Annulations of heterocyclic compounds and their application in synthesis of natural compounds

Cilj ove doktorske teze bio je razvoj nove sinteze protoberberinskih derivata, policikličnih jedinjenja koja sadrže izohinolinski skelet. Protoberberini predstavljaju široko rasprostranjenu, važnu grupu izohinolinskih alkaloida. Zahvaljujući njihovim izraženim farmakološkim osobinama interes za ovu grupu jedinjenja je u stalnom porastu. Novi sintetski put koji omogućuje pristup različitim klasama protoberberina baziran je na dobijanju zajedničkog intermedijera, 1,3-diena izohinolinske strukture. Diels-Alderovom reakcijom sa različitim dienofilima i oksidacijom nastalih cikloadukata omogućena je instalacija prstena C u različitim oksidacionim stanjima kao i dodatnih supstituenata potrebnih za funkcionalizaciju prstena D protoberberina. Na ovaj način dobijene su dve vrste skeleta prirodnih proizvoda, tetrahidroprotoberberinski i oksoprotoberberinski. Ova sintetska metodologija pokazala se primenljivom i na dihidro-β-karbolin i piridin. Alkaloidi koji su derivati β-karbolina su jedinjenja koja pokazuju veoma širok spektar bioloških aktivnosti, tako da postoji interes za razvoj metodologije za funkcionalizaciju ovog heterocikličnog jedinjenja. Polazeći od dihidro-β-karbolina, preko odgovarajućeg intermedijernog 1,3- diena, dobijene su dve klase jedinjenja, ketojobirinska i dihidrogambirtaninska. Piridin se takoñe pokazao pogodnim za ovu vrstu anelacija, pri čemu su dobijene benzohinolizinske strukture, slične nekim biološki aktivnim jedinjenjima. Ispitivano je in vitro citotoksično dejstvo nekih sintetisanih izohinolinskih i β- karbolinskih derivata na maligne ćelijske linije (FemX, HeLa, K562). Najznačajniju citotoksičnu aktivnost od ispitivanih jedinjenja pokazao je izohinolinski cikloadukt 2.17 prema K562 ćelijama (IC50=24,7 μM) Pored ovoga, ispitivana je funkcionalizacija 1,3-dienskog sistema paladijumom katalizovanim reakcijama, što je omogućilo dobijanje alilnih acetata sa izohinolinskom i β-karbolinskom strukturom...The aim of this thesis was the development of a synthetic route for protoberberine derivatives, polycyclic compounds containing the isoquinoline skeleton. The protoberberines are widespread, important group of isoquinoline alkaloids. Due to the potent pharmacological properties they have attracted an attention from medicinal chemist and drug researchers. Our proposed synthetic route enabling access to different classes of protoberberines is based on a common intermediate, an isoquinolinic 1,3-diene. The incorporation of ring C in various oxidative states, as well as the incorporation of additional substituents necessary for the functionalisation of ring D of protoberberines was achieved through Diels-Alder reactions with different dienophiles and the subsequent oxidation of the resulting cycloadducts. Two types of natural products' skeletons, tetrahydroprotoberberines and oxoprotoberberines were efficiently synthesised using this approach. This synthetic methodology proved to be applicable in the preparation of dihydro-β-carbolines and pyridines. Alkaloids derived of β-carboline are important compounds with a broad spectrum of biological activities. Starting with dihydro-β-carboline, through the corresponding intermediary 1,3- diene, ketoyobirines and dihydrogambirtanines were obtained. Pyridine had also shown amenable to these types of annulations, giving benzoquinolizine structures. In vitro cytotoxic activity of some synthetised isoquinolines and β-carbolines was investigated (FemX, HeLa, K562). Cycloadduct 2.17 shows the greatest cytotoxic activity of the compounds tested, with IC50 value of 24,7 μM towards K562 cells. In addition to this, the possibility of functionalization of 1,3-diene system in Pdcatalysed reaction was also explored, enabling access to different allylic acetates with isoquinoline and β-carboline structure..

Supplementary data for article: Husinec, S.; Savić, V.; Simić, M. R.; Tešević, V.; Vidovic, D. Annulations of Isoquinoline and Beta-Carboline Ring Systems: Synthesis of 8-Oxoprotoberberine Derivatives. Tetrahedron Letters 2011, 52 (21), 2733–2736. https://doi.org/10.1016/j.tetlet.2011.03.085

Supplementary material for: [https://doi.org/10.1016/j.tetlet.2011.03.085]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1342

Supplementary data for article: Husinec, S.; Savić, V.; Simić, M. R.; Tešević, V.; Vidovic, D. Annulations of Isoquinoline and Beta-Carboline Ring Systems: Synthesis of 8-Oxoprotoberberine Derivatives. Tetrahedron Letters 2011, 52 (21), 2733–2736. https://doi.org/10.1016/j.tetlet.2011.03.085

Supplementary material for: [https://doi.org/10.1016/j.tetlet.2011.03.085]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1342

Supplementary data for article: Tasić, G.; Simić, M. R.; Popovic, S.; Husinec, S.; Maslak, V.; Savić, V. Indirect N-Vinylation of Indoles via Isomerisation of N-Allyl Derivatives: Synthesis of (+/-)-Debromoarborescidine B. Tetrahedron Letters 2013, 54 (34), 4536–4539. https://doi.org/10.1016/j.tetlet.2013.06.069

