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doctoral thesis
Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost
doktorska disertacija
Split: University of Split, Faculty of Chemistry and Technology, 2021. urn:nbn:hr:167:965908
Jurin, Mladenka
University of Split
Faculty of Chemistry and Technology
Division of Chemistry

Institutional repository: Repository of the Faculty of chemistry and technology

Cite this document

Jurin, M. (2021). Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija (Doctoral thesis). Split: University of Split, Faculty of Chemistry and Technology. Retrieved from https://urn.nsk.hr/urn:nbn:hr:167:965908

Jurin, Mladenka. "Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija." Doctoral thesis, University of Split, Faculty of Chemistry and Technology, 2021. https://urn.nsk.hr/urn:nbn:hr:167:965908

Jurin, Mladenka. "Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija." Doctoral thesis, University of Split, Faculty of Chemistry and Technology, 2021. https://urn.nsk.hr/urn:nbn:hr:167:965908

Jurin, M. (2021). 'Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija', Doctoral thesis, University of Split, Faculty of Chemistry and Technology, accessed 16 November 2024, https://urn.nsk.hr/urn:nbn:hr:167:965908

Jurin M. Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija [Doctoral thesis]. Split: University of Split, Faculty of Chemistry and Technology; 2021 [cited 2024 November 16] Available at: https://urn.nsk.hr/urn:nbn:hr:167:965908

M. Jurin, "Sinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija", Doctoral thesis, University of Split, Faculty of Chemistry and Technology, Split, 2021. Available at: https://urn.nsk.hr/urn:nbn:hr:167:965908

