SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization
Top Cited Papers
- 16 February 2018
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 140 (8), 2919-2925
- https://doi.org/10.1021/jacs.7b12788
Abstract
Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of click chemistry transformations which relies on readily available materials to produce compounds bearing the SVI–F motif. The potential of SuFEx in drug discovery has just started to be explored. We report the first method of SuFEx chemistry for the conversion of phenolic compounds to their respective arylfluorosulfate derivatives in situ in 96-well plates. This method is compatible with automated synthesis and screening to quickly assess the biological activities of the in situ generated, crude products. Using this method, we perform late-stage functionalization of a panel of known anticancer drugs to generate the corresponding arylfluorosulfates. These in situ generated arylfluorosulfates are directly tested in a cancer-cell growth inhibition assay in parallel with their phenolic precursors. We discover three arylfluorosulfates that exhibit improved anticancer cell proliferation activities compared to their phenol precursors. Among these three compounds, the fluorosulfate derivative of Fulvestrant possesses significantly enhanced activity to down-regulate estrogen receptor (ER) expression in ER+ breast cancer cell line MCF-7 and the fluorosulfate derivative of Combretastatin A4—a general anticancer drug currently being evaluated under clinical trials—exhibits a 70-fold increase in potency in the drug resistant colon cancer cell line HT-29.Keywords
Funding Information
- National Institute of General Medical Sciences (R01GM111938, R01GM117145)
This publication has 51 references indexed in Scilit:
- Click Chemistry in Peptide-Based Drug DesignMolecules, 2013
- Late-Stage Deoxyfluorination of Alcohols with PhenoFluorJournal of the American Chemical Society, 2013
- Principles of early drug discoveryBritish Journal of Pharmacology, 2011
- Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2)Breast Cancer Research and Treatment, 2010
- Identification of the Human UDP-Glucuronosyltransferases Involved in the Glucuronidation of Combretastatin A-4Drug Metabolism and Disposition, 2010
- Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants: Potential Use for Cancer PreventionNutrition and Cancer, 2009
- Clinical outcome in children with recurrent neuroblastoma treated with ABT‐751 and effect of ABT‐751 on proliferation of neuroblastoma cell lines and on tubulin polymerization in vitroPediatric Blood & Cancer, 2009
- In vitroandin vivophase II metabolism of combretastatin A-4: Evidence for the formation of a sulphate conjugate metaboliteXenobiotica, 2009
- ACTIVE-SITE DIRECTED IRREVERSIBLE INHIBITORS OF DIHYDROFOLATE REDUCTASEAnnals of the New York Academy of Sciences, 1971
- Specific Irreversible Enzyme InhibitorsAnnual Review of Pharmacology, 1970