Sinteza in biološka aktivnost koordinacijskih spojin analogov piritiona

Kladnik, Jerneja (avtor), Turel, Iztok (mentor)

Preučevanje vloge kovinskih ionov v telesu je izjemnega pomena, saj ti uravnavajo mnoge biološke funkcije. Poleg tega so v klinični rabi mnoge zdravilne učinkovine za terapevtske in diagnostične namene, katerih sestavni del struktur so tudi kovinski ioni. Izjemno zanimanje za raziskave na področju koordinacijskih spojin se je začelo v 70. letih prejšnjega stoletja z odobritvijo klinične rabe cisplatina, prve protitumorske učinkovine platine, ki skupaj s še nekaterimi ostalimi kompleksi platine do danes ostaja ena od najpogosteje uporabljenih učinkovin v terapiji raka. Zaradi mnogih neželenih stranskih učinkov in postopnega razvoja odpornosti na komplekse platine pa je njihova uporaba omejena, zato so nujne raziskave na področju novih, izboljšanih protitumorskih zdravilnih učinkovin. Alternativo kompleksom platine med drugim predstavljajo tudi rutenijeve koordinacijske spojine. Trenutno sta v kliničnih testiranjih rutenijev(III) kompleks NKP1339 in rutenijev(II) kompleks TLD1433 z obetavnimi protitumorskimi rezultati. Poleg tega je uporaba rutenijevih kompleksov dobro raziskana tudi za druge terapevtske aplikacije. Sicer pa se rutenijeve koordinacijske spojine, pa tudi drugih prehodnih elementov, zaradi svojih fizikalno-kemijskih lastnosti preučujejo tudi kot fotokatalizatorji tako v bioloških sistemih, še pogosteje pa v organski in anorganski kemiji. V okviru doktorskega študija smo sintetizirali različne organorutenijeve(II) i) klorido, ii) pta (1,3,5-triaza-7-fosfaadamantan) in iii) N-heterociklične karbenske komplekse s piritionom (1-hidroksipiridin-2(1H)-tion) in njegovimi analogi. Poskusili smo tudi s sintezo iv) rutenijevih(II) karbonilnih kompleksov in nadalje pripravili nekatere v) cinkove(II), vi) bakrove(II), vii) nikljeve(II) ter viii) rutenijeve(II) polipiridinske koordinacijske spojine. Kompleksi so bili fizikalno-kemijsko okarakterizirani z NMR, UV-Vis in IR spektroskopijo, HRMS spektrometrijo, CHN elementno analizo ter v primeru ustreznih kristalov z rentgensko difrakcijo na monokristalu. Za določene pripravljene spojine smo preučili njihovo stabilnost v biološko relevantnih vodnih medijih. Organorutenijeve(II) komplekse smo testirali za njihove protitumorske lastnosti kot tudi za njihovo potencialno zdravljenje nevrodegenerativnih bolezni. Poleg tega smo preučili tudi fotooksidacijske in fotoredukcijske katalitske lastnosti nekaterih koordinacijskih spojin s piritionom in njegovimi analogi.

• Jezik: Slovenski jezik
• Ključne besede: (organo)rutenijeve(II) koordinacijske spojine, kompleksi prehodnih kovin, pirition, protitumorska aktivnost, antinevrodegenerativna aktivnost, fotooksidacija, fotoredukcija
• Vrsta gradiva: Doktorsko delo/naloga
• Tipologija: 2.08 - Doktorska disertacija
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Leto izida: 2020
• PID: 20.500.12556/RUL-122265
• COBISS.SI-ID: 41812739
• Datum objave v RUL: 02.12.2020

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Synthesis and biological activity of coordination compounds of pyrithione analogues

Izvleček

In the body metal ions play an important role in the regulation of many biological functions. Besides, there exists numerous active pharmaceutical ingredients (API), containing also metal ions, for various therapeutic and diagnostic applications. The approval of cisplatin in 1970’s, the first platinum-based anticancer drug, which together with some other platinum complexes still remains one of the leading compounds for the cancer treatment, has further triggered tremendous interest for the research of the coordination compounds. However, the application of platinum complexes is limited due to their severe unwanted side effects and development of the drug resistance. Therefore, the design of the improved anticancer APIs is of the utmost importance. Among other compounds ruthenium coordination compounds represent an alternative to such platinum complexes. Ruthenium(III) complex NKP1339 and ruthenium(II) complex TLD1433 have both already entered clinical trials and have shown encouraging anticancer outcomes. Besides, ruthenium complexes are well-researched also for other therapeutic applications. Furthermore, ruthenium coordination compounds as well as other transition metal complexes are often also applied as photocatalysts in biological systems and even more extensively in organic and inorganic chemistry due to their physico-chemical properties. We have prepared various organoruthenium(II) i) chlorido, ii) pta (1,3,5-triaza-7-phosphaadamantane) and iii) N-heterocyclic carbene complexes with pyrithione (1-hydroxypyridine-2(1H)-thione) and its analogues. Additionally, we have performed the synthesis of iv) ruthenium(II) carbonyl complexes and prepared some v) zinc(II), vi) copper(II), vii) nickel(II) and viii) ruthenium(II) polypyridyl coordination compounds. Complexes have been physico-chemically characterized by NMR, UV-Vis and IR spectroscopy, HRMS spectrometry, CHN elemental analysis and in case of the suitable crystals also by single-crystal X-ray diffraction. For certain compounds stability studies in biologically relevant aqueous media were also carried out. Organoruthenium(II) complexes have been characterized for their anticancer properties as well as some of them also for their potential implication for the treatment of neurodegenerative diseases. Besides, for some coordination compounds with pyrithione and its analogues also photooxidative and photoreductive catalytic activity has been examined.

• Ključne besede: (organo)ruthenium(II) coordination compounds, transition metal complexes, pyrithione, anticancer activity, antineurodegenerative activity, photooxidation, photoreduction