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Dva kompleksa cinka(II) i S-alkenil derivata tiosalicilne kiseline (engl. S-alkenyl derivatives of thiosalicylic acid- SADTA) (ligandi) su sintetisani i karakterisani na osnovu rezultata elementalne mikroanalize, IR, 1H i 13C NMR spektroskopije. Kompleksi su dobijeni direktnom reakcijom ZnCl2 i SADTA, u vodenom rastvoru. Prema fizičkohemijskim i spektroskopskim podacima, zaključujemo da su ligandi bidentatno koordinovani za jon cinka(II). Interakcija kompleksa sa DNA goveđeg timusa (CT-DNA) ispitivana je Uv-vis i fluorimetrijskom metodom. Citotoksična aktivnost kompleksa poređena je sa oksaliplatinom i cisplatinom i analizirana je na dvije različite tumorske ćelijske linije: mišji karcinom debelog crijeva (CT26) i mišji melanom (B16F1), dok su ne-tumorske mišje mezenhimske matične ćelije (mmMSCs) korišćene kao kontrola. Oba kompleksa pokazala su umjerenu aktivnost protiv ćelija mišjeg raka debelog crijeva i melanoma. Smanjenje vijabilnosti ćelija melanoma je izazvano zadržavanjem ćelije u G2 fazi ćelijskog ciklusa i apoptozom. Cink(II) kompleks sa SADTA, iako ima značajno slabiji citotoksični efekat na tumorske ćelije nego oksaliplatina i cisplatina, djeluje selektivnije na tumorske ćelije od poznatih ljekova. In this study, we generated and analized two complexes of zinc (II) and S-alkenyl derivatives of thiosalicylic acid- SADTА (ligands), by microanalysis, IR, H and C NMR spectroscopy. Synthesis of the complexes was accomplished by direct contact of ZnCl2 and SADTА. Physicochemical as well as spectroscopic analysis revealed bidentately coordination of the ligands to the zinc(II) center. Absorption as well as ethidium bromide displacement analyses were used for CTDNA test. Citotoxicity of the complexes was tested in colon carcinoma (CT26) and melanoma (B16F1), as well as in mesenchymal stem cells (mMSCs), all derived from mouse. Citotoxicity of complexes was compared with oxaliplatin and cisplatin. We revealed moderate citotoxicity of complexes against tumor cells. This phenomenon was acompained by induction of apoptosis and G2 phase arrest. The tested zinc (II) complexes has a weaker cytotoxicity than oxaliplatin and cisplatin. However, they show a much more selective effect on tumors than known drugs.

Cilj ove doktorske disertacije je ispitivanje hemijskog sastava, antioksidativne i antitumorske aktivnosti ekstrakata tri vrste lišajeva: Cladonia subulata, Pleurosticta acetabulum i Physcia semipinnata. Ispitivanje hemijskog sastava acetonskih i metanolskih ekstrakata obuhvatao je HPLC-UV analizu ekstrakata kao i određivanje ukupnog sadržaja fenola i flavonoida u ekstraktima. Ispitivani esktrakti su pokazali visok sadržaj ukupnih fenola (21,31±1,19 do 73,45±0,82 mg GA/g) i flavonoida (8,48±0,57 do 19,27±0,37 mg RU/g). Ispitivanje ekstrakata lišajeva HPLC-UV analizom potvrđeno je prisustvo dve grupe sekundarnih metabolita depsidona i depsida: hipoprotocetrarinska kiselina, fumaroprotocetrarinska kiselina, salazinska kiselina, norstihninska kiselina, protocetrarinska kiselina, evernijska kiselina, atranorin, lekanorna kiselina i obtusinska kiselina. Ispitivanje biološke