I. Preparation of β-amino Sulfoxides as Potential Selective Connexin Inhibitors II. Synthesis of Isoxylitone Analogues for the Treatment of Epilepsy
Creators: name: Saikaley, Amanda
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 2015

description: Part I. Preparation of β-amino sulfoxides as potential selective connexin inhibitors Intercellular communication is the basis for the development and homeostasis of tissues and multicellular organisms, influencing functions such as regulation of growth, cell differentiation, and developmental signalling. The connexins are a family of integral membrane proteins that oligomerize into clusters of intercellular channels that connect the cytoplasm of neighbouring cells, allowing gap junction intercellular communication (GJIC). In particular, hemi-channels remain closed to avoid dissolution of ionic gradients and leakage of cytoplasmic constituents, whereas conditions of anoxia provoke the opening of these hemi-channels, often leading to cell death. Thus far, a compound code named AF101 possesses the greatest amount of selectivity and inhibition of GJIC. A series of nearly twenty β-amino sulfoxides using AF102 as the lead structure were prepared by introducing various new substituents to the three aromatic rings on the molecule and by changing the aryl subtituents at the sulfoxide moiety. In each example, the diastereomers were separated and the relative configuration at carbon and sulfur was assigned via 1H NMR. The amino sulfoxides were subsequently transformed into amino sulfones and amino sulfides via oxidation and reduction reactions, respectively. We are awaiting the results of the bioassays of all of these compounds. The results will determine if any of them show selective altering of connexin activity. Part II. Synthesis of Isoxylitone analogues for the treatment of epilepsy. Epilepsy is a chronic disorder of the brain that affects roughly 50 million people worldwide. Extracts of a variety of plants have been used for many years to treat a number of neurological disorders. Delphinium denudatum Wall has been used to treat seizures by local folk medicine practitioners and a bioassay guided fractionation identified the active component as isoxylitone, also referred to as ISOX. Thirty five compound analogues were prepared starting from readily available isophorone [3,5,5, trimethylcyclohex – 2- ene -1one] and other cyclohexenones. Compound 16 possesses the highest activity by inhibiting epileptic seizures in rats by 65% at a concentration of 200 nM. This compound has been further investigated and widely studied in a variety of other in vitro and in vivo models. The E/Z mixture of the ethyl ester 4 also showed promising activity. The Z isomer of 4 and its methyl ester analogue 8, were prepared by reacting the potassium salt of the pure Z acid 7Z with Et3I and CH3I respectively. These Z isomers were less potent than the mixture, indicating that most of the activity resides in the E isomer. Recrystallization of 16 from hexanes afforded the E isomer in 92% purity. Surprisingly, this isomer was less active than the E/Z mixture of 16. Esterification of 7Z in acidic MeOH or EtOH afforded the same E/Z mixture of esters obtained in the initial synthesis. This indicates that a rapid isomerization under acidic conditions. In contrast, 16E remained unchanged upon heating in MeOH containing a catalytic amount of HCl or PTSA over a period of 8 hours.