Mono- and bis-1,2,3-triazolyl derivatives of benzimidazo[1,2-a]quinolines: synthesis and biological evaluations

Benzimidazo[1,2-a]kinolini su tetraciklički heteroaromatski spojevi s izraženom biološkom aktivnošću. U ovom radu priređeni su njihovi novi mono- i bis-1,2,3-triazolilni derivati i ispitana je njihova antitumorska aktivnost. Prekursor 5 za sintezu azida priređen je sintezom u tri stupnja. Azidi 6 i 7 izolirani su kao smjesa te su takvi korišteni za sintezu ciljanih spojeva Huisgenovom 1,3-dipolarnom cikloadicijom s raznim alkinima (8–13). Reakcije su provedene prema načelima click kemije, korištenjem bakrovog acetata monohidrata u metanolu pri čemu su izolirani 1,2,3-triazolilni derivati benzimidazo[1,2-a]kinolina (14–25). Strukture priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom. Biološka aktivnost ispitana je na staničnim linijama karcinoma debelog crijeva (HCT116), karcinoma dojke (MCF-7) i karcinoma pluća (H460). Mono-1,2,3-triazolilni derivati pokazali su izraženiju antitumorsku aktivnost od odgovarajućih bis-1,2,3-triazolnih analoga. Derivati benzimidazo[1,2-a]kinolina 18 i 19 koji sadrže 3-klorpropilni i 2-hidroksietilni lanac na triazolu pokazuju antiproliferativnu aktivnost u nanomolarnim koncentracijama.Benzimidazo[1,2-a]quinolines are tetracyclic heteroaromatic compounds with pronounced biological activity. In this work, their new mono- and bis-1,2,3-triazolyl derivatives are prepared and their antitumor activity was evaluated. Precursor 5 for the azide synthesis was prepared by three-step synthesis. Azides 6 and 7 were isolated as mixture and they were used for the synthesis of target compounds by Huisgen's 1,3-dipolar cycloaddition with various alkynes (8–13). The reaction was carried out according to the principles of click chemistry, using copper acetate monohydrate in methanol, whereby 1,2,3-triazolyl derivatives of benzimidazo[1,2-a]quinoline (14–25) were isolated. The structures of the prepared compounds were confirmed by the 1H and 13C NMR spectroscopy. Biological activity was evaluated on colon cancer (HCT116), breast cancer (MCF-7) and lung cancer (H460) cell lines. Mono-1,2,3-triazolyl derivatives showed more pronounced antitumor activity compared to corresponding bis-1,2,3-triazolyl analogs. Benzimidazo[1,2-a]quinoline derivatives 18 and 19 with chloropropyl and hydroxyethyl side-chain at 1,2,3-triazole ring exhibit antiproliferative activity at nanomolar concentrations

Mono- and bis-1,2,3-triazolyl derivatives of benzimidazo[1,2-a]quinolines: synthesis and biological evaluations

Benzimidazo[1,2-a]kinolini su tetraciklički heteroaromatski spojevi s izraženom biološkom aktivnošću. U ovom radu priređeni su njihovi novi mono- i bis-1,2,3-triazolilni derivati i ispitana je njihova antitumorska aktivnost. Prekursor 5 za sintezu azida priređen je sintezom u tri stupnja. Azidi 6 i 7 izolirani su kao smjesa te su takvi korišteni za sintezu ciljanih spojeva Huisgenovom 1,3-dipolarnom cikloadicijom s raznim alkinima (8–13). Reakcije su provedene prema načelima click kemije, korištenjem bakrovog acetata monohidrata u metanolu pri čemu su izolirani 1,2,3-triazolilni derivati benzimidazo[1,2-a]kinolina (14–25). Strukture priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom. Biološka aktivnost ispitana je na staničnim linijama karcinoma debelog crijeva (HCT116), karcinoma dojke (MCF-7) i karcinoma pluća (H460). Mono-1,2,3-triazolilni derivati pokazali su izraženiju antitumorsku aktivnost od odgovarajućih bis-1,2,3-triazolnih analoga. Derivati benzimidazo[1,2-a]kinolina 18 i 19 koji sadrže 3-klorpropilni i 2-hidroksietilni lanac na triazolu pokazuju antiproliferativnu aktivnost u nanomolarnim koncentracijama.Benzimidazo[1,2-a]quinolines are tetracyclic heteroaromatic compounds with pronounced biological activity. In this work, their new mono- and bis-1,2,3-triazolyl derivatives are prepared and their antitumor activity was evaluated. Precursor 5 for the azide synthesis was prepared by three-step synthesis. Azides 6 and 7 were isolated as mixture and they were used for the synthesis of target compounds by Huisgen's 1,3-dipolar cycloaddition with various alkynes (8–13). The reaction was carried out according to the principles of click chemistry, using copper acetate monohydrate in methanol, whereby 1,2,3-triazolyl derivatives of benzimidazo[1,2-a]quinoline (14–25) were isolated. The structures of the prepared compounds were confirmed by the 1H and 13C NMR spectroscopy. Biological activity was evaluated on colon cancer (HCT116), breast cancer (MCF-7) and lung cancer (H460) cell lines. Mono-1,2,3-triazolyl derivatives showed more pronounced antitumor activity compared to corresponding bis-1,2,3-triazolyl analogs. Benzimidazo[1,2-a]quinoline derivatives 18 and 19 with chloropropyl and hydroxyethyl side-chain at 1,2,3-triazole ring exhibit antiproliferative activity at nanomolar concentrations