aktivnosti ekstrakata obuhvatalo je evaluaciju antioksidativne i antitumorske aktivnosti. Antioksidativna aktivnost je utvrđena praćenjem ukupnog antioksidativnog kapaciteta, sposobnosti neutralizacije DPPH radikala, sposobnosti neutralisanja hidroksil radikala, redukcinog potencijala i inhibicije lipidne peroksidacije. Rezultati ispitivanja in vitro antioksidativne aktivnosti pokazuju da ekstrakti ispitivanih vrsta lišajeva poseduju značajan antioksidativni potencijal. Antitumorska aktivnost ekstrakata lišajeva procenjena je korišćenjem MTT testa ispitivanjem vijabilnosti i proliferacije na ćelijama Hela S3 (adenokarcinom cerviksa) i LS174 (ćelije karcinoma debelog creva). Ispitivani ekstrakti pokazali su antitumorsku aktivnost u različitim koncetracijama (IC50=13,55 do >200 μg/ml), u zavisnosti od ekstrakta i ispitivane ćelijske linije. Na osnovu dobijenih rezultata, može se prepostaviti da vrste lišajeva Cladonia subulata, Pleurosticta acetabulum i Physcia semipinnata u budućnosti mogu naći svoju potencijalnu primenu u medicini, farmaceutskoj, prehrambenoj i kozmetičkoj industriji, kao i u razvoju novih fitopreparata. The aim of this doctoral thesis is to investigate the chemical composition, antioxidant and antitumor activity of the extracts of three lichen species: Cladonia subulata, Pleurosticta acetabulum and Physcia semipinnata. Examination of the chemical composition of acetone and methanol extracts included the HPLC-UV analysis of the extracts as well as the determination of the total content of phenol and flavonoids in the extracts. The examined extracts showed a high content of total phenols (21.31 ± 1.19 to 73.45 ± 0.82 mg GA/g) and flavonoids (8.48 ± 0.57 to 19.27 ± 0.37 mg RU/g). Examination of extracts of lichens by HPLC-UV analysis confirmed the presence of two groups of secondary metabolites of depsidone and depside: hypoprotocetraric acid, fumaroprotocetraric acid, salazinic acid, norstictic acid, protocetraric acid, evernic acid, atranorine, lecanoric acid and obtusic acid. The study of the biological activity of extracts involved the evaluation of antioxidant and antitumor activity. The antioxidant activity was determined by monitoring the total antioxidant capacity, the ability to neutralize DPPH radicals, the ability to neutralize hydroxyl radicals, reducing potential, and inhibiting lipid peroxidation. The results of an in vitro antioxidative activity test show that the extracts of the tested lichen species have a significant antioxidant potential. Antitumor activity of lichen extracts was assessed using the MTT test by testing viability and proliferation of Hela S3 cells (cervix adenocarcinoma) and LS174 (colon cancer cells). The investigated extracts showed antitumor activity in different concentrations (IC50 = 13.55 to> 200 μg / ml), depending on the extract and the cell line examined. On the basis of the obtained results, it can be assumed that the species of lichens of Cladonia subulata, Pleurosticta acetabulum and Physcia semipinnata can find their potential application in the medical, pharmaceutical, food and cosmetic industries, as well as in the development of new phytopharmaceuticals, in the future.

