Sinteza i karakterizacija hibrida 6-, 7- i 9-supstituiranih derivata beta-karbolina i ferocena amidnog tipa

master's thesis

• Title (english): Synthesis and characterization of amide type hybrid compounds composed of 6-, 7- and 9-substituted beta-carboline and ferrocene derivates
• Author: Petra Urek
• Mentor: Ivana Perković (mentor)
• Committee member: Ivana Perković (predsjednik povjerenstva)
• Committee member: Zrinka Rajić (član povjerenstva)
• Committee member: Daniela Amidžić Klarić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2021-07-09, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

U ovom radu sintetizirana su tri nova hibridna derivata β-karbolina i ferocena (7, 11, 15), kao i prekursori za njihovu sintezu (1-4, 8, 9, 10, 12-14). Broj reakcijskih koraka za pojedini derivat razlikuje se ovisno o položaju supstitucije β-karbolina. Sinteza 6-supstituiranog derivata 7 odvija se u sedam koraka. Pictet-Spenglerovom reakcijom dolazi do zatvaranja šesteročlanog prstena te nakon oksidacije nastaje derivat s β-karbolinskim prstenom (2). Slijedi kisela hidroliza metilnog etera čime nastaje fenol 3, kojemu je u četvrtom koraku vezana Boc-zaštićena amino skupina preko etilenske poveznice (4).
Ishodišna molekula u sintezi derivata β-karbolina na položaju 7 i 9 je harmin. Derivat na položaju 7 (11) sintetiziran je u pet, a derivat na položaju 9 (15) u četiri reakcijska koraka. U prvom koraku sinteze 7-supstituiranog derivata, kiselom hidrolizom metilnog etera nastaje harmol. Boc-zaštićena aminoetilna skupina povezana je u slučaju harmola preko fenolne skupine (8) a u slučaju harmina preko amino skupine (12). Reagens za navedene sinteze je u oba slučaja 2(tert-butoksikarbonilamino)etil bromidom te se reakcije provode uz cezijev karbonat.
Sljedeći koraci jednaki su za sve produkte. Nakon hidrolize zaštitne Boc-skupine sa spojeva 4, 8 i 12 uz klorovodičnu kiselinu, nastali amini 5, 9 i 13 se oksidiraju u odgovarajuće azide 6, 10 i 14. U zadnjem koraku sinteze dobiveni azidi 6, 10 i 14 reagiraju s etinil ferocenom u reakciji bakrom (I) katalizirane azid-alkin cikloadicije u kojoj dolazi do zatvaranja triazolskog prstena između dva farmakofora te nastaju konačni produkti 7, 11 i 15.
Pripravljenim spojevima potvrđene su strukture korištenjem standardnih analitičkih i spektroskopskih metoda (IR, MS, 1H i 13C NMR) te su im određena tališta. Njihov biološki učinak bit će ispitan u daljnjim istraživanjima koji prelaze okvire ovog rada.

Abstract (english)

In this paper three new β-carboline derivatives (7, 11, 15) have been synthesized, as well as their precursors (1-4, 8, 9, 10, 12-14). The number of reaction steps differs depending on the β-carboline derivatization position. 6-substituted derivative 7 was synthesized in a seven step procedure. Firstly, the six-membered ring was closed using the Pictet-Spengler reaction and, after oxidation, a β-carboline ring was formed (2). This was followed by acidic hydrolysis of the methyl ether, yielding phenol 3, which was then linked to a Boc-protected amino group using ethylene as a spacer (4).
In the synthesis of 7- and 9-substituted derivatives of β-carboline, harmine was used as a starting compound. Derivatives at position 7 (11) and 9 (15) were synthesized in a five and four step procedure. In the first step of the synthesis of harmol was performed by acidic hydrolysis of methyl ether. The Boc-protected aminoethyl group was linked via phenol group in harmol (8) and via amino group in harmine (12). The reagent for both reactions was 2(tert-butoxycarbonylamino)ethyl bromide and the reactions were carried out in the presence of cesium carbonate.
The following steps were equal to all three derivatives. After hydrolysis of the Boc-protecting group from compounds 4, 8 and 12 with hydrochloric acid, the resulting amines 5, 9 and 13 were then oxidized to azides 6, 10 and 14. Finally, azides 6, 10 and 14 reacted with ethinyl ferrocene in a copper (I) catalyzed azide-alkyne cycloaddition reaction, and a triazole ring connecting the two pharmacophores was formed (7, 11 and 15).
Structures of the newly prepared compounds were confirmed using conventional analytical and spectroscopic methods (IR, MS, 1H and 13C NMR) and melting points of the compounds were determined. The biological activity of the compounds will be investigated.

• Keywords: 1H-1; 2; 3-triazol; ferocen; harmin; hibrid; malarija
• Keywords (english): 1H-1; 2; 3-triazole; ferrocene; harmine; hybrid; malaria
• Language: croatian
• URN:NBN: urn:nbn:hr:163:057690
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-07-09
• Created on: 2022-08-30 13:40:57