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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...

Vinova loza (Vitis vinifera L., familija Vitaceae), globalno, je jedna od najznačajnijih voćaka zbog velike upotrebne vrijednosti grožđa. Grožđe i proizvodi od grožđa predmet su mnogih savremenih istraživanja, posebno zbog biološki aktivnih sekundarnih metabolita. Među ovim jedinjenjima se izdvajaju fenolna jedinjenja zbog izraženog antikancerogenog, antimutagenog, antiinflamatornog, antialergijskog i antimikrobnog djelovanja. Iako je fenolni sastav genetski određen, sadržaj fenolnih jedinjenja kao sekundarnih metabolita umnogome zavisi od primijenjenih agrotehničkih mjera, ali i uslova životne sredine. Od posebnog značaja su istraživanja vezana za mogućnost uticaja na akumulaciju fenolnih jedinjenja, kao na primjer preko primjene različitih formulacija, doza i kombinacija đubriva. Glavni cilj ove doktorske disertacije bilo je ispitivanje hemijskog sastava grožđa i praćenje uticaja folijarnog đubrenja sa fosforom i kalijumom na sadržaj fenolnih jedinjenja, kao i šećera i organskih kiselina. Imajući u vidu da su P i K od krucijalnog značaja za sintezu ugljenih hidtrata, kao i transport asimilata do skladišnih organa, očekivan je pozitivan efekat na akumulaciju primarnih, a indirektno i sekundarnih metabolita. S druge strane, mogućnost da sadržaj P u pojedinim organima vinove loze gajene na krečnjačkim zemljištima bude nizak predstavljala je još jedan od razloga zbog kojeg je odlučeno da se sprovede prihranjivanje preko lista sa đubrivom koje u svom sastavu sadrži i P. Sastavni dio istraživanja bilo je i proučavanje međusobnih veza primarnih i sekundarnih metabolita u grožđu sa hranljivim elementima u listu vinove loze. Istraživanje je izvedeno na stonoj sorti 'Kardinal' tokom sazrijevanja u tri termina, tokom dvije uzastopne godine. Folijarno je primjenjivano PK đubrivo, sa veoma malim količinama B, Mn i Mo, u tri navrata svakih 14–15 dana. Prvo tretiranje obavljeno je 15 dana prije početka šarka. Zbog boljeg definisanja agroekoloških uslova, urađena je i analiza zemljišta, a podaci o srednjoj dnevnoj temperaturi, padavinama i broju sunčanih sati bili su obezbijeđeni preko Hidrometeorološkog zavoda Crne Gore... he grapevine ( Vitis vinifera L., Vitaceae family), is one of the most important fruit at a global level because of the extensive us e of grapes around the world. Grapes and grape products are subject to many modern studi es, especially those looking at biologically active secondary metabolites. Among th ese, phenolic compounds have received great attention due to their strong antica rcinogenic, antimutagenic, anti- inflammatory, antiallergenic and antimicrobial acti vity. Although phenolic composition is genetically determined, the content of phenolic compounds as secondary metabolites largely depends on applied agricultural practices a nd environmental conditions. Of particular interest are investigations on the possi bility of influencing the accumulation of phenolic compounds, e.g. through the application of different formulations, rates and combinations of fertilisers. The main objective of this dissertation was to exam ine the chemical composition of grapes and monitor the impact of foliar feeding with phosphorus and potassium on the content of phenolic compounds, sugars and organ ic acids. Bearing in mind the crucial importance of P and K in the synthesis of c arbohydrates and transport of assimilates to storage organs, a positive effect on the accumulation of primary metabolites and indirect influence on secondary met abolites is expected. On the other hand, foliar fertilisation with P was also carried out because the possibility of low P content in some organs of grapevine grown on calcar eous soils. An integral part of the research was the study of the relationships between primary and secondary metabolites in grapes and nutrients in the grapevine leaf. This study was conducted on cv. ‘Cardinal’ during g rape ripening in three terms over two consecutive years. PK foliar fertiliser co ntaining very small amounts of B, Mn and Mo, was applied three times every 14–15 days. T he first treatment was performed 15 days before the beginning of veraison. For a bet ter definition of agricultural conditions, a soil analysis was conducted, and the data on mean daily temperature, rainfall and number of sunshine hours were provided by the Hydrological and Meteorological Service of Montenegro...