Supplementary material for: [https://doi.org/10.1016/j.tetlet.2013.06.069]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1382

Supplementary data for the article: Mesarović, J.; Srdić, J.; Mladenović-Drinić, S.; Dragičević, V.; Simić, M.; Brankov, M.; Milojković-Opsenica, D. Evaluation of the Nutritional Profile of Sweet Maize after Herbicide and Foliar Fertilizer Application. J. Cereal Sci. 2019, 87, 132–137. https://doi.org/10.1016/j.jcs.2019.03.017

Supplementary material for: [https://doi.org/10.1016/j.jcs.2019.03.017]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2870]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/2978

Supplementary data for article: Mandić, B. M.; Vlajić, M. D.; Trifunović, S. S.; Simić, M. R.; Vujisić, L. V.; Vučković, I. M.; Novaković, M. M.; Nikolić-Mandić, S. D.; Tešević, V. V.; Vajs, V. V.; et al. Optimisation of Isolation Procedure for Pyrrolizidine Alkaloids from Rindera Umbellata Bunge. Natural Product Research 2015, 29 (9), 887–890. https://doi.org/10.1080/14786419.2014.991929

Supplementary material for: [https://doi.org/10.1080/14786419.2014.991929]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1692

Pyrrolizidine Alkaloids and Fatty Acids from the Endemic Plant Species Rindera umbellata and the Effect of Lindelofine-N-oxide on Tubulin Polymerization

The examination of the aerial parts, roots, and seeds of the endemic plant Rindera umbellata is reported in this paper for the first time. Phytochemical investigation of R. umbellata led to the isolation and characterization of ten pyrrolizidine alkaloids and eleven fatty acids in the form of triglycerides. Pyrrolizidine alkaloids 1-9 were found in the aerial parts, 7 and 8 in the roots, and 6-10, together with eleven fatty acids, in the seeds of this plant species. The structures of compounds 1-10 were established based on spectroscopic studies (H-1- and C-13-NMR, 2D NMR, IR and CI-MS). After trans-esterification, methyl esters of the fatty acids were analyzed using GC-MS. The effect of lindelofine-N-oxide (7) on tubulin polymerization was determined

Supplementary data for article: Mandić, B. M.; Vlajić, M. D.; Trifunović, S. S.; Simić, M. R.; Vujisić, L. V.; Vučković, I. M.; Novaković, M. M.; Nikolić-Mandić, S. D.; Tešević, V. V.; Vajs, V. V.; et al. Optimisation of Isolation Procedure for Pyrrolizidine Alkaloids from Rindera Umbellata Bunge. Natural Product Research 2015, 29 (9), 887–890. https://doi.org/10.1080/14786419.2014.991929

Supplementary material for: [https://doi.org/10.1080/14786419.2014.991929]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1692

Water-induced isomerism of salicylaldehyde and 2-acetylpyridine mono- and bis-(thiocarbohydrazones) improves the antioxidant activity: spectroscopic and DFT study

Thiocarbohydrazones (TCHs) and structurally related molecules are versatile organic compounds which exert antioxidant, anticancer, and other beneficial health effects. The combination of UV/Vis, NMR spectroscopy, and quantum chemical calculations was used to rationalize the experimentally observed increase in the radical scavenging activity upon the addition of water in DMSO solution of TCHs. Mono- and bis(salicylaldehyde) TCHs (compounds 1 and 2) undergo water-induced E-to-Z isomerization which is followed by disruption of intramolecular hydrogen bond, ground state destabilization, and 11 kcal/mol decrease in the bond dissociation enthalpy (BDE). Electron spin delocalization is more pronounced in Z-isomers of 1 and 2. On the other hand, 2-acetylpyridine TCHs (compounds 3 and 4) undergo thione-to-thiol tautomerism which also decreases the BDE and facilitates the hydrogen atom transfer to 2,2-diphenyl-1-picrylhydrazyl radical (DPPH.). The appearance of thiolic -SH group as another reactive site toward free radicals improves the antioxidant activity of 3 and 4. The spin density of 3- and 4-thiol radicals is delocalized over the entire thiocarbohydrazide moiety compared to more localized spin of thione radicals. Additional stabilization of thiol radicals corroborates with the increased antioxidant activity. This study provides the new insights on the solution structure of TCHs, and also highlights the importance of solution structure determination when studying the structure-antioxidant relationships of isomerizable compounds

Supplementary data for the article: Assaleh, M. H.; Božić, A. R.; Bjelogrlić, S.; Milošević, M.; Simić, M.; Marinković, A. D.; Cvijetić, I. N. Water-Induced Isomerism of Salicylaldehyde and 2-Acetylpyridine Mono- and Bis-(Thiocarbohydrazones) Improves the Antioxidant Activity: Spectroscopic and DFT Study. Struct Chem 2019, 30 (6), 2447–2457. https://doi.org/10.1007/s11224-019-01371-4

Supplementary material for: [https://doi.org/10.1007/s11224-019-01371-4]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3846