Browsing by Author "Krol, Ed"
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Item The Effect of Diphenylethane Side-chain Substituents on Dibenzocyclohexadiene Formation and their Inhibition of α-Synuclein Aggregation in vitro(2023-01-15) Dalio Bernardes da Silva, Gabriel; Munir, Omer; Krol, EdThe naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson's disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization. Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10-30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein.Item Novel dimers as inhibitors of alpha-synuclein aggregation(2022) Ruiz, Priscila; Krol, EdParkinson’s Disease is characterized by the death of dopaminergic neurons in the substantia nigra as a result of the aggregation of alpha synuclein (AS) Nicotine from smoking and 1 aminoindan (a metabolite of Rasagiline) seem to be neuroprotective compounds and both have been associated with the reduction of the risk to develop Parkinson’s disease These compounds bind to AS at both the N and C terminus, forcing the protein to adopt a loop conformation, which appear to contribute to the neuroprotective activity of the drugs Dimer molecules linked with two neuroprotective compounds should increase the binding constants to AS and increase the efficacy to prevent AS aggregation Phase 1 metabolic studies using hepatic microsomes in vitro are needed to determine the susceptibility of the compounds to biotransformation