U okviru ove disertacije opisani su sinteza, strukturna karakterizacija i rezultati ispitivanja antioksidativne i citotoksične aktivnosti novih derivata 1,3,4-tiadiazola koji u svojoj strukturi sadrže fenolne hidroksilne grupe. U cilju određivanja mehanizma antitumorskog delovanja, za odabrana jedinjenja izvršena su dodatna ispitivanja poput analize raspodele faza ćelijskog ciklusa, ispitivanja uticaja na stvaranje ROS-a u malignim ćelijama usled dejstva vodonik-peroksida, morfološke analize tipa ćelijske smrti, određivanja ciljnih kaspaza, analize ekspresije gena, kao i ispitivanja interakcija sa DNK. Sintetizovane su tri serije jedinjenja koje ukupno sadrže 44 amidna derivata 1,3,4-tiadiazola, polazeći od fenolnih kiselina. Prve dve serije amida sintetizovane su kuplovanjem 5-supstituisanih-2-amino-1,3,4-tiadiazola izvedenih iz fenolnih kiselina sa različitim hloridima kiselina, koji su u slučaju serije B u svojoj strukturi sadržali i halkonsku jedinicu. Treća serija amidnih derivata dobijena je reakcijom hlorida fenolne kiseline sa supstituisanim 2-amino-1,3,4- tiadiazolima. Sva novosintetizovana jedinjenja strukturno su okarakterisana primenom NMR i IR spektroskopskih metoda. Antioksidativna aktivnost svih sintetizovanih 1,3,4-tiadiazolskih derivata ispitana je primenom DPPH metode, a dobijeni rezultati upoređeni su sa poznatim antioksidantima, askorbinskom i/ili nordihidrogvajaretinskom kiselinom. Jedinjenja sve tri serije pokazala su umerenu do dobru aktivnost neutralisanja DPPH radikala. Antioksidativni kapacitet sintetizovanih jedinjenja može se objasniti mogućnošću stabilizacije radikala, formiranog nakon apstrakcije vodonikovog atoma DPPH radikalom, delokalizacijom nesparenog elektrona preko 1,3,4- tiadiazolskog prstena. Ispitana je i aktivnost neutralisanja ABTS radikal-katjona amidnih derivata serije V, a dobijeni rezultati su pokazali da sintetizovana jedinjenja, pored kapaciteta za neutralizaciju DPPH radikala, imaju bolju sposobnost neutralisanja ABTS radikal-katjona u odnosu na askorbinsku kiselinu, NDGA i polaznu 3,4-dihidroksibenzojevu kiselinu. Within this study, the synthesis, structural characterization, and evaluation of the antioxidant and cytotoxic activities of novel 1,3,4-thiadiazole derivatives containing phenolic hydroxyl groups in their structure were described. In order to elucidate the mechanism of the antitumor activity, additional tests were performed for the selected compounds, such as cell cycle phase distribution analysis, investigation of their influence on ROS generation in malignant cells due to the action of hydrogen peroxide, cell death type morphology analysis, target caspase determination, gene expression analysis, and DNA interaction assays. Three series containing a total of 44 1,3,4-thiadiazole amide derivatives were synthesized starting from phenolic acids. The first two series of amides were synthesized by coupling 5-substituted-2-amino-1,3,4-thiadiazoles derived from phenolic acids with different acid chlorides, which in the case of series Б contained a chalcone unit in their structure. The third series of amide derivatives was obtained by the reaction of the phenolic acid chloride with substituted 2-amino-1,3,4-thiadiazoles. All newly synthesized compounds were structurally characterized using NMR and IR spectroscopic methods. The antioxidant activity of all synthesized 1,3,4-thiadiazole derivatives was examined using the DPPH method, and the obtained results were compared with well-known antioxidants, ascorbic and/or nordihydroguaiaretic acid. Compounds of all three series showed moderate to good DPPH radical scavenging activity. The antioxidant capacity of the synthesized compounds can be explained by the possibility of stabilizing the radical formed after abstraction of the hydrogen atom by the DPPH radical, via delocalization of the unpaired electron across the 1,3,4-thiadiazole ring. ABTS radical cation scavenging activity of amide derivatives of series В was also investigated and the obtained results showed that the synthesized compounds, in addition to the DPPH radical scavenging capacity, have a better ABTS radical cation scavenging ability compared to ascorbic acid, NDGA and starting 3,4-dihydroxybenzoic acid.