Predmet istraživanja ove doktorske teze je in vitro određivanje antiradikalske aktivnosti odabranih neurotranmitera, njihovih prekursora i metabolita, a u cilju uspostavljanja odnosa na liniji struktura-antiradikalska aktivnost. Rezultati su upotpunjeni teorijskim proračunima kako bi se dobila potpuna slika parametara važnih za aktivnost prema radikalima od interesa, ali odredili termodinamički i kinetički najpovoljniji mehanizmi. Veliki broj spoljašnjih faktora utiče na povećanje koncentracije slobodnih radikala u organizmu pri čemu nastaje oksidacioni stres. U ovom procesu se ireverzibilno oštećuju biološki značajni molekuli i to dejstvom reaktivnih vrsta kiseonika, azota, hlora i sumpora. U literaturi je pokazano da su slobodni radikali direktno ili indirektno povezani sa razvojem neurodegenerativnih bolesti (Parkinsonove, Alchajmerove, šizofrenije i amiotrofične lateralne skleroze). Aktivnost može biti izražena ili kroz oksidaciju biološki molekula ili formiranje polimernih struktura, odnosno plakova. Većina ispitivanih egzogenih antioksidanasa ne može preći krvno-moždanu barijeru, tako da se ne mogu direktno koristiti za lečenje neurodegenerativnih bolesti. Zbog toga se sve veći značaj pridaje molekulima koji su prisutni u organizmu. Po svojoj strukturi, većina neurotransmitera pripada klasi kateholamina, odnosno poseduju kateholnu grupu koja je i čest strukturni parametar dobrih antioksidanasa. Dopamin, norepinefrin, epinefrin, njihov prekursor L-DOPA i dopaminski metabolit DOPAC poseduju ovu strukturnu jedinicu. Zamenom jedne hidroksilne grupe metoksigrupom nastaju 3-metoksitiramin, homovanilinska kiselina, vanililbademova kiselina (vanillylmandelic acid – VMA), značajni metaboliti neurotransmitera koji se eksperimentalno određuju prilikom dijagnoze bolesti povezanih sa promenom koncentracije dopamina. Tiramin, tirozin i oktopamin imaju hidroksilnu grupu u ppoložaju u odnosu na alifatični niz dok fenilalanin i feniletilamin u strukturi nemaju hidroksilne grupe na aromatičnom prstenu. Tri hidroksilne grupe na aromatičnom prstenu v su prisutne kod 6-hidroksidopamina. Svi ovi molekuli su uključeni u istraživanje kako bi se eksperimentalno i teorijski odredili strukturni parametri, broj i vrsta supstituenata, kao i krajnje grupe alifatičnog niza značajni za antiradikalsku aktivnost. The research topic of this doctoral dissertation is in vitro determination of antiradical activity of selected neurotransmitters, their precursors and metabolites, with the main goal of establishment of the structure-antiradical activity relationship. The results incorporate theoretical calculations in order to obtain a full picture of parameters important for activity towards radicals of interest, but also to determine the thermodynamically and kinetically most favorable mechanism. A large number of external factors influences the increase in the concentration of free radicals which leads to oxidative stress. In this process, the biologically important molecules are irreversibly damaged by the activity of reactive oxygen, nitrogen, chlorine and sulfur species. It is shown in the literature that free radicals are directly or indirectly connected to the development of neurodegenerative diseases (Parkinson, Alzheimer, schizophrenia, amyotrophic lateral sclerosis). The activity of the reactive species is expressed through oxidation of biologically important molecules or the formation of polymeric structures, plaque. The most of investigated exogenous antioxidants cannot cross the blood-brain barrier, therefore they cannot be used for the treatment of neurodegenerative diseases. Because of this, there is an increased interest in the naturally occurring molecules in an organism. Structurally, the majority of neurotransmitters are catecholamines, which means that they possess catechol moiety, the common structural motif of good antioxidants. Dopamine, norepinephrine, epinephrine, their precursor L-DOPA and dopamine metabolite DOPAC have this group. When one of the hydroxyl groups is exchanged with methoxy group the following molecules are obtained: 3-methoxytyramine, homovanillic acid and vanillylmandelic acid. These molecules are experimentally determined in the diagnosis of diseases resulting from a change in the dopamine concentration. Tyramine, tyrosine, and octopamine have one hydroxyl group in p-position with respect to the aliphatic chain. Phenylalanine and phenylethylamine do not possess any hydroxyl groups viii attached to the aromatic ring. There are three hydroxyl groups in the structure of 6- hydroxydopamine. All of these molecules are included in the investigation so experimentally and theoretically important structural parameters like number and type of substituents and end groups of the aliphatic chain are determined.

