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Photocatalytic degradation of torasemid with photocatalyst with torasemide imprinted molecule
No full textFarmaceutici su biološki aktivne molekule koje se koriste za liječenje, dijagnosticiranje ili sprječavanje bolesti u ljudi te kao promotori rasta u veterini. Njihova kontinuirana uporaba i nepropisano odlaganje dovelo je do povećane količine ovih spojeva u otpadnim komunalnim vodama, iz kojih dospijevaju u okoliš, u kojemu reagiraju s drugim tvarima ostavljajući negativne posljedice na organizme i prirodu. Napredne se oksidacijske metode obrade otpadnih voda kontinuirano ispituju, a kombinacija fotokatalitičke razgradnje uz polimer s otiskom molekule kao fotokatalizator novi je pristup ovoj vrsti obrade. Ovaj rad detaljno prikazuje ispitivanje fotokatalitičke razgradnje torasemida uporabom fotokatalizatora s otiskom molekule torasemida (MIP) pri čemu su usporedno sva ispitivanja provedena i na fotokatalizatoru bez otiska molekule torasemida (NIP). Preliminirani eksperimenti uključivali su adsorpciju za utvrđivanje sorpcijskog ponašanja torasemida na MIP i NIP te fotokatalizu, kako bi se utvrdilo kolika se količina torasemida razgradila više u odnosu na proces bez djelovanja UV zračenja. Utjecaj početnog pH otopine i početne koncentracije torasemida u otopini ispitan je u tri kombinacije pH-vrijednosti (4, 7, 10) pri tri početne koncentracije (5, 10, 15 mg L^-1). Najbrža se razgradnja torasemida odvijala pri početnoj koncentraciji torasemida od 5 mg L^-1 i pH-vrijednosti 4. Konstanta brzine razgradnje za MIP iznosila je 0,0105 min^-1, dok je za NIP iznosila 0,0319 min^-1. Mehanizam fotokatalitičke razgradnje ispitan je scavenging testom, a ispitivani hvatači bili su izopropanol, natrijev azid, mravlja kiselina i para-benzokinon. Eksperimenti su pokazali kako hidroksilni radikali imaju dominantnu ulogu u razgradnji torasemida, bilo da se radi o MIP-u ili NIP-u. Utjecaj matice ispitan je u eksperimentima s dodatkom soli uobičajeno prisutnih u vodi (bikarbonati, nitrati, kloridi i huminska tvar) u ultračistu vodu. Svi su ioni pokazali negativan utjecaj na konstantu brzine razgradnje torasemida, kao i smjesa tih iona. Eksperiment ispitivanja utjecaja smjese farmaceutika (amoksicilin, atenolol, sulfametazin, sulfametoksazol, deksametazon, diklofenak) na brzinu razgradnje rezultirao je najvećim utjecajem, tj. najvećim usporenjem razgradnje torasemida. Procjena toksičnosti smjese torasemida i njegovih razgradnih produkata rezultirala je inhibicijom luminiscencije ispitivane biote (Vibrio fischeri). Svi uzorci analizirani su na HPLC-DAD instrumentu.Pharmaceuticals are bioactive molecules used to treat, prevent or diagnose illnesses in human medicine and as growth-promoting agents in veterinary medicine. Their continuous use and unmonitored disposal have led to their increased appearance in wastewaters. In the environment, they tend to react with other substances, negatively affecting organisms and nature. Advanced oxidation processes for wastewater treatment are continuously being investigated, and the combination of photocatalytic degradation with a molecularly imprinted polymer as the photocatalyst represents a novel approach to this type of treatment. This study provides a detailed analysis of the photocatalytic degradation of torasemide using a molecularly imprinted polymer (MIP) as the photocatalyst. All experiments were conducted using a non-imprinted polymer (NIP) in parallel and compared with the given results. Adsorption and photocatalysis as preliminary experiments determined the sorption affinity of torasemide and its degradation ability compared to the process without UV radiation, using MIP and NIP. The effect of the initial pH and concentration of the analyte was tested via combinations of three initial concentrations (5, 10, 15 mg L^-1) and three pH values (4, 7, 10). The fastest rate of torasemide photocatalytic degradation was observed at a pH value of 4 and the initial concentration of 5 mg L^-1. The degradation rate constant at optimum conditions was 0,0105 min^-1 using MIP and 0,0319 min^-1 using NIP. The mechanism of the photocatalytic degradation was determined through the scavening test using isopropanol, sodium azide, formic acid and para-benzoquinone as scavengers. The experiments showed that hydroxyl radicals play a dominant role in the degradation of torasemide, regardless of whether MIP or NIP was used. The matrix effect was studied using four different salts (bicarbonates, nitrates, chlorides and humic acids), usually present in wastewater. All salts, including their mixture, slowed down the degradation process. The effect of pharmaceutical mixture (amoxicillin, atenolol, sulfamethazine, sulfamethoxazole, dexamethasone, diclofenac) was also investigated and resulted in the slowest rate of all experiments. The toxicity assessment of the mixture of torasemide and its degradation products showed a an inhibition effect on luminescence of the tested biota (Vibrio fischeri). All samples were analyzed using an HPLC-DAD instrument