Osnovni cilj ove doktorske disertacije je karakterizacija hemijskog sastava etarskih ulja i ekstrakata retkih i endemičnih vrsta iz Republike Makedonije koje su delimično ili potpuno neistražene: Ferulago macedonica Micevski et Mayer, Echinophora sibthorpiana Guss., Laserpitium ochridanum Micevski, Heracleum orphanidis Boiss. i Angelica pancicii Vandas (Apiaceae). Drugi deo ovog istraživanja odnosi se na utvrđivanje in vitro biološkog potencijala etarskih ulja, metanolnih, etanolnih i vodenih ekstrakata navedenih vrsta i to njihovog antioksidativnog, antimikrobnog i anti-quorum sensing dejstva. U ovom radu su prvi put predstavljeni rezultati hemijske analize etarskih ulja vršnog i nadzemnog dela F. macedonica kao i metanolnih ekstrakata nadzemnog dela i korena vrsta H. orphanidis i A. pancicii. Do sada nije bilo ni literaturnih podataka o biološkim aktivnostima vrsta F. macedonica, H. orphanidis i A. pancicii. GC-FID i GC-MS analiza sastava etarskih ulja proučavanih vrsta pokazala je dominantno prisustvo monoterpenskih i seskviterpenskih ugljovodonika i njihovih oksidovanih formi. Ove analize su pokazale da su etarska ulja vršnog i nadzemnog dela F. macedonica bogata α-pinenom (43,10%; 22,78%) i sabinenom (26,73%; 15,46%). Za etarsko ulje E. sibthorpiana karakteristično je prisustvo velike koncentracije metil eugenola (60,40%), p-cimena (11,18%) i α-felandrena (10,23%), a za etarsko ulje L. ochridanum veliki sadržaj sabinena (22,8%), viridiflorola (14,7%) i α-pinena (11,4%). U etarskom ulju H. orphanidis kao glavna jedinjenja identifikovani su n-oktanol (39,57%), n-oktil heksanoat (17,62%) i n-oktil acetat (14,12%), dok su bornil acetat (8,08%), n-oktanol (5,82%), kesan (4,26%) i β-selinen (4,25%) najzastupljenije komponente etarskog ulja A. pancicii. Rezultati tentativne analize sastava metanolnih ekstrakata odabranih vrsta, dobijenih pomoću HPLC-DAD/ESI-ToF-MS sistema, prvi put su predstavljeni i opisani u ovoj disertaciji. Identifikacija sekundarnih metabolita ekstrakata urađena je na osnovu molekulske formule dobijene korišćenjem Mass Hunter Workstation softvera za prikupljanje i obradu podataka i na osnovu literaturnih podataka o hemijskom sastavu vrsta odgovarajućih rodova i predstavnika drugih rodova familije Apiaceae... The main goal of this doctoral dissertation was chemical characterization of essential oils and methanolic extracts of rare and endemic unexplored or partially investigated species originating from Republic of Macedonia: Ferulago macedonica Micevski & Mayer, Echinophora sibthorpiana Guss. Laserpitium ochridanum Micevski, Heracleum orphanidis Boiss. and Angelica pancicii Vandas (Apiaceae). Other part of this investigation was dedicated to determination of in vitro biological potential of essential oils, methanol, ethanol and aqueous extracts of selected species including antioxidant, antimicrobial and anti-quorum sensing effects. To date, no published results are available on phytochemical investigation of essential oils of F. macedonica and H. orphanidis and metanolic extracts of H. orphanidis and A. pancicii aerial parts and roots. Additionally, there is no literature data about biological potential of F. macedonica, H. orphanidis and A. pancicii species. GC-FID and GC-MS analysis showed a dominant presence of monotererpene and sesquiterpene hydrocarbons and their oxygenated forms in essential oils. This analisys showed that essential oils of F. macedonica apical and aerial parts were rich in α-pinene (43,10%; 22,78%) and sabinene (26,73%; 15,46%). E. sibthorpiana essential oil was characterised by dominant presence of methyl eugenol (60,40%), p-cymene (11,18%) i α-phellandrene (10,23%), while the most abundant compounds of L. ochridanum essential oil were sabinene (22,8%), viridiflorol (14,7%) and α-pinene (11,4%). As the main components of H. orphanidis essential oil were identified n-octanol (39,57%), n-octyl hexanoate (17,62%) and n-octyl acetate (14,12%), while bornyl acetate (8,08%), n-octanol (5,82%), kessane (4,26%) and β-selinene (4,25%) were present in the highest percentage in A. pancicii essential oil. The results of tentative analysis of methanol extracts of selected species, using HPLC-DAD/ESI-ToF-MS system, were described for the first time in this work. The identification of secondary metabolites of these samples was based on molecular formulas obtained by Mass Hunter Workstation software and based on literature data on the composition of the respective genera and other species from Apiaceae family...