Sinteza 2-substituiranih derivatov 4-(furan-2-il)-6-(trifluorometil)pirimidina z antagonističnim delovanjem na Tollu podobni receptor 8

Tekavec, Sara (author), Sova, Matej (mentor), Dolšak, Ana (comentor)

Tollu podobni receptorji (TLR) predstavljajo pomemben del prirojene imunosti, ki ima ob vdoru tujka v naš organizem vlogo prve obrambne linije. Med desetimi poznanimi humanimi TLR, katerih naloga je prepoznavanje za patogene in za poškodbe značilnih molekulskih vzorcev (PAMP in DAMP), spada TLR8 v skupino endosomalnih receptorjev in prepoznava ssRNA virusov. Po aktivaciji teh receptorjev se sproži kaskada reakcij, ki na koncu inducira izražanje genov z zapisi za provnetne citokine. V kolikor TLR prepozna tudi telesu lastne molekule, kar je značilno za nekatere avtoimunske bolezni (revmatoidni artritis, sistemski eritematozni lupus), je prekomerni imunski odziv smiselno zdraviti z antagonisti. V sklopu magistrske naloge smo na osnovi že znanega antagonista TLR8, ki je bil predhodno odkrit z virtualnim rešetanjem, v okviru štiristopenjske sinteze pripravili sedemnajst končnih spojin, in sicer novih 2-substituiranih derivatov 4-(furan-2-il)-6-(trifluorometil)pirimidina. Uporabljena sinteza je zajemala pripravo 1,3-dikarbonilne spojine, njeno kondenzacijo s S-metilizotiosečnino do pirimidinskega obroča, oksidacijo sulfida do sulfona ter substitucijo izbranega amina z metilsulfonsko skupino na mestu 2 pirimidinskega obroča. Končnim spojinam smo z različnimi analitskimi tehnikami potrdili istovetnost in čistost. Na podlagi rezultatov biokemijskega testiranja smo za sintetizirano serijo naših spojin pridobili nekaj novih informacij o odnosu med strukturo in antagonističnim delovanjem na TLR8. Najmočnejše antagonistično delovanje je izkazala spojina 20, pri čemer smo ugotovili, da hidroksilna skupina ključno prispeva k jakosti delovanja. Poleg te spojine so šibko antagonistično delovanje izkazovale tudi spojine 17 - 19. Vsem štirim spojinam je skupna vsebnost substituiranega benzilamina na mestu 2, kar zaradi možnosti tvorbe hidrofobnih in π-π interakcij pozitivno vpliva na vezavo liganda. Spojina 20 tako predstavlja nov strukturni razred modulatorjev TLR8 in pomembno izhodišče za nadaljnje raziskave in razvoj novih antagonistov TLR8 kot potencialnih učinkovin za zdravljenje avtoimunskih bolezni.

• Language: Slovenian
• Keywords: Tollu podobni receptorji, TLR8, antagonisti, avtoimunske bolezni, derivati pirimidina
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-117137
• Publication date in RUL: 25.06.2020

Secondary language

• Language: English
• Title: Synthesis of 2-substituted 4-(furan-2-yl)-6-(trifluoromethyl)pyrimidine derivatives as Toll-like receptor 8 antagonists

Abstract

Toll-like receptors (TLRs) represent an important part of innate immunity, which is the first line of defence against any invasion of the human body. Among the ten-known human TLRs, whose function is to recognise pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), TLR8 belongs to the group of endosomal receptors and recognizes viral ssRNA. Upon activation of these receptors, a cascade reaction is triggered that eventually induces gene expression of pro-inflammatory cytokines. If TLR also recognizes the body’s own molecules, which is a characteristic of some autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), it is reasonable to treat the excessive immune response with antagonists. As a part of this Master’s thesis, using four-step synthetic route, we synthesized 17 final compounds, i.e. new 2-substituted derivatives of 4-(furan-2-yl)-6-(trifluoromethyl) pyrimidine, on the basis of a known TLR8 antagonist, which was previously discovered by virtual screening. The synthesis involved the preparation of a 1,3-dicarbonyl compound, its condensation with S-methylisothiourea to form a pyrimidine ring, the oxidation of sulfide to sulfone, and substitution of selected amine with methylsulfone group at the position 2 of the pyrimidine ring. The identity and purity of the final compounds was confirmed by various analytical techniques. Based on the results of biochemical assays determined for the series of our synthesized compounds new information about TLR8 antagonists’ structure and activity relationship was obtained. Compound 20 exhibited the most potent antagonist activity. Furthermore, it was found that the hydroxyl group significantly contributes to its potency. In addition, compounds 17-19 also showed weak antagonist activity. All four compounds have in common the substituted benzylamine at position 2, which has a positive effect on the ligand binding due to the possible formation of hydrophobic and π-π interactions. Compound 20 thus represents a new structural class of TLR8 ligands and an important starting point for further research and development of novel TLR8 antagonists as potential immunosuppressive drugs.

• Keywords: Toll-like receptors, TLR8, antagonists, autoimmune diseases, pyrimidine derivatives