Vitamin E je generičko ime koje obuhvata dve klase jedinjenja, tokoferole i tokotrienole, od kojih svaka klasa sadrži 4 izomera (α, β, γ, δ). Analozi vitamina E putem različitih mehanizama mogu ispoljiti snažnu citotoksičnu aktivnost na više tipova tumorskih ćelija, a da pritom ne remete u velikoj meri aktivnost zdravih ćelija. Ovu doktorsku disertaciju čine tri celine čiji će rezultati imati potencijalni značaj za primenu derivata vitamina E u terapiji malignih bolesti. Prva celina obuhvata studije kvantitativnog odnosa strukture i dejstva (Quantitative Structure-Activity Relationship, QSAR) derivata vitamina E i određivanje strukture farmakofore. U drugoj celini opisani su: (1) sinteza estara α-tokoferola sa aminokiselinama lizinom, prolinom, glutaminom, asparaginom i estara γ-tokotrienola sa lizinom, prolinom, glutaminom; (2) in vitro ispitivanja biološke aktivnosti sintetisanih estara na MCF-7 i MDA-MB 231 ćelijskim linijama tumora dojke, A549 ćelijskoj liniji tumora pluća i MRC-5 zdravoj ćelijskoj liniji fetalnih fibroblasta pluća; (3) ispitivanje ćelijskih mehanizama antiproliferativne aktivnosti i sinergističkog efekta najaktivnijeg sinetisanog jedinjenja sa doksorubicinom na multirezistentnoj MDA-MB 231 ćelijskoj liniji; (4) studije stabilnosti u humanoj plazmi; (5) pretraživanje ChEMBL baze bioaktivnih molekula primenom metode virtelnog skrininga zasnovanog na strukturi liganda. Treću celinu predstavlja dizajn novih analoga vitamina E sa potencijalno snažnijim antitumorskim dejstvom... Vitamin E is a generic name comprising of two classes of compounds, tocopherols and tocotrienols, each class containing 4 isomers (α, β, γ, δ). Analogs of vitamin E, via different mechanisms, may exhibit strong cytotoxic activity to many types of malignant cells, while not disrupting in a greater extent activity of healthy cells. This doctoral thesis includes three sections whose results will have potential importance for the use of vitamin E derivatives in the treatment of malignant diseases. The first section includes Quantitative Structure-Activity Relationship (QSAR) study of vitamin E analogues and pharmacophore structure determination. The second section covers: (1) synthesis of α-tocopherol esters with amino acids lysine, proline, glutamine, asparagine, and γ-tocotrienol esters with lysine, proline, glutamine; (2) in vitro testing of biological activities of the synthesized esters on the MCF-7 and MDA-MB 231 breast cancer cell lines, A549 lung cancer cell line, and the MRC-5 healthy fetal lung fibroblasts cell line; (3) testing of cellular mechanisms which underlie the antiproliferative activity and synergistic effect of the most active compound with doxorubicin on multidrug-resistant MDA-MB 231 cell line; (4) stability study in human plasma; (5) filtering of the ChEMBL database of bioactive molecules using the ligand based virtual screening protocol. The third section represents design of new analogues of vitamin E with enhanced antitumor activity. 2D- and 3D-QSAR studies were conducted on a series of vitamin E analogues with experimentally determined antiproliferative activity on MCF7 cell line, using PLS statistical method...

