately 7:3 ratio, differing in configuration at the phosphorus atom. A parallel analysis of heteronuclear 2D H-1-C-13 spectra (HSQC and HMBC) and homo-nuclear 2D spectra (NOESY) enabled complete H-1 and C-13 assignments of each isomer. Also, analysis of NOESY correlations provided evidence for the preferred conformation. X-ray analysis of 3a confirmed the structure and absolute configuration on phosphorus. A pathway for the formation of 1,3,2-oxathiaphospholane ring was proposed. Cytotoxic activity in vitro was tested against three tumor cell lines (human cervix carcinoma HeLa cells and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compound 3a and mixture 3a,b showed a moderate activity against HeLa and MDA-MB-453 cell lines while against MDA-MB-361 cell line all tested compounds exerted very weak cytotoxic effect. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, toxicity to brine shrimp Artemia sauna, were evaluated. All tested compounds showed strong antifungal activity. (C) 2012 Elsevier Inc. All rights reserved.

Screens of antioxidant activity (AA) of various natural products have been a focus of the research community worldwide. This work aimed to differentiate selected samples of Merlot wines originated from Montenegro, with regard to phenolic profile and antioxidant capacity studied by survival rate, total sulfhydryl groups and activities of glutathione peroxidase (GPx), glutathione reductase and catalase in H2O2&ndash, stressed Saccharomyces cerevisiae cells. In this study, DPPH assay was also performed. Higher total phenolic content leads to an enhanced AA under both conditions. The same trend was observed for catechin and gallic acid, the most abundant phenolics in the examined wine samples. Finally, the findings of an Artificial Neural Network (ANN) model were in a good agreement (r2 = 0.978) with the experimental data. All tested samples exhibited a protective effect in H2O2&ndash, stressed yeast cells. Pre-treatment with examined wines increased survival in H2O2&ndash, stressed cells and shifted antioxidative defense towards GPx&ndash, mediated defense. Finally, sensitivity analysis of obtained ANN model highlights the complexity of the impact that variations in the concentrations of specific phenolic components have on the antioxidant defense system.

Nine alkyl(aryl)thio derivatives of the marine sesquiterpene quinone avarone were synthesized by nucleophilic addition of thiols or thiophenol to avarone. In most cases only one regioisomer was obtained. Their cytotoxic activities, brine shrimp lethality and antibacterial activity were evaluated, as well as those of some previously synthesized avarone derivatives. Anti-HIV activity of two derivatives was tested. Electrochemical properties were determined for all the derivatives in Order to obtain more accurate information on structure-activity relationships. Most derivatives showed cytotoxic activity against tumor cell lines, with IC(50) values less than 10 mu M for some of them, in particular those with electron-donating substituents. The most active Compound was 4'-(methylamino)avarone, with IC(50) value of 2.4 mu M to melanoma Fem-X cells, and no cytotoxicity to normal lymphocytes. (C) 2009 Elsevier Masson SAS. All Fights reserved.

The quinone avarone, isolated from the marine sponge Dysidea avara, possesses the ability to chemically modify proteins. In this work, modification of lectin isolated from the coral Gerardia savaglia by avarone was examined. The techniques used for studying the modification were: SDS PAGE, isoelectric focusing and hemagglutination testing. The results of the SDS PAGE indicate dimerization of the protein. A shift of the pI toward lower value occurs upon modification. The change of the hemagglutination activity of the protein confirms that chemical modification of G. savaglia lectin by avarone changes its ability to interact with the membrane of erythrocytes.

New complexes of Pt(II) with condensation derivatives of ethyl hydrazinoacetate and either 2-acetylpyridine or 2-quinolinecarboxaldehyde, and of Pd(II) with the condensation derivative of ethyl hydrazinoacetate and 2-quinolinecarboxaldehyde were synthesized and characterized by elemental analysis, IR, 1H- and 13C-NMR spectroscopy, and molar conductivity measurements. The complexes have a square planar geometry, ligands binding as bidentates in the neutral form, and the remaining two coordination sites being occupied by chloride ions. Biological activity of new complexes, and of previously synthesized Pd(II), Cd(II), Co(III) and Zn(II) complexes with this ligand type was evaluated by the brine shrimp test. All the complexes showed a moderate activity.

