Konjugati 1,2,3-triazola i heterocikla: sinteza, antimikrobna i citostatska ispitivanja

doctoral thesis

• Title (english): 1,2,3-triazole and heterocycle conjugates: synthesis, antimicrobial and cytostatic evaluations
• Author: Silvija Maračić
• Mentor: Silvana Raić-Malić (mentor)
• Committee member: Tatjana Gazivoda Kraljević (predsjednik povjerenstva)
• Committee member: Svjetlana Krištafor (član povjerenstva)
• Committee member: Senka Djaković (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2019-07-18, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

U doktorskom radu opisana je sinteza i biološko djelovanje novih konjugata 1,2,3-triazola i heterocikličkih baza, poput benzimidazola, indola, benzotiazola, kumarina i kinolina.
1,4-disupstituirani 1,2,3-triazolni derivati sintetizirani su regioselektivnom 1,3-dipolarnom cikloadicijom kataliziranom bakrom Cu(I) (CuAAC). Sinteza prekursora 6 i 24, potrebnih za pripremu acikličkih pirimidinskih nukleozidnih analoga, kao i sinteza 1,2,3-triazolnih
bis-heterocikla 39–53 i 55–60, provedena je pod utjecajem mikrovalnog zračenja kako bi se povećalo iskorištenje i skratilo vrijeme trajanja reakcije. Konjugati 1,2,3-triazola i
6-fenil-2-(trifluormetil)kinolina 75a–75d dodatno su sintetizirani mehanokemijskom klik reakcijom te je ispitan utjecaj p-supstituenta aromatskih azida na tijek reakcije.
Cijano-suptituirani derivati 79a–79i prevedeni su reakcijom s hidroksilaminom u prisutnosti baze u odgovarajuće amidoksim-suptituirane derivate (80–90), odnosno Pinnerovom reakcijom u amidino-suptituirane derivate 91–98. Reakcijom CuAAC azidoferocena i propargiliranih derivata kinolina dobiveni su O-alkilirani derivati kinolina (104a–104d, 105a–105d) i N-alkilirani derivati kinolona i 1,2,3-triazola (106a, 106b, 107a i 107b), dok su konjugati s 1,4-disupstituiranim 1,2,3-triazolom 109a–109d dobiveni reakcijom 4-(azidoetoksi)kinolina i etinil-ferocena. Sintetiziranim spojevima ispitano je antitumorsko djelovanje na niz staničnih linija karcinoma porijeklom iz čovjeka te antibakterijsko djelovanje na odabrane gram-pozitivne i gram-negativne bakterijske vrste.
Hibrid benzotiazol–1,2,3-triazol–kumarina 59 pokazao je izraženo antibakterijsko djelovanje protiv bakterije Moraxella catarrhalis. Amidino-supstituiranim konjugatima 1,2,3-triazola i heterocikla koji su pokazali snažno antitumorsko djelovanje (91–93, 95 i 96) ispitane su interakcije s dvolančanim polinukleotidima ctDNK i dsRNK (pApU) primjenom UV/Vis i
CD-spektroskopije te određivanjem temperature mekšanja. Konjugati ferocena i kinolina povezani 1,2,3-triazolnim prstenom 106a i 109c pokazali su značajnu antiproliferativnu aktivnost na stanice kronične mijeloidne leukemije (K562) i Burkittov limfoma (Raji).
Spoj 109c je također pokazao udvostručenu proizvodnju reaktivnih kisikovih spojeva (ROS) u stanicama Raji, u odnosu na kontrolu.

Abstract (english)

This thesis describes synthesis and biological activity of novel 1,2,3-triazole and heterocycle conjugates. 1,4-Disubstituted 1,2,3-triazole derivatives were synthesized by copper-catalyzed 1,3-dipolar cycloaddition (CuAAC). Synthesis of precursors 6 i 24 used for preparation of acyclic pyrimidine nucloside analogues, and 1,2,3-triazole bis-heterocycles 39–53 and 55–60 were conducted under microwave assisted reactions in order to increase yields and shorten reaction time. 1,2,3-Triazole and 6-phenyl-2(trifluoromethyl)quionline conjugates 75a–75d were additionally synthesized by mechanochemical click reaction and the effect of p-substituent of aromatic azide on reaction course was analyzed. Reaction of cyano substituted derivatives 79a–79i with hydroxylamine in the presence of base resulted in the desired amidoxime substituted heterocycles 80–90, while amidino substituted heterocycles 91–98 were synthesized acording to the Pinner method. Novel O‐alkylated quinoline (104a–104d, 105a–105d) and N‐alkylated (106a, 106b, 107a and 107b) 4‐quinolone derivatives attached to the ferrocene moiety through 1,4‐disubstituted 1,2,3‐triazole were prepared by CuAAC reaction of azidoferrocene precursors and propargylated quinoline derivatives, while quinoline‐ferrocene conjugates 109a–109d with 1,4‐disubstituted
1,2,3‐triazole were obtained by reaction of 4‐(azidoethoxy)quinoline derivatives and ethynylferrocene. All prepared compounds were tested for their in vitro antitumor activities on several human cancer cells and normal fibroblasts and antibacterial activity against selected Gram-pozitive and Gram-negative bacteria. Benzothiazole–1,2,3-triazole–coumarin hybrid 59 showed a strong antibacterial activity against Gram-negative bacteria Moraxella catarrhalis. The interactions with double-stranded polynucleotides ctDNA and dsRNA (pApU) of chosen amidino substituted compounds 91–93, 95 i 96 that displayed strongest antiproliferative activity were studied by using UV-Vis and CD spectroscopy and thermal denaturation experiments. 1,2,3-Triazole tethered quinoline-ferrocene conjugates 106a and 109c displayed marked activities on chronic myeloid leukemia in blast crisis (K562) and
Burkitt lymphoma (Raji). Also, compound 109c showed doubled intracellular reactive oxygen species (ROS) generation in Raji cells compared with control.

• Keywords: amidini; antibakterijsko djelovanje; antitumorsko djelovanje; feroceni; kinolin; kumarin; mehanokemija; molekulska hibridizacija; 1 2 3-triazoli
• Keywords (english): amidines; antibacterial activity; antitumor activity; ferrocenes; quinoline; coumarin; mechanochemistry; molecular hybridization; 1 2 3-triazoles
• Language: croatian
• URN:NBN: urn:nbn:hr:149:799503
• Promotion: 2019
• Project: Number: IP-2013-11-5596; Title: Sinteza i citostatska ispitivanja biblioteke novih dušikovih heterocikla; Title: Synthesis and cytostatic evaluations of novel nitrogen heterocycles library; Acronym: SCIENcENTRY; Leader: Silvana Raić-Malić; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Engineering Chemistry - Doctoral Course; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 188 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-08-28 13:00:35