Biološka aktivnost alkiltio i ariltio derivata 2-terc-butil-1,4-benzohinona

Abstract

U ovoj disertaciji su sintetisana jedinjenja sa istom farmakoforom kao i biološki aktivna jedinjenja poreklom iz prirodnih proizvoda, alkiltio i ariltio derivati 2-terc-butil-1,4-benzohinona – TBQ i ispitana je njihova biološka aktivnost. Jedinjenja pokazuju dobar antioksidativni potencijal i dovode do produkcije slobodnih radikala, pri čemu se najviše ističe 2-terc-butil-5,6-(etileneditio)-1,4-benzohinon (derivat 4), koji zajedno sa 2-terc-butil-5-(propiltio)-1,4-benzohinonom (derivat 3) pokazuje najjači antineurodegenerativni potencijal. Mikrodilucionim testom uočena je jača antimikrobna aktivnost prema gram-pozitivnim bakterijama, naročito prema Staphylococcus aureus i Bacillus subtilis. Svi derivati, osim 2-terc-butil-6-(feniltio)-1,4-benzohinona (derivat 6), pokazuju manju toksičnost od TBQ prema Artemia salina. MTT i MTS testom je uočeno da jedinjenja, generalno, pokazuju umeren citotoksični efekat prema humanim ćelijskim linijama dok je derivat 4 pokazao najjači efekat. Jedinjenja su pokazala jači efekat na inhibiciju migracije tumorske A549 ćelijske linije u odnosu na zdravu MRC-5 ćelijsku liniju. Genotoksična aktivnost jedinjenja primenom SOS/umuC testa na prokariotskom model sistemu nije uočena, niti je primećena interakcija sa plazmidnom DNK. Komet testom, na eukariotskim model sistemima, pokazano je da izabrane hemijske modifikacije pojačavaju genotoksični potencijal dok je derivat 4 pokazao najjači efekat, uključujući indukciju dvolančanih oštećenja DNK γH2AX testom i značajno veće zaustavljanje ćelijskog ciklusa HepG2 ćelija u G2/M fazi u odnosu na TBQ. Analizom svih dobijenih rezultata, derivat 4 je pokazao najjaču biološku aktivnost.

In this dissertation, compounds with the same pharmacophore as well as biologically active compounds originating from natural products, alkylthio and arylthio derivatives of 2-tert-butyl-1,4-benzoquinone - TBQ, were synthesized, and their biological activity was examined. The compounds have good antioxidant potential and lead to the production of free radicals, with 2-tert-butyl-5,6-(ethylenedithio)-1,4-benzoquinone (derivative 4) standing out the most, along with 2-tert-butyl-5-(propylthio)-1,4-benzoquinone (derivative 3), showing the strongest antineurodegenerative potential. A stronger antimicrobial activity against gram-positive bacteria, particularly Staphylococcus aureus and Bacillus subtilis, was observed through a microdilution test. All derivatives, except 2-tert-butyl-6-(phenylthiol)-1,4-benzoquinone (derivative 6), exhibit lower toxicity than TBQ to Artemia salina. Using MTT and MTS assays, compounds generally have moderate cytotoxic effects on human cell lines, with derivative 4 showing the strongest effect. The compounds have demonstrated a stronger effect on inhibiting the migration of the tumor A549 cell line compared to the healthy MRC-5 cell line. No genotoxic activity of the compounds was observed using the SOS/umuC test on the prokaryotic model system, nor was there any interaction with plasmid DNA. On eukaryotic model systems, using the comet assay, selected chemical modifications enhance the genotoxic potential, with derivative 4 showing the strongest effect, including induction of double-strand DNA damage as assessed by the γH2AX test, and significantly greater cell cycle arrest in the G2/M phase in HepG2 cells compared to TBQ. All obtained results reveal that derivative 4 exhibits the strongest biological activity.