Antimicrobial activity of fourteen diarylheptanoids isolated from the bark of black and green alder against twelve bacterial species (five Gram-positive and seven Gram-negative) and eight fungal strains has been reported. The most sensitive bacterial species were Klebsiella pneumoniae and Pseudomonas aeruginosa (Gramnegative), and Streptosporangium longisporum and Bacillus subtilis (Gram-positive). Among fungal strains the most sensitive to the diarylheptanoids were Fusarium equiseti, F. tricinctum, Candida albicans, and Saccharomyces cerevisiae. Oregonin (8), platyphyllenone (13), hirsutenone (14), (5S)-5-hydroxy-1,7-bis(4-hydroxyphenyl)heptan-3-one-5-O-beta-D-apiofuranosyl(1 - gt 6)-beta-D-glucopyranoside (2), and platyphylloside (1) were the most active diarylheptanoids against both bacteria and fungi, especially against fungi. Eleven of fourteen investigated diarylheptanoids exhibited stronger antifungal activity than standards nystatin and fluconazole against C. albicans and eight against S. cerevisiae. Structure/activity analysis revealed the importance of the enone moiety in the structure of diarylheptanoids for the antifungal activity. Significant antifungal activity and high content of oregonin (8) and hirsutenone (14) in the black alder bark chloroform/methanol (1:1) extract recommend the use of these compounds as easily accessible potential antifungal remedies.

A series of eighteen derivatives of marine sesquiterpene quinone avarone and its model system tert-butylquinone with amino acids has been synthesized by nucleophilic addition of amino acids to the quinones. In vitro cytotoxic activity toward human cancer cell lines (HeLa, A549, Fem-X, 1(562, MDA-MB-453) and normal MRC-5 cell line was determined. Several compounds showed very strong inhibitory activity with IC50 values less than 10 mu M. Avarone derivatives were more active than the corresponding tert-butylquinone derivatives. The results of the cytofluorimetric analysis of cell cycle of HeLa cells showed that apoptosis might be one of possible mechanism of action of these compounds in cancer cells. In order to examine the influence of caspases on cell death, the apoptotic mechanisms induced by the tested compounds were determined using specific caspases 3, 8 and 9 inhibitors. For all compounds antibacterial activities against six strains of Gram-positive and four strains of Gram-negative bacteria were determined, as well as antifungal activity against three fungal species. This is the peer-reviewed version of the following article: Vilipić, J.; Novaković, I.; Stanojković, T.; Matić, I.; Šegan, D.; Kljajić, Z.; Sladić, D. Synthesis and Biological Activity of Amino Acid Derivatives of Avarone and Its Model Compound. Bioorganic and Medicinal Chemistry 2015, 23 (21), 6930–6942. [https://doi.org/10.1016/j.bmc.2015.09.044] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3439]

Amyloglucosidase from A. niger was covalently immobilized onto poly(GMA-co-EGDMA) by the glutaraldehyde and periodate method. The immobilization of amyloglucosidase after periodate oxidation gave a preparate with the highest specific activity reported so far on similar polymers. The obtained immobilized preparates show the same pH optimum, but a higher temperature optimum compared with the soluble enzyme. The kinetic parameters for the hydrolysis of soluble starch by free and both immobilized enzymes were determined. Amiloglukozidaza iz A.niger je imobilizovana na poly(GMA-co-EGDMA) glutaraldehidnom i perjodatnom metodom. Imobilizacija amiloglukozidaze nakon perjodatne oksidacije daje preparat sa najvećom do sada objavljenom specifičnom aktivnosti na sličnim polimerima. Dobijeni imobilizovani preparat ima isti pH optimum ali povećani termooptimum u poređenju sa rastvornim enzimom. Određeni su i kinetički parametri za hidrolizu rastvornog skroba imobilizovanim kao i rastvornim enzimom.

The avarone/avarol quinone/hydroquinone couple shows considerable antitumor activity. In this work, covalent modification of ?-lactoglobulin by avarone and its derivatives as well as by the synthetic steroidal quinone 2,5(10)-estradiene- 1,4,17-trione and its derivatives were studied. The techniques for studying chemical modification of ?-lactoglobulin by quinones were: UV/Vis spectrophotometry, SDS PAGE and isoelectrofocusing. SDS PAGE results suggest that polymerization of the protein occurs. It could be seen that the protein of 18 kD gives the bands of 20 kD, 36 kD, 40 kD, 45 kD, 64 kD and 128 kD depending on modification agent. The shift of the pI of the protein (5.4) upon modification toward lower values (from pI 5.0 to 5.3) indicated that lysine amino groups are the principal site of the reaction of ?-lactoglobulin with the quinones.