Metadata
TitleSinteza kiralnih 3,5-disuostituranih i fenilamino derivata parazoantina A i F iz beta-laktama: eneantoseparacija, apsolutna konfigurcija i biološka aktivnost : doktorska disertacija
Title (english)Synthesis of chiral 3,5-disupstituted hydantoins and phenylamino derivates of parazoanthines a and f from betalactams: enantioseparation, absolute configuration and biological activity : doctoral thesis
AuthorMladenka Jurin
MBZ: 74487933062
MentorMarin Roje (mentor)
Committee memberIgor Jerković (predsjednik povjerenstva)
Committee memberAni Radonić (član povjerenstva)
Committee memberAndreja Jakas (član povjerenstva)
GranterUniversity of Split
Faculty of Chemistry and Technology
(Division of Chemistry)
Split
Defense date and country2021, Croatia
Scientific / art field,
discipline and subdiscipline		NATURAL SCIENCES
Chemistry
Universal decimal classification
(UDC)		54 - Chemistry. Crystallography. Mineralogy
Abstract
β-Laktami i hidantoini pokazuju raznoliku biološku aktivnost. Cilj ove doktorske disertacije bio je priprava kiralnih 3,5-disupstituiranih hidantoina i fenilamino-derivata parazoantina A i F polazeći iz β-laktama. Provedena istraživanja obuhvatila su njihovu enantioseparaciju, određivanje apsolutne konfiguracije te ispitivanja biološkog djelovanja. Dijastereomerna smjesa cis- i trans-3-amino-β-laktama 3 i 4 dobivena je reakcijom ciklokondenzacije metilnog estera glicina i imina 1a,b. Enantiomerno čisti trans-3-amino-β-laktami 4c,d dobiveni su reakcijom ciklokondenzacije (+)- ili (−)-mentilnog estera glicina s iminom 1a. Racemični trans-3-amino-β-laktam 4e dobiven je Staudingerovom reakcijom između karboksilne kiseline aktivirane 2-klor-1-metilpiridin-jodidom i imina 1a. Amino skupina na C-3 položaju β- laktamskog prstena poslužila je u daljnjoj sintetskoj nadogradnji prstena. Kondenzacijom amino skupine β-laktama s različitim aromatskim i alifatskim izocijanatima pripravljene su β- laktamske uree 12a-v, koje su potom intramolekulskom transformacijom prevedene u kiralne 3,5-disupstituirane hidantoine 13a-i/14a-i. U pokušajima sinteza fenilamino-derivata parazoantina A i F, reakcija kondenzacije između N-Boc-aminopropanala i anilina nije uspjela. S ciljem enantioseparacije novosintetiziranih molekula razvijene su enantioselektivne HPLC i SFC metode za odjeljivanje kiralnih β-laktamskih urea 12a-v i 3,5-disupstituiranih hidantoina 13a-i i 14a-i upotrebom polisaharidnih kiralnih nepokretnih faza. Kod primjene SFC kromatografije, ispitan je utjecaj kiralne nepokretne faze, vrste alkoholnog modifikatora, udjela trietilamina, temperature kolone i povratnog tlaka na enantioseparaciju β-laktamskih urea 12a- v. Apsolutne konfiguracije 3-amino-β-laktama i 3,5-disupstituiranih hidantoina određene su primjenom ECD spektroskopije i TDDFT matematičke metode. U sklopu određivanja in silico biološke aktivnosti novosintetiziranih molekula predviđeni su ADME i toksikološki parametri trans--laktamskih urea, 3,5-disupstituiranih hidantoina, prirodnih parazoantina A-J i fenilamino-derivata parazoantina A i F. Antimikrobno djelovanje β-laktamskih urea 12a-v ispitano je u in vitro uvjetima na odabranim sojevima bakterija i gljivica. Novosintetizirane trans-3-amino-β-laktamske uree 12a-v nisu pokazale antibakterijsko i antifungalno djelovanje. Antiproliferativno djelovanje trans-3-amino-β-laktamskih urea 12a, 12b, 12c, 12f, 12h, 12o, 12p, 12r i 12t i 3,5-disupstituiranih hidantoina 13a-i i 14a-i ispitano je u in vitro uvjetima pomoću MTT testa na staničnim linijama hepatocelularnog karcinoma jetre (HepG2), karcinoma jajnika (A2780), karcinoma dojke (MCF-7) te netransformiranih ljudskih fibroblasta (HFF-1). Najjači citotoksični učinak na staničnu liniju MCF-7 pokazao je hidantoin 14c a - laktamska urea 12p na staničnu liniju A2780. Spojevi 13g, 13h, 14c, 14g i 14h pokazuju citotoksični učinak na zdrave HFF-1 stanice.
Abstract (english)
β-Lactams and hydantoins show various biological activities. The goal of this doctoral thesis was to synthesize chiral 3,5-disubstituted hydantoins and phenylamino derivatives of Parazoanthine A and F from -lactams. Conducted research comprised their enantioseparation, absolute configuration determination and biological evaluation. Diastereomeric mixture of cis- and trans-3-amino-β-lactams 3 and 4 was synthesized using cyclocondensation reaction of glycine methyl ester and imine 1a,b. Enantiomerically pure trans-3-amino-β-lactams 4c,d were synthesized using cyclocondensation reaction of (+)- or (−)-glycine menthyl ester with imine 1a. Racemic trans-3-amino-β-lactam 4e was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide with imine 1a. The amino group at the C-3 position of the β-actam ring was used for further structural upgrade. β-Lactams ureas 12a-v were prepared by the condensation reaction of the amino group of β-lactam ring with variuos aromatic and aliphatic isocyanates, which were then converted into chiral 3,5- disubstituted hydantoins 13a-i/14a-i via intramolecular transformation. Furthermore, the synthesis of phenylamino derivatives of Parazoanthine A and F was attempted, but the condensation reaction of N-Boc-aminopropanal with aniline did not proceed. Enantioselective HPLC methods were developed for the separation of trans--lactam ureas 12a-v and 3,5- disubstituted hydantoins 13a-i and 14a-i, and also SFC method for the separation of trans-- lactams ureas 12a-v, on the polysaccharide-based chiral stationary phases. The effect of the chiral stationary phase, type of alcoholic modifier, the volume fraction of triethylamine, column temperature, and backpressure on the separation efficiency were investigated. The absolute configurations of 3-amino-β-lactams and 3,5-disubstituted hydantoins was determined by ECD spectroscopy and TDDFT calculations. In addition, set of ADME and toxicity parameters were predicted for trans--lactam ureas, 3,5-disubstituted hydantoins, natural Parazoanthines A-J and phenylamino derivatives of Parazoanthines A i F. The antimicrobial activity of trans-- lactams ureas 12a-v was tested in vitro against different strains of bacteria and fungi. All new trans--lactams ureas 14a-v have shown no antibacterical and antifungal activity. The antiproliferative activity of trans--lactam ureas 12a, 12b, 12c, 12f, 12h, 12o, 12p, 12r and 12t and 3,5-disubstituted hydantoins 13a-i and 14a-i was determined in vitro using the MTT assay on liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF-7) and untransformed human fibroblasts (HFF-1). Hydantoin 14c showed the strongest cytotoxic effect against MCF-7 cell line and -lactam urea 12p against A2780 cell line. Compounds 13g, 13h, 14c, 14g and 14h showed cytotoxic effect against healthy HFF-1 cells.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:167:965908
Promotion2021
Study programmeTitle: Chemistry of Mediteranean Cultures
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 resourceText
File originBorn digital
Access conditionsOpen access
Embargo expiration date: 2023-09-17
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Created on2021-09-16 10:19:51