Sulfones are useful bioisosteres in drug discovery, and have an unusual ability to engage in binding with both polar and nonpolar regions of target proteins. Despite this, they have seen limited use in drug-screening campaigns, compared with other functional groups. With the goal of generating a library of bicyclo[3.2.1]sulfone-containing molecules to probe biological function, a tandem 1,2-addition/anionic oxy-Cope/1,2-addition reaction proceeding from 3-sulfolene and discovered by previous members of our group was used to prepare highly substituted scaffolds for diversification. Functional group manipulations on this scaffold were partially successful, but ultimately provided limited scope for exploring three-dimensional space.
Moving to a less-substituted bicyclo[3.2.1]sulfone scaffold that could be accessed using methodology developed by the Chou group, it was found that a greater range of chemical diversification could be achieved. Using both substrate-directed methods and intrinsic functional group reactivity, about 70% of the skeletal framework was functionalized with high levels of regioselectivity and (in some cases) good levels of diastereoselectivity.
Chemoinformatic analysis was performed on our collection of synthesized bicyclo[3.2.1]sulfone-containing molecules, and diverse molecular descriptors were obtained. Collaborations were established with industrial partners and non-profit institutions for the purpose of determining biological properties in medicinally relevant areas. Significantly, each of these partners joined the project with therapeutic expertise in a different field (oncology, neurodegenerative diseases, antimicrobial agents, and skin inflammation), thereby maximizing the chances of finding useful lead compounds for future development. Preliminary biological screening data were obtained, which suggest future potential for sulfone-containing conformationally restricted small molecules to be impactful in therapeutic development. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/11751 |
| Date | 18 May 2020 |
| Creators | Un, Chak Hong Andy |
| Contributors | Wulff, Jeremy Earle |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Available to the World Wide Web |
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