Vitamin E je generičko ime koje obuhvata dve klase jedinjenja, tokoferole i tokotrienole, od kojih svaka klasa sadrži 4 izomera (α, β, γ, δ). Analozi vitamina E putem različitih mehanizama mogu ispoljiti snažnu citotoksičnu aktivnost na više tipova tumorskih ćelija, a da pritom ne remete u velikoj meri aktivnost zdravih ćelija.Ovu doktorsku disertaciju čine tri celine čiji će rezultati imati potencijalni značaj za primenu derivata vitamina E u terapiji malignih bolesti.Prva celina obuhvata studije kvantitativnog odnosa strukture i dejstva (Quantitative Structure-Activity Relationship, QSAR) derivata vitamina E i određivanje strukture farmakofore.U drugoj celini opisani su: (1) sinteza estara α-tokoferola sa aminokiselinama lizinom, prolinom, glutaminom, asparaginom i estara γ-tokotrienola sa lizinom, prolinom, glutaminom; (2) in vitro ispitivanja biološke aktivnosti sintetisanih estara na MCF-7 i MDA-MB 231 ćelijskim linijama tumora dojke, A549 ćelijskoj liniji tumora pluća i MRC-5 zdravoj ćelijskoj liniji fetalnih fibroblasta pluća; (3) ispitivanje ćelijskih mehanizama antiproliferativne aktivnosti i sinergističkog efekta najaktivnijeg sinetisanog jedinjenja sa doksorubicinom na multirezistentnoj MDA-MB 231 ćelijskoj liniji; (4) studije stabilnosti u humanoj plazmi; (5) pretraživanje ChEMBL baze bioaktivnih molekula primenom metode virtelnog skrininga zasnovanog na strukturi liganda.Treću celinu predstavlja dizajn novih analoga vitamina E sa potencijalno snažnijim antitumorskim dejstvom... Vitamin E is a generic name comprising of two classes of compounds, tocopherols and tocotrienols, each class containing 4 isomers (α, β, γ, δ). Analogs of vitamin E, via different mechanisms, may exhibit strong cytotoxic activity to many types of malignant cells, while not disrupting in a greater extent activity of healthy cells.This doctoral thesis includes three sections whose results will have potential importance for the use of vitamin E derivatives in the treatment of malignant diseases.The first section includes Quantitative Structure-Activity Relationship (QSAR) study of vitamin E analogues and pharmacophore structure determination.The second section covers: (1) synthesis of α-tocopherol esters with amino acids lysine, proline, glutamine, asparagine, and γ-tocotrienol esters with lysine, proline, glutamine; (2) in vitro testing of biological activities of the synthesized esters on the MCF-7 and MDA-MB 231 breast cancer cell lines, A549 lung cancer cell line, and the MRC-5 healthy fetal lung fibroblasts cell line; (3) testing of cellular mechanisms which underlie the antiproliferative activity and synergistic effect of the most active compound with doxorubicin on multidrug-resistant MDA-MB 231 cell line; (4) stability study in human plasma; (5) filtering of the ChEMBL database of bioactive molecules using the ligand based virtual screening protocol.The third section represents design of new analogues of vitamin E with enhanced antitumor activity.2D- and 3D-QSAR studies were conducted on a series of vitamin E analogues with experimentally determined antiproliferative activity on MCF7 cell line, using PLSstatistical method...

U disertaciji je ostvarena sineza amida i oksazolina žučnih kiselina, kao i njihovih alkil i alkilidenskih derivata polazeći od holne kiseline. Ipitano je ponašanje različitih okso derivata žučnih kiselina u uslovima Grignard-ove i Wittig-ove reakcije. Ispitana je biološka aktivnost odabranih sintetizovanih jedinjenja, Synhesis of bile acid amide and oxazoline derivatives, and their alkyl and alkylidene derivatives was accomplished starting from cholic acid. Also, chemical behavior of different bile acid oxo derivatives in Grignard and Wittig reaction was investigated. Biological activity of selected synthesized compounds was evaluated.