Synthesis and characterization of SnO2 quantum dots
No full textU ovom radu istraživana je priprava SnO2 kvantnih točaka hidrolizom i oksidacijom SnCl2·2H2O u vodenoj otopini u prisutnosti tioureje kao akceleratora reakcije. Završetkom sinteze nastala suspenzija SnO2 je centrifugirana te se istaloženi i osušeni produkt
(SnO2 prah) analizirao različitim metodama. Neke od metoda analize korištene u ovom radu jesu rendgenska difrakcija na prahu (PXRD), energijski razlučujuća rendgenska spektroskopija (EDS), pretražna elektronska mikroskopija (SEM), mikroskopija atomskih sila (AFM) i UV – Vis difuzna refleksijska spektrometrija (DRS). Dispergiranjem SnO2 praha u sintetičkom baznom ulju pripravljena je suspenzija za analizu pomoću dinamičkog raspršenja svjetlosti (DLS), a dispergiranjem SnO2 praha u vodi suspenzija za fluorescencijsku spektroskopiju. Provedenim analizama dobiveni su podaci o veličini kristalita, čestica te morfologiji i drugim svojstvima dobivenog produkta. Ovisno o metodi i uvjetima sinteze utvrđeno je da veličina pripravljenih kvantnih točaka SnO2 iznosi 2-5 nm.In this work the preparation of SnO2 quantum dots was investigated. The synthesis path through hydrolysis and oxidation of SnCl2 x 2H2O in an aqueous solution in the presence of thiourea as a reaction accelerator is utilized. Upon the completion of synthesis, the resulting SnO2 suspension was centrifuged and dried. The precipitated product (SnO2 powder) was analyzed using powder X-ray diffraction (PXRD), energy-dispersive X-ray spectroscopy (EDS), scanning electron microscopy (SEM), atomic force microscopy (AFM), and UV-Vis diffuse reflectance spectroscopy (DRS). By dispersing the SnO2 powder in a synthetic base oil, a suspension was prepared for analysis using dynamic light scattering (DLS), while dispersing the SnO2 powder in water resulted in a suspension for fluorescence spectroscopy. Through these analyses, crystallite and particle size, as well as morphology and other properties of the obtained product was determined. The size of the SnO2 quantum dots was determined to be in the range of 2-5 nm, depending on the method and various synthesis conditions used
Synthesis and biological activity of N-substituted benzoxazole
No full textU ovom radu opisana je sinteza novih derivata 2-benzoksazolinona u svrhu ispitivanja njihove biološke aktivnosti. Reakcijom nukleofilne supstitucije 5-supstituiranih 2-aminofenola i
1,1`-karbonildiimidazolom u tetrahidrofuranu pripravljeni su 5-supstituirani benzo[d]oksazol-2-oni (1a–c). 5-supstituirani N-propargilbenzo[d]oksazol-2-oni (2a–c) priređeni su reakcijom propargiliranja 5-supstituiranih benzo[d]oksazol-2-ona (1a–c) s propargil-bromidom u acetonu uz prisustvo kalijeva karbonata kao baze. Različito supstituirani 1-azidobenzeni (3a–e) potrebni za klik reakciju sintetizirani su reakcijom odgovarajućih supstituiranih anilina s natrijevim azidom u vodenoj otopini natrijeva nitrita. Huisgenovom 1,3-dipolarnom cikloadicijom kataliziranom bakrom N-propargiliranih benzoksazolona (2a–c) i odgovarajućih azidobenzena (3a–e) dobiveni su ciljani derivati benzoksazolinona supstituirani 1,2,3-triazolnim prstenom (4a–8c). Strukture sintetiziranih spojeva potvrđene su spektroskopijom 1H- i 13C-NMR.This paper describes the synthesis of new 2-benzoxazolinone derivatives with the aim of evaluating their biological activity. 5-substituted benzo[d]oxazol-2-ones (1a–c) were obtained by nucleophylic reaction of 5-substituted 2-aminophenols with 1,1`-carbonyldiimidazole in the tetrahydrofuran. 5-substituted N-propargylbenzo[d]oxazol-2-ones (2a–c) were prepared by the propargylation reaction of 5-substituted benzo[d]oxazol-2-ones (1a–c) with propargyl bromide in the acetone and in the presence of potassium carbonate as a base. Differently substituted 1-azidobenzenes (3a–e) were synthesized using corresponding substituted anilines with sodium azide in an aqueous solution of sodium nitrite. Finally, targeted benzoxazolinone derivatives substituted with 1,2,3-triazole ring (4a–8c) were prepared by copper catalyzed Huisgen's 1,3-dipolar cycloaddition reaction of N-propargylated benzoxazolones (2a–c) and corresponding azidobenzenes (3a–e). The structures of the synthesized compounds were confirmed by 1H- and 13C-NMR spectroscopy
Monometallic and heterobimetallic complexes of N-heterocycles – synthesis, structural characterization and biological evaluation