Mono- and bis-1,2,3-triazolyl derivatives of benzimidazo[1,2-a]quinolines: synthesis and biological evaluations

Benzimidazo[1,2-a]kinolini su tetraciklički heteroaromatski spojevi s izraženom biološkom aktivnošću. U ovom radu priređeni su njihovi novi mono- i bis-1,2,3-triazolilni derivati i ispitana je njihova antitumorska aktivnost. Prekursor 5 za sintezu azida priređen je sintezom u tri stupnja. Azidi 6 i 7 izolirani su kao smjesa te su takvi korišteni za sintezu ciljanih spojeva Huisgenovom 1,3-dipolarnom cikloadicijom s raznim alkinima (8–13). Reakcije su provedene prema načelima click kemije, korištenjem bakrovog acetata monohidrata u metanolu pri čemu su izolirani 1,2,3-triazolilni derivati benzimidazo[1,2-a]kinolina (14–25). Strukture priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom. Biološka aktivnost ispitana je na staničnim linijama karcinoma debelog crijeva (HCT116), karcinoma dojke (MCF-7) i karcinoma pluća (H460). Mono-1,2,3-triazolilni derivati pokazali su izraženiju antitumorsku aktivnost od odgovarajućih bis-1,2,3-triazolnih analoga. Derivati benzimidazo[1,2-a]kinolina 18 i 19 koji sadrže 3-klorpropilni i 2-hidroksietilni lanac na triazolu pokazuju antiproliferativnu aktivnost u nanomolarnim koncentracijama.Benzimidazo[1,2-a]quinolines are tetracyclic heteroaromatic compounds with pronounced biological activity. In this work, their new mono- and bis-1,2,3-triazolyl derivatives are prepared and their antitumor activity was evaluated. Precursor 5 for the azide synthesis was prepared by three-step synthesis. Azides 6 and 7 were isolated as mixture and they were used for the synthesis of target compounds by Huisgen's 1,3-dipolar cycloaddition with various alkynes (8–13). The reaction was carried out according to the principles of click chemistry, using copper acetate monohydrate in methanol, whereby 1,2,3-triazolyl derivatives of benzimidazo[1,2-a]quinoline (14–25) were isolated. The structures of the prepared compounds were confirmed by the 1H and 13C NMR spectroscopy. Biological activity was evaluated on colon cancer (HCT116), breast cancer (MCF-7) and lung cancer (H460) cell lines. Mono-1,2,3-triazolyl derivatives showed more pronounced antitumor activity compared to corresponding bis-1,2,3-triazolyl analogs. Benzimidazo[1,2-a]quinoline derivatives 18 and 19 with chloropropyl and hydroxyethyl side-chain at 1,2,3-triazole ring exhibit antiproliferative activity at nanomolar concentrations