U ovoj Doktorskoj disertaciji je opisana sinteza i karakterizacija (2S)-2- -(2-okso-1,3-oksazinan-3-il)propanske kiseline kao i estara tipa O-alkil-N-(3-hloropropil)-(2S)-alaninata monohlorhidrata (R = propil-, butil-) u nameri da se dobiju 1,3-propandiamin-N,N′-di-(S,S)-2-propanska kiselina, (H2-(S,S)-rddp) i O,O′-dialkil estara tetradentatnog liganda 1,3- -propandiamin-N,N′-di-(S,S)-2-propanske kiseline, R2-(S,S)-rddp). Estri O-alkil-N-(3-hloro-propil)-(2S)-alaninata monohlorhidrata dobijeni su direktnom reakcijom između (2S)-2-(2-okso-1,3-oksazinan-3-il) propanske kiseline i odgovarajućeg apsolutnog alkohola( 1-propanol, 1-butanol) u molskom odnosu 1:2, uz uvođenje gasovitog hlorovodonika. Potom je sintetisana etilendiamin-N,N′-di-S,S-(2,2'-dibenzil)etanska kiselina trihidrat, N2-(S,S)-eddba·3N2O. Na prethodno opisan način sintetisani su O,O'-dialkil estri etilendiamin-N,N′-di-(S,S)-(2,2'-dibenzil) etanske kiseline kao dihlorhidrati, R2-(S,S)-eddba·2NSl (R =etil-, propil-, butil- i pentil-). Strukture i sastav izolovanih liganada pretpostavljene su primenom elementalne mikroanalize, infracrvene, 1H i 13C NMR spektroskopije, a potvrđene na bazi rezultata rendgenske strukturne analize u slučaju: (2S)-2-(2- -okso-1,3-oksazinan-3-il)propanske kiseline, O-propil-N-(3-hloropropil)-(2S)- -alaninata i O-butil-N-(3-hloropropil)-(2S)-alaninata kao monohlorhidrati, i O,O'-dipropil-etilendiamin-N,N'-di-(S,S)-(2,2'-dibenzil)etanoat kao trihidrata, N2-(S,S)eddba·3N2O. Dobijeni O,O'-dialkil estri etilendiamin-N,N′-di-(S,S)-(2,2'-dibenzil) etanske kiseline su upotrebljeni za sintezu odgovarajućih kompleksa platine(IV) i paladijuma(II). Sastav dobijenih kompleksa platine(IV), [PtCl4(R2- -(S,S)-eddba)] i paladijuma(II), [PdCl2(R2-S,S-eddba)] potvrđeni su elementalnom mikroanalizom. Struktura izolovanih kompleksa potvrđena je na osnovu infracrvene, 1H i 13C NMR spektroskopije. In vitro antitumorska aktivnost kompleksa platine(IV) sa tetradentatnim ligandima (sa navedenim O,O′-dialkil estrima N2-(S,S)-eddba) određivana je na ćelijama CCL u periodu od 72 sata korišćenjem MTT tehnike. Zaključak je da kompleksi pokazuju jak citotoksični efekat. Citotoksični efekti svih kompleksa su dozno-zavisni i svi ispitivani kompleksi su pokazali znatno veći citotoksični efekat na CLL ćelije od cisplatine. In vitro antimikrobna aktivnost sintetisanih liganada i odgovarajućih kompleksa paladijuma(II) testirana je određivanjem minimalnih inhibitorskih (MIK) i minimalnih baktericidnih koncentracija (MBC). Ove supstance u poređenju sa pozitivnim kontrolama, pokazale su nisko antibakterijsko delovanje Antibakterijsko delovanje kompleksa je bilo izraženije na gram pozitivne bakterije, a znatno manje na gram negativne bakterije. Najsenzitivnija bila je bakterija vrste Enterococcus faecalis, Ligandi su pokazali slabo delovanje na gram negativne bakterije posebno na vrstu Proteus vulgaris. In this Work, the synthesis and characterization of the compounds (2S)-2-(2-oxo- -1,3-oxazinan-3-yl)propionic acid nd esters of type O-alkyl-N-(3-chloro-propyl)-(2S)-- alaninate monohlorhydrate (R = propyl-, butyl-) in order to obtain 1,3-propanediamine--N,N′-ди-(S,S)-2-propanoic acid, (H2-(S,S)-рddp) and O,O'-dialkyl esters with tetradentate ligand of 1,3-propanediamine-N,N'-di-(S,S)-2-propanoicb acid, (R2-(S,S)--pddp). Esters of O-alkyl-N-(3-chloropropyl)-(2S)-alaninate monohlorhydrate obtained by the direct reaction between (2S)-2-(2-oxo-1,3-oxazinan-3-yl)propionic acid and the corresponding absolute alcohol (1-propanol, 1-butanol) in the molar ratio 1:2, with the addition of gaseous hydrogenchloride. Then, the synthesized ethylenediamine-N,N'-di-(S,S)-(2,2'-dibenzyl) ethanoic acid trihydrate, Н2-(S,S)-eddbа·3Н2О. As described above were synthesized by the O,O'--dialkyl esters of ethylenediamine-N,N'-di-(S,S)-(2,2'-dibenzyl)ethanoic acid as the dihydrochloride, R2-(S,S)-eddbа·2НСl (R = ethyl-, propyl-, butyl- and pentyl-). Structure and composition of the isolated ligands were assumed using by elemental microanalysis, IR, 1H and 13C NMR spectroscopy, and confirmed by X-ray diffraction analysis in the case (2S)-2-(2-okso-1,3-oksazynan-3-yl)propanoic acid, О-аlkyl-N-(3-chloropropyl)-(2S)-alaninate