Paper Spotlight: ASDRP's Dr. Edward Njoo & Dr. Joey Pazzi publish with their student researchers.

Dr. Joey Pazzi and Dr. Edward Njoo are thrilled to share our latest publication with students, now online in Springer Nature’s Discover Chemistry "Synthesis and evaluation of carmofur analogs as antiproliferative agents, inhibitors to the main protease (Mpro) of SARS-CoV-2, and membrane rupture-inducing agents" where we disclose the synthetic preparation of a library of 5-fluorouracil analogs that double down between acting as anti cancer agents through nanomolar-range membrane rupture, and inhibiting the main protease of SARS-CoV-2.

This study was led by seniors Tiffany Gu (Harker), Natalie Brahan (Irvington), Eileen Zhang (Amador Valley) and Kaitlyn Su (Harker) with key contributions by now-alumni Amber Lu (UCLA), Xina Wang (UC Berkeley), Julia Vu (Stanford), Charissa Luk (Johns Hopkins), Jade Lee (Cornell), Kody Seow (UCLA), Lexi Xu (Rice) and Anirudh Raman (USC).

Abstract

Initially developed as a derivatized analog of 5-fluorouracil for the treatment of colorectal cancer, carmofur has more recently demonstrated potent covalent inhibition of the main protease (Mpro) of SARS-CoV-2. Harnessing our previously described workflow for the optimized preparation of carmofur using benchtop 19F NMR spectroscopy, here, we prepared and evaluated a synthetic library of nine carmofur analogs with a selection of side chain motifs or single-atom substitution to explore the diversifiability of these compounds as Mpro inhibitors, where we discovered that a hexyl carbamate analog outperformed carmofur, and as antiproliferative agents in model human cell lines to identify differences in potency when the carbonyl electrophilicity and/or alkyl side chains are modified. Finally, we describe a novel workflow for the evaluation of membrane-rupturing small molecules through imaging of fluorescently labeled giant unilamellar vesicles (GUVs), and through this, we identified two lipophilic urethane analogs of carmofur bearing dodecyl urethane and octadecyl urethane side chains that have potent membrane-rupturing capability in the nanomolar range, providing insight into a potential mechanism for the in vitro activities of lipidated 5-fluorouracil analogs.

Paper Spotlight