Synthesis of heterocycle and ferrocene conjugates and their metal complexes

Ferocen pripada skupini metalocena te predstavlja značajan farmakofor u medicinskoj kemiji, a njegovi su derivati važni ligandi u koordinacijskoj kemiji. U ovom radu opisana je sinteza novih mono- i bis-ferocenskih derivata aromatskih amina s 1,2,3-triazolnom premosnicom te njihovih metalnih kompleksa. Mono- i bis-propargilirani terminalni alkini (1–3) dobiveni su alkiliranjem 2,2'-dipiridilamina, anilina i 2-aminobenzotiazola s propargil-bromidom u bazičnom mediju, dok su azidni prekursori za klik reakcije 1-azidometilferocen (4), 1-azidoferocen (5) i 1-azidoetilferocen (6) pripravljeni iz odgovarajućih derivata ferocena s natrijevim azidom. Ciljani konjugati ferocena i heterocikla (7–9) sintetizirani su regioselektivnom 1,3-dipolarnom cikloadicijom propargiliranih aromatskih amina (1–3) i ferocenskih azida (4–6). Konjugati ferocena i heterocikla korišteni su kao ligandi u sintezi kompleksa s metalima Zn(II) i Cu(II). Strukture novosintetiziranih derivata potvrđene su spektroskopijom 1H i 13C NMR. Spektroskopska svojstva dobivenih kompleksa istražena su spektroskopijom NMR, UV-Vis i IR. Kristalna struktura Cu(II) kompleksa konjugata ferocena i 2,2'-dipiridilamina povezanih 1,2,3-triazolnom premosnicom određena je difrakcijom X-zraka na monokristalu.Ferrocene belongs to the group of metallocenes and represents a significant pharmacophore in medicinal chemistry along with its derivatives being important ligands in coordination chemistry. In this work, novel mono- and bis-ferrocenyl derivatives connected to aromatic amine through 1,2,3-triazolyl linker and their metal complexes were prepared. Mono- and bis-propargylated terminal alkynes (1–3) were obtained by reaction of 2,2'-dipyridylamine, aniline and 2-aminobenzothiazole with propargyl bromide in a basic media while azide precursors for the „click“ reaction of 1-azidomethylferocene (4), 1-azidoferocene (5) and 1-azidoethylferocene (6) were prepared from corresponding ferrocene derivatives and sodum azide. Conjugates of ferrocene and heterocycles (7–9) were prepared by the Huisgen 1,3-dipolar cycloaddition of propargylated aromatic amines (1–3) and ferrocene azides (4–6). The reactions were performed using copper(II) acetate in methanol as a source of Cu(I) ionsConjugates of ferrocene and heterocycles were used as ligands in the synthesis of Zn(II) and Cu(II) metal complexes. The structures of the newly synthesized derivatives were confirmed by 1H and 13C NMR spectroscopy. The spectroscopic properties of the obtained complexes were investigated by NMR, UV-Vis and IR spectroscopy. The crystal structure of the Cu(II) complex of ferrocene and 2,2'-dipyridylamine conjugates linked by a 1,2,3-triazole was determined by single-crystal X-ray diffraction

Synthesis of heterocycle and ferrocene conjugates and their metal complexes

Ferocen pripada skupini metalocena te predstavlja značajan farmakofor u medicinskoj kemiji, a njegovi su derivati važni ligandi u koordinacijskoj kemiji. U ovom radu opisana je sinteza novih mono- i bis-ferocenskih derivata aromatskih amina s 1,2,3-triazolnom premosnicom te njihovih metalnih kompleksa. Mono- i bis-propargilirani terminalni alkini (1–3) dobiveni su alkiliranjem 2,2'-dipiridilamina, anilina i 2-aminobenzotiazola s propargil-bromidom u bazičnom mediju, dok su azidni prekursori za klik reakcije 1-azidometilferocen (4), 1-azidoferocen (5) i 1-azidoetilferocen (6) pripravljeni iz odgovarajućih derivata ferocena s natrijevim azidom. Ciljani konjugati ferocena i heterocikla (7–9) sintetizirani su regioselektivnom 1,3-dipolarnom cikloadicijom propargiliranih aromatskih amina (1–3) i ferocenskih azida (4–6). Konjugati ferocena i heterocikla korišteni su kao ligandi u sintezi kompleksa s metalima Zn(II) i Cu(II). Strukture novosintetiziranih derivata potvrđene su spektroskopijom 1H i 13C NMR. Spektroskopska svojstva dobivenih kompleksa istražena su spektroskopijom NMR, UV-Vis i IR. Kristalna struktura Cu(II) kompleksa konjugata ferocena i 2,2'-dipiridilamina povezanih 1,2,3-triazolnom premosnicom određena je difrakcijom X-zraka na monokristalu.Ferrocene belongs to the group of metallocenes and represents a significant pharmacophore in medicinal chemistry along with its derivatives being important ligands in coordination chemistry. In this work, novel mono- and bis-ferrocenyl derivatives connected to aromatic amine through 1,2,3-triazolyl linker and their metal complexes were prepared. Mono- and bis-propargylated terminal alkynes (1–3) were obtained by reaction of 2,2'-dipyridylamine, aniline and 2-aminobenzothiazole with propargyl bromide in a basic media while azide precursors for the „click“ reaction of 1-azidomethylferocene (4), 1-azidoferocene (5) and 1-azidoethylferocene (6) were prepared from corresponding ferrocene derivatives and sodum azide. Conjugates of ferrocene and heterocycles (7–9) were prepared by the Huisgen 1,3-dipolar cycloaddition of propargylated aromatic amines (1–3) and ferrocene azides (4–6). The reactions were performed using copper(II) acetate in methanol as a source of Cu(I) ionsConjugates of ferrocene and heterocycles were used as ligands in the synthesis of Zn(II) and Cu(II) metal complexes. The structures of the newly synthesized derivatives were confirmed by 1H and 13C NMR spectroscopy. The spectroscopic properties of the obtained complexes were investigated by NMR, UV-Vis and IR spectroscopy. The crystal structure of the Cu(II) complex of ferrocene and 2,2'-dipyridylamine conjugates linked by a 1,2,3-triazole was determined by single-crystal X-ray diffraction