monocholorohydrate, and O,O'-dipropyl- -ethylen dianine-N,N'-di-(S,S)-(2,2'-dibenzyl)etanoate threehydrate, Н2-(S,S)eddbа·3Н2О. The obtained ligands О,О'-dialkyl estars of ethylendianine-N,N'-di-(S,S)-(2,2'--dibenzyl)etanoic acide were used for synthesis of the corresponding platinum(IV) and palladium(II) complexes. The composition of obtained platinum(IV), [PtCl4(R2-(S,S)--eddbа)] and palladium(II) complexes, [PdCl2(R2-S,S-eddbа)] was confirmed by elemental microanalysis. The structure of isolated complexes is assumed on basis of infrared, 1H and 13C NMR spectroscopy. In vitro antitumor activity of platinum complex (IV) with tetradentate ligands (with the above O,O'-dialkyl esters of Н2-(S,S)-eddbа) was determined on cells of CCL for a period of 72 hours by using the MTT techniques. The conclusion is that the complexes show strong cytotoxic effect. Cytotoxic effects of the complex are dose-depe- -ndent, and all tested complexes showed much higher cytotoxic effect on CLL cells by cisplatin. The in vitro antimicrobial activity of the synthesized ligands and the corresponding complexes of palladium (II) was tested by determination of minimal inhibitory (MIC) and minimum bactericidal concentration (MBC). These substances when compared to the positive controls, showed high antibacterial activity. The antibacterial activity of the complex was more pronounced in the gram-positive bacteria and much less of the gramnegative bacteria. Was the most sensitive species of bacteria Enterococcus faecalis. Ligands showed weak activity against gram-negative bacteria in particular of the type of Proteus vulgaris.

Rod Alnus Mill. (jove), sa više od 30 vrsta, pripada familiji Betulaceae. Alnus vrste koje rastu u Srbiji su A. glutinosa (crna jova), A. viridis subsp. viridis (zelena jova) i A. incana (siva jova). U ovom radu izolovani su i okarakterisani diarilheptanoidi iz kore crne jove i zelene jove i određena je njihova biološka aktivnost. Biljke ovog roda su u tradicionalnoj medicini korišćene u brojne svrhe, kao alterativi, astringenti, purgativi, emetici, antipiretici, hemostatici, antiparazitici i antihelmintici, za lečenje različitih bolesti, uključujući tumor. Jedinjenja izolovana iz jova poseduju širok spektar bioloških aktivnosti, a najvažnija su citotoksična, antitumorska, antivirusna, anti-inflamatorna, antimikrobna i antiparazitska. Vrste roda Alnus su bogat izvor diarilheptanoida. Oni se u biljci prvenstveno nalaze u kori i lišću, kao prosti, glikozidi ili složeni - diarilheptanoid glikozidi esterifikovani različitim fenolnim kiselinama, najčešće cinamičnim. U okviru ove disertacije iz kora zelene i crne jove izolovano je i okarakterisano 39 jedinjenja, od kojih je 19 novih prirodnih proizvoda. Iz zelene jove izolovano je 13 jedinjenja (1-13), a iz crne 28 (1, 5, 14-39), pri čemu su diarilheptanoidi platifilozid (1) i acerozid VII (5) izolovani iz obe biljne vrste. Od 13 jedinjenja izolovanih iz zelene jove, 11 pripada grupi diarilheptanoida (1-11), od kojih je 6 novih prirodnih proizvoda (3, 7, 8, 9, 11 i 13). Svih 28 jedinjenja izolovanih iz crne jove su diarilheptanoidi, a 13 (19, 27, 29-39) je novih. Strukturne karakteristike diarilheptanoida zelene jove su da isključivo imaju phidroksifenil grupe kao aromatične sisteme i da se, pored prostih, sreću glikozidi koji se sastoje iz mono- i disaharida. Složeni diarilheptanoidi su retki, izolovan je samo jedan sa galnom kiselinom (3). Za većinu diarilheptanoida crne jove karakteristično je da imaju bar jednu kateholsku grupu. Od glikozida su zastupljeni isključivo oni sa monosaharidnom jedinicom, prvenstveno glukozidi i ksilozidi. Za crnu jovu su karakteristični složeni diarilheptanoidi sa različitim cinamičnim