No full textU okviru disertacije proučavani su N-heterociklički ligandi i njihovi metalni kompleksi. Provedena je sinteza heterocikličkih spojeva, poput derivata piridina, 2,2'-dipiridilamina, benzimidazola i benzotiazola, koji sadrže monodentatne, bidentatne i tridentatne koordinirajuće skupine, te njihovih koordinacijskih kompleksa s prijelaznim metalima. Pripravljeni derivati podijeljeni su u šest klasa. Bidentatni i tridentatni heterociklički ligandi sintetizirani su višestupnjevitom sintezom primjenom konvencionalnih sintetskih metoda i reakcijama „zelene“ kemije potpomognutih mikrovalovima. Strukture ligadana i metalnih kompleksa potvrđene su spetroskopskopijom NMR, IR i UV, te difrakcijom rendgenskog zračenja u jediničnom kristalu, a heterobimetalni kompleksi karakterizirani su voltametrijski te računalnom analizom. Pripravljenim ligandima i metalnim kompleksima ispitano je antiproliferativno djelovanje na niz tumorskih staničnih linija in vitro, kao i na zdrave stanice uz referentne kliničke lijekove. Koordinacija metalom poboljšala je antitumorsku aktivnost i selektivnost u većini slučajeva. Heterobimetalni kompleks konjugata ferocena i
2,2'-dipiridilamina s bakrom(II) [Cu(A8c)2](CF3SO3)2 pokazao je selektivno inhibitorno djelovanje na stanice HeLa, MES-OV, A549 i MDA-MB-231 uz povećanje stanične populacije u fazama staničnog ciklusa S i G2/M. Aktivnost 2,2'-dipiridilaminskih kompleksa poboljšana je koordinacijom s Re(I), pri čemu je najizraženiju aktivnost, bolju u odnosu na cisplatinu, pokazao kompleks [Re(B4a)(CO)3]Cl. Kompleks strukturno fleksibilnijeg
bis(2,2'-pikolil)aminskog liganda i Ni(II), [Ni(C1)2](NO3)2, pokazao je istaknuto antiproliferativno djelovanje ometajući proces replikacije DNK i smanjujući ekspresiju antiapoptotskog markera Bcl-2. Rutenijevi(II) polusendvič kompleksi 2-arilbenzotiazola i 2-pikolila povezani 1,2,3-triazolnom premosnicom imali su antiproliferativno djelovanje u submikromolarnom području, pokazujući selektivnost prema PANC1 stanicama. Konjugati acil-tiourea i benzotiazola te njihovi Ru(II) kompleksi imali su inhibitorno djelovanje u niskom mikromolarnom i nanomolarnom području na stanice H460, MCF-7, SW 620 i HepG2, s izraženim djelovanjem na staničnoj liniji raka dojke (MCF-7). Spojevi su, osim toga, pokazali slabo do umjereno antibakterijsko djelovanje prema E. faecalis. Ligand E5c i kompleksi D4aRu, E4cRu i E5cRu odabrani su za daljnja testiranja mehanizma biološkog djelovanja.In this dissertation, selected N-heterocyclic ligands and their metal complexes were studied. The synthesis of heterocyclic compounds, such as derivatives of pyridine,
2,2'-dipyridylamine, benzimidazole and benzothiazole, containing monodentate, bidentate and tridentate coordinating groups, and their coordination complexes with transition metals was carried out. The prepared derivatives are divided into corresponding six classes. The bidentate and tridentate heterocyclic ligands were synthesized by multi-step synthesis using conventional synthetic methods and „green“ microwave-assisted synthesis. The structures of the ligands and metal complexes were confirmed by NMR, UV and IR-spectroscopy and single-crystal X-ray diffraction. Heterobimetallic complexes were additionally characterized by voltammetry and computational analysis. The prepared ligands and metal complexes were evaluated for their antiproliferative activity in vitro against several tumor cell lines, as well as on normal cells with clinical drugs as references. Generally, metal coordination improved activity and selectivity in most cases. The heterobimetallic complex of ferrocene and
2,2'-dipyridylamine conjugate with copper(II) [Cu(A8c)2](CF3SO3)2 showed a selective inhibitory effect on HeLa, MES-OV, A549 and MDA-MB-231 cells with an increase in cell population in the S and G2/M phase of the cell cycle. The activity of 2,2'-dipyridylamine complexes was improved by coordination with Re(I), where [Re(B4a)(CO)3]Cl showed the most pronounced activity, better than cisplatin. The Ni(II) complex of the more structurally flexible bis(2,2'-picolyl)amine ligand, [Ni(C1)2](NO3)2, showed prominent antiproliferative activity by interfering with the DNA replication process and reducing the expression of the antiapoptotic marker Bcl-2. Ruthenium(II) half-sandwich complexes of 2-arylbenzothiazole and 2-picolyl linked by a 1,2,3-triazole bridge showed antiproliferative activity in the submicromolar range, displaying selectivity towards PANC1 cells. Acyl thiourea and benzothiazole conjugates and their Ru(II) complexes exhibited cytostatic activity in the low micromolar and nanomolar range against H460, MCF-7, SW 620 and HepG2 cells, with prominent activity against the MCF-7 breast cancer cell line. Besides, compounds showed weak to moderate antibacterial activity against E. faecalis. Ligand E5c and complexes D4aRu, E4cRu and E5cRu were selected for further evaluation of their mechanism of biological action