Synthesis of heterocycle and ferrocene conjugates and their metal complexes

Ferocen pripada skupini metalocena te predstavlja značajan farmakofor u medicinskoj kemiji, a njegovi su derivati važni ligandi u koordinacijskoj kemiji. U ovom radu opisana je sinteza novih mono- i bis-ferocenskih derivata aromatskih amina s 1,2,3-triazolnom premosnicom te njihovih metalnih kompleksa. Mono- i bis-propargilirani terminalni alkini (1–3) dobiveni su alkiliranjem 2,2'-dipiridilamina, anilina i 2-aminobenzotiazola s propargil-bromidom u bazičnom mediju, dok su azidni prekursori za klik reakcije 1-azidometilferocen (4), 1-azidoferocen (5) i 1-azidoetilferocen (6) pripravljeni iz odgovarajućih derivata ferocena s natrijevim azidom. Ciljani konjugati ferocena i heterocikla (7–9) sintetizirani su regioselektivnom 1,3-dipolarnom cikloadicijom propargiliranih aromatskih amina (1–3) i ferocenskih azida (4–6). Konjugati ferocena i heterocikla korišteni su kao ligandi u sintezi kompleksa s metalima Zn(II) i Cu(II). Strukture novosintetiziranih derivata potvrđene su spektroskopijom 1H i 13C NMR. Spektroskopska svojstva dobivenih kompleksa istražena su spektroskopijom NMR, UV-Vis i IR. Kristalna struktura Cu(II) kompleksa konjugata ferocena i 2,2'-dipiridilamina povezanih 1,2,3-triazolnom premosnicom određena je difrakcijom X-zraka na monokristalu.Ferrocene belongs to the group of metallocenes and represents a significant pharmacophore in medicinal chemistry along with its derivatives being important ligands in coordination chemistry. In this work, novel mono- and bis-ferrocenyl derivatives connected to aromatic amine through 1,2,3-triazolyl linker and their metal complexes were prepared. Mono- and bis-propargylated terminal alkynes (1–3) were obtained by reaction of 2,2'-dipyridylamine, aniline and 2-aminobenzothiazole with propargyl bromide in a basic media while azide precursors for the „click“ reaction of 1-azidomethylferocene (4), 1-azidoferocene (5) and 1-azidoethylferocene (6) were prepared from corresponding ferrocene derivatives and sodum azide. Conjugates of ferrocene and heterocycles (7–9) were prepared by the Huisgen 1,3-dipolar cycloaddition of propargylated aromatic amines (1–3) and ferrocene azides (4–6). The reactions were performed using copper(II) acetate in methanol as a source of Cu(I) ionsConjugates of ferrocene and heterocycles were used as ligands in the synthesis of Zn(II) and Cu(II) metal complexes. The structures of the newly synthesized derivatives were confirmed by 1H and 13C NMR spectroscopy. The spectroscopic properties of the obtained complexes were investigated by NMR, UV-Vis and IR spectroscopy. The crystal structure of the Cu(II) complex of ferrocene and 2,2'-dipyridylamine conjugates linked by a 1,2,3-triazole was determined by single-crystal X-ray diffraction

Monometallic and heterobimetallic complexes of N-heterocycles – synthesis, structural characterization and biological evaluation

U 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

Monometallic and heterobimetallic complexes of N-heterocycles – synthesis, structural characterization and biological evaluation

U 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

Monometallic and heterobimetallic complexes of N-heterocycles – synthesis, structural characterization and biological evaluation

U 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

Green solvent-free synthesis of new N-heterocycle-L-ascorbic acid hybrids and their antiproliferative evaluation

The authors’ aim was to improve the application of copper-catalyzed azide-alkyne cycloaddition in the synthesis of hybrids containing biologically significant nucleobases and L-ascorbic acid scaffolds by introducing an environmentally friendly and waste-free ball mill. Results: Two series of hybrids with a purine, pyrrolo[2,3-d]pyrimidine or 5-substituted pyrimidine attached to 2,3-dibenzyl-L-ascorbic acid via a hydroxyethyl- (15a–23a) or ethylidene-1,2,3-triazolyl (15b–23b) bridge were prepared by ball milling and conventional synthesis. The unsaturated 6-chloroadenine L-ascorbic acid derivative 16b can be highlighted as a lead compound and showed strong antiproliferative activity against HepG2 (hepatocellular carcinoma) and SW620 (colorectal adenocarcinoma) cells. Conclusion: Mechanochemical synthesis was superior in terms of sustainability, reaction rate and yield, highlighting the advantageous applications of ball milling over classical reactions