Sulfur fluoride exchange (SuFEx) chemistry emerged as a new field of click chemistry in 2014 due to contributions from the Sharpless group. The stability of the bond allows the S(VI)F group to tolerate a variety of conditions, from biological environments to harsh synthetic conditions. However, under the right conditions, controlled nucleophilic S-F exchange can occur at the sulfur atom. SuFEx chemistry can be used for late-stage drug functionalization of bioactive molecules which allows for diversification of known drugs in an attempt to improve their therapeutic properties. Temozolomide is the standard of care drug used to treat glioblastoma multiforme (GBM). Its mechanism of action is to alkylate guanine bases in DNA which leads to base-pair mismatch and ultimately cell apoptosis. Due to methylguanine-DNA methyltransferase, GBM cells are often resistant to temozolomide. Thus, the mean life expectancy for patients undergoing standard treatment is around one year. This study employs various SuFEx methodologies in an attempt to attach a sulfonyl fluoride functional group to temozolomide to improve its drug properties and overall potency. Although SuFEx chemistry is being employed in other late-stage drug functionalization for other anti-cancer medications, to our knowledge this would be the first attempt to target glioblastoma therapeutics.

SuFEx chemistry for late-stage drug functionalization of temozolomide

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.