Synthesis and structural characterization of novel benzimidazole and benzothiazole derivatives as potential antiproliferative agents with antioxidative activity
No full textU ovom radu opisana je sinteza nekoliko klasa derivata benzimidazola i benzotiazola kojima je ispitana antiproliferativna i antioksidativna aktivnost. U linearnoj višestupanjskoj sintezi novih konjugata benzazola primijenjeni su klasični sintetski pristupi kao i neke suvremene sintetske metode, uključujući sintezu u ekološki prihvatljivim otapalima ili sintezu potpomognutu mikrovalovima. Novi akrilonitrilni derivati N-supstituiranih derivata benzazola 32‒71 i 77‒107 priređeni su aldolnom kondenzacijom odgovarajućih cijanometilbenzazola s benzaldehidima supstituirani promjenjivim brojem metoksi i hidroksi skupina te 4-N,N-dimetilamino i
4-N,N-dietilamino skupinom. Derivati Schiffovih baza supstituirani benzimidazolom 117‒132 priređeni su kondenzacijom N-supstituiranih 2-aminobenzimidazola 108‒115 s odgovarajućim 4-N,N-dimetilamino i 4-N,N-dietilamino supstituiranim benzaldehidima. Derivati iminokumarina i kumarina 134‒149 te amidino-supstituirani derivati kumarina 164‒175 priređeni su ciklokondenzacijom različito supstituiranih 2-hidroksibenzaldehida s odgovarajućim 2-cijanometilbenzimidazolima, te iz kumarinskih aldehida reakcijom kondenzacije s odgovarajućim 4-amidino-supstituiranim 1,2-fenilendiaminima uz korištenje p-benzokinona kao oksidansa. Amidino-supstituirani benzimidazoli 193‒216 priređeni su kondenzacijom 5-supstituiranih salicilaldehida s odgovarajućim 4-amidino-supstituiranim
1,2-fenilendiaminima. Amidino-supstituirani benzotiazoli 179‒181 i 216‒227 priređeni su iz različito supstituiranih 2-hidroksibenzaldehida i odgovarajućih zwitter iona u ledenoj octenoj kiselini. Metoksi-supstituirani karboksamidi 235‒262 priređeni su kondenzacijom benzoilnih klorida s N-supstituiranim derivatima 2-aminobenzimidazola. Hidroksi-supstituirani amidni derivati N-benzimidazola 263‒268 i 280‒286 priređeni su uklanjanjem zaštitnih metoksi skupina, korištenjem BBr3 na niskim temperaturama, te benzilnih zaštitnih skupina katalitičkim hidrogeniranjem uz Pd/C u metanolu. Amidino-supstituirani derivati benzamida 289‒293 priređeni su kiselo-kataliziranom Pinnerovom reakcijom iz odgovarajućih cijano-supstituiranih polaznih spojeva. Strukture novosintetiziranih spojeva potvrđene su
1H i 13C NMR spektroskopijom, a nekim je spojevima struktura dodatno okarakterizirana i masenom spektrometrijom. Svim priređenim spojevima ispitana je antiproliferativna aktivnost in vitro na niz staničnih linija humanih karcinoma i zdravih stanica, dok je ispitivanje antioksidativne aktivnosti in vitro provedeno primjenom spektroskopskih metoda DPPH, FRAP i ABTS. Amidino-supstituiranim derivatima 164‒175 i 179‒181 ispitana je antiviralna aktivnost in vitro na nekoliko sojeva virusa, te su neki od derivata pokazali jako dobru i selektivnu aktivnost prema pojedinim sojevima virusa. Derivatima Schiffovih baza 117‒132 te amidino-supstituiranim benzazolima 193‒216 i 217‒228 ispitana je i antibakterijska aktivnost prema Gram pozitivnim i Gram negativnim bakterijama. Iz dobivenih rezultata ispitivanja biološke aktivnosti i SAR studije, utvrđeno je da na antioksidativnu aktivnost značajno utječe broj metoksi i hidroksi skupina na fenilnom prstenu, te supstituent na dušikovom atomu benzimidazolne jezgre. Najizraženiji utjecaj na povećanje antiproliferativne aktivnosti pokazuje 4-N,N-dietilamino skupina smještena na položaju 7 kumarinskog prstena i fenilnom prstenu akrilonitrilnih derivata, te izobutilni supstituent na N atomu benzimidazolne jezgre. Nekima od najaktivnijih derivata benzazola dodatno su ispitani mehanizmi biološkog djelovanja, te je tako utvrđeno da neki derivati akrilonitrila i iminokumarina djeluju kao inhibitori polimerizacije tubulina, dok je amidnim derivatima ispitana i antioksidativna aktivnost u stanicama. Dokazano je i da najbolju antivirusnu aktivnost ima kumarinski derivat benzimidazola supstituiran nesupstituiranim amidinom koji inhibira ranu fazu replikacijskog ciklusa virusa, odnosno sintezu virusne RNK.This thesis describes the synthesis of several classes of benzimidazoles and benzothiazoles in order to investigate their antiproliferative and antioxidant activity. By using multi-step linear synthesis of new benzazole conjugates, classical synthetic approaches as well as some modern synthetic methods, including synthesis in environmentally friendly solvents or microwave-assisted synthesis, were applied. New acrylonitrile derivatives of N-substituted benzazoles 32‒71 and 77‒107 were prepared by aldol condensation of the corresponding cyanomethylbenzazoles with benzaldehydes with a variable number of methoxy and hydroxy groups and 4-N,N-dimethylamino and 4-N,N-diethylamino groups. Benzimidazole derived Schiff bases 117‒132 were prepared by condensation of N-substituted 2-aminobenzimidazoles 108‒115 with corresponding 4-N,N-dimethylamino and