kiselinama, pretežno onim sa metoksi grupama... The genus Alnus Mill. (Alder), with more than 30 species, belongs to the Betulaceae family. Alnus species growing in Serbia are A. glutinosa (black alder), A. viridis subsp. viridis (green alder) and A. incana (gray alder). In this work, diarylheptanoids from the bark of black alder and green alder were isolated and characterized, and their biological activity was determined. Plants of this genus have been traditionally used for numerous purposes, e.g. as an alterative, astringent, cathartic, emetic, febrifuge, hemostatic, parasiticide, vermifuge, in the treatment of various diseases, including tumors. Compounds isolated from the Alder species possess a wide spectrum of biological activities and the most important are cytotoxic, antitumoral, antiviral, anti-inflammatory, antimicrobial and antiparasitic. Alnus species are a rich source of diarylheptanoids. These are predominantly found in the bark and leaves as simple diarylheptanoids, glycosides and complex diarylheptanoids – diarylheptanoid glycosides esterified with some phenolic acid, most commonly with some cinnamic acid. In this work, 39 compounds were isolated and characterized from the barks of green and black alder, of which 19 are new natural products. Thirteen compounds were isolated from green alder (1-13), and 28 from black alder (1, 5, 14-39), of which diarylheptanoids platyphylloside (1) and aceroside VII (5) were isolated from both species. Of the 13 compounds isolated from green alder, 11 belong to diarylheptanoids (1-11) from which 6 are new natural products (3, 7, 8, 9, 11, and 13). All 28 compounds isolated from black alder are diarylheptanoids and 13 (19, 27, 29-39) are new. The structural characteristics of the diarylheptanoids isolated from green alder are that they have only p-hydroxyphenyl groups as aromatic systems and that besides simple diarylheptanoids, diarylheptanoid glycosides are found which consist of mono- and disaccharides. Complex diarylheptanoids are rare and only one was isolated with gallic acid (3). For the most diarylheptanoids isolated from black alder the presence of at least one catechol moiety as an aromatic component is characteristic...

Otkriće antitumorskih osobina cis-diamindihloridoplatina(II)kompleksa, poznatijeg pod imenom cisplatina (cis-DDP) i sličnih kompleksa platine povećalo je interesovanje za dobijanje još efikasnijih kompleksa drugih metala i liganada. Među prvim kompleksima korišćenim u kliničkim ispitivanjima protiv tumora bili su paladijum(II) analozi cisplatine. Iako prvobitni rezultati nisu bili ohrabrujući, kompleksi paladijuma(II) su mnogo šire proučavani. Paladijum(II) kompleksi su skoro uvek pokazivali manju antitumorsku aktivnost u odnosu na odgovarajuće komplekse platine zbog njihove velike labilnosti. Da bi se ovi problemi prevazišli, mnoga istraživanja su bila usmerena ka upotrebi helatnih liganada koji bi umanjili reaktivnost paladijum(II) kompleksa. The discovery of anticancer activity of cis-diammindichloridoplatinum(II)complexes, better known as cisplatin (cis-DDP) and related platinum complexes has stimuled the interest for obtaining more efficient complexes of other metals and ligands. Some the first complexes used in clinical treatments against tumors were palladium(II)complexes as analogues of cisplatin. Although the first results were not encouraging,palladium complexes have been studied to longer extent. Palladium(II) complexes show less antitumor activity than corresponding platinum complexes due to their high instability. In order to overcome these problems, many studies have been directed toward the use of chelating ligands which would reduce the reactivity of palladium(II) complexes.