The regioselectivity of the reaction of conjugate addition of thiols amines, methanol and hydrogen chloride with the monoalkyl-1,4-benzoquinones avarone and 2-tert-butyl- 1,4-benzoquinone was investigated. It was shown that the regioselectivity of the reaction is influenced by the electrophilicity of position 5 in unprotonated 2-alkylquinones, the increased electrophilicity of position 6 in acidic medium, and by the acidity of the intermediate hydroquinones.

The in vitro cytotoxic activity of previously synthesized steroid dimers with different spacer group (sulfide, trithiolane ring or phosphorotrithioate) and the substituent at C-17 position was tested for their possible effects against following human tumor cell lines: cervical adenocarcinoma (HeLa), chronic myelogenous leukemia (K562) and two human breast cancer cell lines (MDA-MB-361 and MDA-MB-453). These compounds, applied at micromolar concentrations, exhibited cytotoxic activity of different intensity (compared with cisplatin as a control), modality and selectivity in these malignant cell lines. The best activity against all four cell cancer lines was exhibited by dimer-sulfides. All screened compounds exerted concentration-dependent cytotoxic activity against leukemia K562 cells. The compounds which exerted the most pronounced cytotoxic action exhibited notably higher cytotoxic activities against K562, HeLa and MDA-MB-453 cells in comparison to resting and PHA-stimulated PBMC, pointing to a significant selectivity in their antitumor actions. Examination of the mechanisms of cytotoxicity on leukemia K562 cells revealed pro-apoptotic action of each of the investigated compounds applied at concentrations 2IC(50). The most prominent pro-apoptotic action was exhibited by dimer-sulfide of cholest-4-en-3-one. Furthermore, almost all of the tested compounds at IC50 concentrations induced G1 phase cell cycle arrest in K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia sauna, were evaluated. There was no antibacterial activity. The best antifungal activity was exhibited against Saccharomyces cerevisiae by dimers linked with trithiolane ring, indicating a selective activity of investigated compounds. (C) 2014 Elsevier Ltd. All rights reserved.

The reactions of 21-hydroxyprogesterone with Lawesson’s reagent in toluene or $$\mathrm {{CH}_{2}{Cl}_{2}}$$ gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17 $$\upbeta $$ -yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17 $$\upbeta $$ -ylidene)-1,3,2-oxathiaphospholane–2-sulfide (3), 4-(3-oxoandrost-4-en-17 $$\upbeta $$ -yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17 $$\upbeta $$ -ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D $$^{1}\mathrm {H}$$ - $$^{13}\mathrm {C}$$ spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete $$^{1}\mathrm {H}$$ and $$^{13}\mathrm {C}$$ assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.

A conjugate of lysozyme with avarone, a bioactive sesquiterpene quinone of marine origin, and its three derivatives were synthesized. MALDI TOF mass spectral analysis and tryptic digestion showed that the only residue in lysozyme that was modified by all derivatives was lysine 97. The identity of the residue was in full correlation with the prediction obtained by molecular modeling. All bioconjugates preserved most of the enzymatic activity of lysozyme. The melting point of the conjugates was slightly increased in comparison to lysozyme, indicating a slight stabilization of structure. The antibacterial activity of all the conjugates to both Gram positive and Gram negative bacteria was stronger than the activity of either lysozyme or the quinones, the MIC values being in low micromolar range for some conjugates. This is the peer-reviewed version of the article: Novaković, I., Anđelković, U., Zlatović, M., Gašić, M.J., Sladić, D., 2012. Bioconjugate of Lysozyme and the Antibacterial Marine Sesquiterpene Quinone Avarone and Its Derivatives. Bioconjugate Chem. 23, 57–65. [https://doi.org/10.1021/bc200330m]

Three novel copper(II) complexes as condensation derivatives of 2-pyridinecarboxaldehyde, 2-acetylpyridine or 2-quinolinecarboxaldehyde with ethyl hydrazinoacetate hydrochloride were synthesized. X-ray crystal structures of all three complexes were determined. Crystallographic data indicate a common basis of the structures with some major differences. Both pyridine derivatives form complexes of the type [CuCl(2)L] with distorted square-planar geometry around copper(II), but show a decisive difference in the side chain orientation. The quinoline derivative forms a dimeric complex of type [Cu(2)Cl(4)L(2)] with distorted trigonal bipyramidal geometry around copper(II), but a rather short Cu center dot center dot center dot Cu contact, which is reflected in its magnetic properties. All three complexes showed antibacterial activity. (c) 2008 Elsevier B.V. All rights reserved.