4-N,N-diethylamino-substituted benzaldehydes. Iminocoumarin and coumarine derivatives 134‒149 and amidino-substituted coumarine derivatives 164‒175 obtained by cyclocondensation of substituted 2-hydroxybenzaldehydes with corresponding 2-cyanomethylbenzimidazoles as well as from coumarine aldehydes with corresponding 4-amidino-substituted 1,2-phenylenediamines using p-benzoquinone as an oxidant. Amidino-substituted benzimidazoles 193‒216 were synthesized within the condensation of 5-substituted salicylaldehydes with corresponding 4-amidino-substituted
1,2-phenylenediamines. Amidino-substituted benzothiazoles 179‒181 i 216‒227 were prepared by condensation of differently substituted 2-hydroxybenzaldehydes and corresponding zwitter ions in glacial acetic acid. Methoxy-substituted carboxamides 235‒262 were prepared by condensation of benzoyl chlorides with N-substituted 2-aminobenzimidazole derivatives. Hydroxy-substituted amide derivatives of N-benzimidazole 263‒268 and 280‒286 obtained by removing protective methoxy groups, using BBr3 at low temperatures, and benzyl protective groups by catalytic hydrogenation with Pd/C in methanol. Amidino-substituted benzamide derivatives 289‒293 were synthesized via acid-catalyzed Pinner reaction from the corresponding cyano-substituted starting precursors. Structures of all newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy while some of them were additionally characterized by mass spectrometry. All prepared compounds were tested for their antiproliferative activity in vitro on a number of human cancer cell lines as well as normal fibroblasts, while antioxidant activity in vitro was performed using spectroscopic DPPH, FRAP and ABTS methods. Amidino-substituted derivatives 164‒175 and 179‒181 were tested for antiviral activity in vitro on several virus strains, and some compounds have shown pronounced and selective activity against some viruses. Schiff base derived benzazoles 117‒132 and amidino-substituted benzazoles 193‒216 and 217‒228 were tested for antibacterial activity against Gram positive and Gram negative bacteria. Results obtained from evaluation of biological activity and SAR studies, revealed that the antioxidant activity is affected by the number of methoxy and hydroxy groups on the phenyl ring as well as the substituent on the nitrogen atom of the benzimidazole nucleus. The strongest impact on the enhancement of antiproliferative activity was observed by 4-N,N-diethylamino group placed at the position 7 on coumarin ring and phenyl ring of acrylonitrile derivatives. The isobutyl substituent on the N atom of the benzimidazole core has the greatest influence on increasing the activity of the synthesized compounds. Some of the most active benzazole derivatives were additionally evaluated to study their mechanisms of biological action and it was confirmed that some of the acrylonitrile and iminocoumarin derivatives have proven to be tubuline polymerization inhibitors, while for amide derivatives the antioxidative activity was tested also in the cells. It has been proven that the most promising antiviral activity has been possessed by coumarine derived benzimidazole substituted with amidine group, being inhibitor of an early step in the replication cycle of virus, respectively the synthesis of viral RNA
Synthesis of novel coumarin-isoxazole hybrids with potential antitumor activity
No full textCilj ovog rada bio je sintetizirati i spektroskopski okarakterizirati nove hibride kumarina i izoksazola s potencijalnim antitumorskim djelovanjem. Spojevi (6a−h) su sintetizirani bazno kataliziranom reakcijom 1,3-dipolarne cikloadicije O-alkiliranog derivata kumarina (2) i kloriranih oksima (5a−h). Spoj 2 pripravljen je propargiliranjem 4-hidroksikumarina (1). Klorirani oksimi (5a−h) sintetizirani su kloriranjem benzaldehidoksima (4a−h) s N-klorsukcinimidom. Strukture spojeva potvrđene su spektroskopijom 1H i 13C NMR. U tijeku je ispitivanje antitumorske aktivnosti novosintetiziranih spojeva.The aim of this work was to synthesize and spectroscopically characterize new coumarine-isoxazole hybrids with potential anticancer activity. Compounds (6a−h) were synthesized by the base-catalyzed 1,3-dipolar cycloaddition from O-alkylated coumarine derivative (2) and chlorinated oximes (5a−h). Compound 2 was prepared by propargylation of 4-hydroxycoumarine (1). Chlorinated oximes (5a−h) were synthesized from benzaldehyde oximes (4a−h) with N-chlorosuccinimide. The structures of compounds were confirmed by
