Sinteza i karakterizacija amida 3- i 6-supstituiranog derivata beta-karbolina i analoga klorokina

master's thesis

• Title (english): Synthesis and characterization of amides of 3- and 6- substituted β-carboline derivatives and chloroquine analogs
• Author: Ivana Vilenica
• Mentor: Ivana Perković (mentor)
• Committee member: Ivana Perković (predsjednik povjerenstva)
• Committee member: Kristina Pavić (član povjerenstva)
• Committee member: Mirela Matić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2021-06-17, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

U ovom radu sintetizirana su i strukturno okarakterizirana dva nova hibridna spoja 4a i 4b, sastavljena od β-karbolinskog prstena koji je amidnom poveznicom preko položaja 3 i 6 povezan s kinolinskim derivatom po uzoru na klorokin.
Za sintezu ovih spojeva bilo je potrebno sintetizirati obje građevne jedinice, kinolinski derivat, (7-klorokinolin-4-il)glicin, i 3- i 6- supstituirane β-karbolinske amine 1e i 2e. Priprava amina 1e i 2e na položajima β-karbolinskog prstena polazi iz metilnog estera triptofana i 5-metoksitriptamina te se odvija u pet reakcijskih koraka. Najprije Pictet-Spenglerovom kondenzacijom dolazi do nastanka tetrahidro-β-karbolina (1a i 2a), koji se zatim oksidiraju do odgovarajućih β-karbolina 1b i 2b. U slučaju amina iz serije 1, metilni ester na položaju 3 se reducira do primarnog alkohola 1c. Slijedi konverzija alkoholne u azidnu skupinu uz pomoć donora azida ADMP-a u bazičnim uvjetima čime nastaje odgovarajući azid 1d, te njegova redukcija u primarni amin 1e.
Eter na položaju 6 spoja 2b hidrolizom u kiselom prelazi u odgovarajući fenol 2c, koji u reakciji nukleofilne supstitucije u bazičnim uvjetima prelazi u spoj 2d kod kojeg terminalna amino skupina posjeduje Boc-zaštitnu skupinu. Potom se amino skupina oslobađa zaštite, hidrolizom funkcionalne skupine karbamata u kiselom, te nastaje amin 2e.
Konačni produkti 4a i 4b dobiveni su u reakciji amina 1e i 2e s (7-klorokinolin-4-il)glicinom (3), koristeći standardne coupling uvjete (T3P, TEA, DMF).
Strukture sintetiziranih spojeva potvrđene su uobičajenim spektroskopskim/spektrometrijskim metodama (1H i 13C NMR, MS, IR). Sva četiri spoja zadovoljavaju Lipinskijeva i Veberova pravila, a dobru oralnu bioraspoloživost predviđa im i alat SwissADME. Sintetiziranim derivatima će u daljnjim istraţivanjima biti ispitano biološko djelovanje.

Abstract (english)

In this work, two novel hybrid compounds 4a and 4b, consisting of a β-carboline ring which is connected to a quinoline derivative via the chloroquine model by an amide bond in positions 3 and 6, were synthesized and characterized.
In order to achieve this goal, building blocks for these compounds were prepared, a quinoline derivative (7-chloroquinolin-4-yl) glycine and 3- and 6-substituted β-carboline amines 1e and 2e. The preparation of amines 1e and 2e at the β-carboline ring positions starts from the methyl ester of tryptophan and 5-methoxytryptamine and takes place in five reaction steps. First, Pictet-Spengler condensation produces tetrahydro-β-carbolines (1a and 2a), which are then oxidized to the corresponding β-carbolines 1b and 2b. In case of amine from series 1, the methyl ester at position 3 is reduced to the primary alcohol 1c. This is followed by the conversion of the alcohol 1c to the corresponding azide 1d by using ADMP under basic conditions, and reduction to the primary amine 1e.
The ether moiety at the position 6 of the compound 2b is hydrolized in acidic conditions to corresponding phenol 2c, which in the reaction of nucleophilic substitution under basic conditions is converted to compound 2d in which the terminal amino group carries a Boc-protecting group. The amino group is then deprotected by acid hydrolysis of the carbamate, and amine 2e is formed.
The final products 4a and 4b were obtained by the reaction of amines 1e and 2e with (7-chloroquinolin-4-yl) glycine (3), by using standard coupling conditions (T3P, TEA, DMF).
Structures of the newly prepared compounds were confirmed using conventional analytical and spectroscopic methods (1H i 13C NMR, MS, IR). All four novel derivatives meet all of the Lipinski's and Veber's criteria for good oral bioavailability of potential drugs. SwissADME tool predicts good oral bioavailability of all four derivatives. Further studies will investigate biological activity of the prepared coumpounds.

• Keywords: hibrid; β-karbolin; klorokin; amid; sinteza
• Keywords (english): hybrid; β-carboline; chloroquine; amide; synthesis
• Language: croatian
• URN:NBN: urn:nbn:hr:163:627856
• 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: 2023-06-17
• Created on: 2022-02-28 14:27:17