1H and 13C NMR spectroscopy. Anticancer evaluations of the newly synthesized compounds are in progress
Metal complexes of bis-1,2,3-triazole ligands with various central heteroatoms
No full text1,2,3-triazol predstavlja bitan farmakofor u dizajnu lijekova, a njegovi derivati stvaraju koordinativno-kovalentne veze s metalnim ionima što ih čini dobrim kandidatima u području anorganske medicinske kemije. U ovom radu opisana je sinteza simetričnih triazolnih tridentatnih liganada te njihovih metalnih kompleksa. Sinteza liganada provedena je regioselektivnom reakcijom 1,3-dipolarne cikloadicije dipropargilamina, dipropargil-etera i dipropargil-sulfida s aromatskim azidima kataliziranom bakrom(I). Strukture svih pripravljenih liganada potvrđene su spektroskopijom 1H i 13C NMR te FTIR. Novosintetizirani ligandi 5a–5d, 6a–6d i 7a–7d korišteni su za sintezu metalnih kompleksa s bakrom(II), cinkom(II), kobaltom(II) i niklom(II). Struktura i stabilnost sintetiziranih kompleksa potvrđena je pomoću spektroskopije UV-Vis i 1H NMR. Za ligand 6b i komplekse [Co(5d)2](NO3)2,
[Cu(6d)2](CF3SO3)2, [Ni(7a)2](BF4)2 i [Ni(7b)2](BF4)2 određene su kristalne strukture pomoću rendgenske difrakcije na jediničnom kristalu. Dobivene kristalne strukture metalnih kompleksa ML2 stehiometrije pokazuju trans-fac stereokemiju.1,2,3-triazole is a significant pharmacophore in drug design, while its derivatives form coordinative-covalent bonds with metal ions, which makes them good candidates in the field of inorganic medicinal chemistry. In this work, the syntheses of symmetric triazole tridentate ligands and their metal complexes were described. The syntheses of ligands were performed by the regioselective reaction of 1,3-dipolar copper(I)-catalyzed cycloaddition of dipropargyl amine, dipropargyl ether and dipropargyl sulfide with aromatic azides. The structures of the prepared ligands were confirmed by infrared spectroscopy and 1H and 13C NMR spectroscopy. The newly synthesized ligands 5a–5d, 6a–6d and 7a–7d were used for the preparation of metal complexes with copper(II), zinc(II), cobalt(II) and nickel(II). The structure and stability of the synthesized complexes were confirmed by UV-Vis and 1H NMR spectroscopy. For ligand 6b and complexes [Co(5d)2](NO3)2, [Cu(6d)2](CF3SO3)2, [Ni(7a)2](BF4)2 and [Ni(7b)2](BF4)2 crystal structures were determined by single-crystal X-ray diffraction. The crystal structures of metal complexes of ML2 stoichiometry show trans-fac stereochemistry
Synthesis of novel C6-substituted purine derivatives using Pd-catalyzed cross-coupling reactions
No full textU ovom radu opisana je sinteza novih C6-supstituiranih purinskih derivata Pd-kataliziranim reakcijama unakrsnog spajanja. N-9 propargilirani derivati purina 1a i 1b priređeni su reakcijom N-alkiliranja. Odgovarajući aldoksim 3 potreban za sintezu izoksazolnih derivata priređen je reakcijom kloriranja piridin-2-aldoksima 2. Novi 2,3-disupstituirani purinski izoksazoli 4a i 4b priređeni su bazno-kataliziranom 1,3-dipolarnom cikloadicijom iz N-9 propargiliranih derivata purina 1a i 1b te kloriranog aldoksima 3. Dobiveni 2,3-disupstituirani purinski izoksazoli 4a i 4b supstituirani su u položaju C-6 uporabom paladij-katalizirane Suzuki-Miyaurine i Sonogashirine reakcije unakrsnog povezivanja. Na taj su način uspješno sintetizirani C6-supstituirani izoksazolni derivati purina 5a, 5b i 6a–d. Nadalje, odabrani
C6-supstituirani izoksazolni derivati purina 5a, 5b i 6b korišteni su kao ligandi za sintezu renij(I) trikarbonilnih kompleksa 7a, 7b i 8. Strukture novosintetiziranih spojeva potvrđene su spektroskopijom 1H i 13C NMR te UV/Vis i IR-spektroskopijom. Antitumorska ispitivanja novosintetiziranih spojeva su u tijeku.In this work the synthesis of novel C6-substituted purine derivatives using Pd-catalyzed cross-coupling reactions is described. N-9 propargylated purine derivatives 1a and 1b were prepared by N-alkylation. The corresponding aldoxime 3 for the synthesis of isoxazole derivatives was synthesized by the chlorination reaction of pyridine-2-aldoxime 2. A novel 2,3-disubstituted purine isoxazole derivatives 4a and 4b were prepared by base-catalyzed 1,3-dipolar cycloaddition of N-9 propargylated purine derivatives 1a and 1b and chlorinated oxime 3. Synthesized 2,3-disubstituted purine-isoxazole derivatives 4a and 4b were functionalized at C-6 position using Pd-catalyzed Suzuki-Miyaura and Sonogashira cross-coupling reaction and so C6-substituted purine-isoxazole derivatives 5a, 5b and 6a–d were synthesized. Selected C6-substituted purine-isoxazole derivatives 5a, 5b and 6b were also used as ligands for the synthesis of rhenium(I) tricarbonyl complexes 7a, 7b and 8.
The structures of all compounds were determined by 1H NMR and 13C NMR spectroscopy as well as by UV/Vis and IR spectroscopy. Anticancer evaluations of novel compounds are in progress
Promiscuous aldol additions of phosphoenolpyruvate to aliphatic and aromatic aldehydes catalysed by PEP-dependent synthases
No full textStvaranje C-C veze ključna je u sintetskoj organskoj kemiji jer povezuje manje podjedinice u složenije molekule. Klasična sinteza zahtijeva sofisticirane asimetrične metode i zaštitu funkcionalnih skupina. Biokatalitička kondenzacija postaje sve zanimljivija jer omogućava dobivanje sterički čistih molekula bez potrebe za zaštitom funkcionalnih skupina. Ovaj rad istražuje neprirodne aldolne adicije fosfoenolpiruvata (PEP) na alifatske i aromatske aldehide, katalizirane PEP-ovisnim aldolazama, fokusirajući se na enzime DHAPH i KDOH iz metagenomske zbirke. Cilj rada bio je optimizirati reakcijske uvjete i ispitati konverziju i enantioselektivnost ovih enzima kako bi se utvrdila njihova primjenjivost u formiranju C-C veze. U eksperimentalnom dijelu, istraženo je 38 enzima iz metagenomske zbirke s različitim aldehidima. Najbolji rezultati postignuti su s enzimom KDOH i aldehidom fenilacetaldehidom, gdje su konverzije dosegle do 92,7 %. Posebno su se istaknuli karbamatni spojevi, s konverzijama koje su prelazile 56,6 %. Optimizacija udjela dimetilformamida (DMF) pokazala je da smanjenje DMF-a povećava enzimske aktivnosti, ali je njegovo potpuno uklanjanje nepoželjno zbog netopivosti aldehida u vodi. DMF udio od 5 % naspram 20 % doveo je do značajnog povećanja konverzije, čak do 44,9 %. Daljnja ispitivanja pročišćenih enzima pokazala su niže stope konverzije u usporedbi s početnim probirom, a neki od razloga mogu biti gubitk stabilizirajućih faktora ili parcijalne denaturacije enzima tijekom pročišćavanja. Također, enantioselektivnost se nije mogla jasno odrediti zbog niske aktivnosti enzima i formiranja nusprodukata umjesto ciljanih produkata reakcije. DHAPH i KDOH enzimi imaju potencijal za daljnju primjenu u formiranju C-C veze, ali su potrebna dodatna istraživanja i optimizacija reakcijskih uvjeta kako bi se postigli zadovoljavajući rezultati.The formation of C-C bonds is crucial in synthetic organic chemistry as it connects smaller subunits into more complex molecules. Sophisticated asymmetric methods and protection of functional groups are required in classical synthesis. Biocatalytic condensation is becoming increasingly interesting as it allows the production of sterically pure molecules without the need for functional group protection. Unnatural aldol additions of phosphoenolpyruvate (PEP) to aliphatic and aromatic aldehydes, catalyzed by PEP-dependent aldolases, are investigated in this study, focusing on DHAPH and KDOH enzymes from a metagenomic library. The aim was to optimize reaction conditions and examine the conversion and enantioselectivity of these enzymes to determine their applicability in C-C bond formation.
In the experimental part, 38 enzymes from the metagenomic library were tested with different aldehydes. The best results were achieved with the KDOH enzyme and phenylacetaldehyde, with conversions reaching up to 92,7 %. Carbamate compounds were particularly notable, with conversions exceeding 56,6 %. Optimization of dimethylformamide (DMF) content showed that reducing DMF increases enzyme activities, but its complete removal is undesirable due to the insolubility of aldehydes in water. A DMF content of 5 % compared to 20% led to a significant increase in conversion, up to 44,9 %. Further testing of purified enzymes showed lower conversion rates compared to initial screening, possibly due to the loss of stabilizing factors or partial denaturation of enzymes during purification. Additionally, enantioselectivity could not be clearly determined due to low enzyme activity and the formation of by-products instead of target reaction products. DHAPH and KDOH enzymes have potential for further application in C-C bond formation, but additional research and optimization of reaction conditions are needed to achieve satisfactory results
Sinteza sijalinskih kiselina potpomognuta reakcijskim inženjerstvom
No full textThis dissertation explores the enzymatic synthesis of sialic acids, particularly Nacetylneuraminic acid and its analogs, by employing sialic acid synthases
N-acetylneuraminic acid synthase from Neisseria meningitidis (NmNeuS) and putative
N-acetylneuraminic acid synthase homolog 5 (PNH5) from Prozomix. Recognizing the limitations of traditional chemical synthesis methods, which often involve environmentally toxic processes and limited scalability, this research investigates biocatalysis as a sustainable alternative. Through rigorous screening of metagenomic enzyme libraries, NmNeuS and PNH5 were identified as key biocatalysts, with each enzyme showing distinct catalytic properties: NmNeuS demonstrated broad substrate tolerance and high efficiency with monosaccharides, notably N-acetyl mannosamine, positioning it as a strong candidate for large-scale sialic acid production. In contrast, PNH5 exhibited a narrower substrate scope limited specificity and activity with monosaccharides, making it suitable for targeted applications with the potential for enhancement through reaction and enzyme engineering. Furthermore, this study examined promiscuous aldol addition reactions catalyzed by
3-deoxy-7-phosphoheptulonate synthase and 3-deoxy-8-phosphooctulonate synthase enzymes, highlighting their capacity for C–C bond formation with a range of aromatic aldehydes. The substantial substrate promiscuity of these enzymes, coupled with their high substrate conversions to select substrates such as benzyloxyacetaldehyde, underscores their utility in synthesizing complex chiral intermediates with potential pharmaceutical applications. Optimization of solvent systems, particularly through DMF concentration adjustments, was shown to significantly influence enzyme activity, marking an important step in fine-tuning reaction conditions for higher yields and improved enantioselectivity. A robust mathematical modeling approach underpinned the reaction engineering strategies in this work, facilitating kinetic parameter estimation and enabling reaction optimization to enhance enzyme performance across various conditions. By integrating these models with experimental data, this research successfully scaled up Neu5Ac synthesis, demonstrating the practical feasibility of biocatalysis for industrial applications. The findings from this dissertation advance the potential for sustainable biocatalytic synthesis of sialic acids and derivatives, paving the way for their application in antiviral, antibacterial, and anticancer therapies.Ovaj doktorski rad istražuje enzimsku sintezu sijalinskih kiselina, posebno Nacetilneuraminske kiseline (Neu5Ac) i njezinih analoga, primjenom sintaza sijalinske kiseline iz mikroorganizma Neisseria meningitidis (NmNeuS) i homologa sintaze sijalinskih kiselina br. 5 (PNH5) dobivenog od Prozomix-a. Uzimajući u obzir ograničenja tradicionalnih metoda kemijske sinteze, koje često uključuju procese štetne za okoliš i ograničenu primjenu, u ovom radu istražuje se biokataliza kao održiva alternativa. Kroz pretraživanje metagenomskih zbirki enzima, NmNeuS i PNH5 identificirani su kao ključni biokatalizatori, pri čemu je svaki enzim pokazao različita katalitička svojstva: NmNeuS je pokazao široku toleranciju na supstrate i visoku učinkovitost s monosaharidima, posebno s N-acetilmanozaminom, što ga čini dobrim kandidatom za proizvodnju Neu5Ac-a u uvećanom mjerilu. Suprotno tome, PNH5 je pokazao uži spektar supstrata, s većom specifičnošću prema heksozama, ali ograničenom aktivnošću prema monosaharidima, što ga čini prikladnim za ciljane primjene s potencijalom za poboljšanje kroz enzimsko inženjerstvo. Nadalje, u ovom istraživanju ispitane su i aldolne adicije katalizirane enzimima 3-deoksi-7-fosfoheptulonat-sintazom i
3-deoksi-7-fosfoheptulonat-sintazom, naglašavajući njihovu sposobnost stvaranja C–C veza s nizom aromatskih aldehida. Značajna promiskuitetnost supstrata kod ovih enzima, u kombinaciji s visokim konverzijama kod odabranih supstrata poput benziloksiacetaldehida, naglašava njihovu korisnost u sintezi složenih kiralnih intermedijera s potencijalnom farmaceutskom primjenom. Optimizacija reakcijskog medija, posebno kroz prilagodbu koncentracije DMF-a, pokazala je značajan utjecaj na aktivnost enzima, čime je postignut važan korak u prilagodbi reakcijskih uvjeta za postizanje visokih iskorištenja i poboljšane enantioselektivnosti. Robustan pristup matematičkog modeliranja naglasio je strategije reakcijskog inženjerstva u ovom radu, olakšavajući procjenu kinetičkih parametara i omogućavajući optimizaciju reakcije za poboljšanje performansi enzima u različitim uvjetima. Validacijom modela na eksperimentalnim podacima, u ovom istraživanju uspješno je provedena sinteza Neu5Ac na uvećanom mjerilu, pokazujući praktičnu izvedivost biokatalize za industrijske primjene. Kinetički modeli ne samo da su usmjerili optimizaciju procesa za sintezu Neu5Ac već su uspostavili okvir primjenjiv i na druge biokatalitičke sustave. Rezultati ove disertacije unapređuju potencijal za održivu biokatalitičku sintezu sijalinskih kiselina i njihovih derivata, otvarajući put za njihovu potencijalnu primjenu u antivirusnim, antibakterijskim i antitumorskim terapijama