Modular synthesis of functional libraries by accelerated SuFEx click chemistry

Joshua A. Homer; Rebecca A. Koelln; Andrew S. Barrow; Timothy L. Gialelis; Zlata Boiarska; Nikita S. Steinohrt; Erinna F. Lee; Wen-Hsuan Yang; Robert M. Johnson; Taemoon Chung; Amber N. Habowski; Dharmendra S. Vishwakarma; Debmalya Bhunia; Charlotte Avanzi; Adam D. Moorhouse; Mary Jackson; David A. Tuveson; Scott K. Lyons; Michael J. Lukey; W. Douglas Fairlie; Shozeb M. Haider; Michel O. Steinmetz; Andrea E. Prota; John E. Moses

doi:10.1039/D3SC05729A

Modular synthesis of functional libraries by accelerated SuFEx click chemistry†

Joshua A. Homer,

^a Rebecca A. Koelln,

^a Andrew S. Barrow,

^b Timothy L. Gialelis,

^b Zlata Boiarska,

^cd Nikita S. Steinohrt,

^ef Erinna F. Lee,

^efg Wen-Hsuan Yang,

^a Robert M. Johnson,

^a Taemoon Chung,

^a Amber N. Habowski,

^a Dharmendra S. Vishwakarma,

^a Debmalya Bhunia,

^a Charlotte Avanzi,

^h Adam D. Moorhouse,^a Mary Jackson,

^h David A. Tuveson,

^a Scott K. Lyons,

^a Michael J. Lukey,

^a W. Douglas Fairlie,

^efg Shozeb M. Haider,

ⁱ Michel O. Steinmetz,

^cj Andrea E. Prota

^c and John E. Moses

*^a

Author affiliations

* Corresponding authors

^a Cancer Center, Cold Spring Harbor Laboratory, 1 Bungtown Rd, Cold Spring Harbor, NY 11724, USA
E-mail: moses@cshl.edu

^b La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia

^c Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, Villigen PSI, Switzerland

^d Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, 20133 Milan, Italy

^e Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia

^f School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia

^g Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia

^h Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA

ⁱ School of Pharmacy, University College London, 29-39 Brunswick Square, London, UK

^j Biozentrum, University of Basel, 4056 Basel, Switzerland

Abstract

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.

This article is part of the themed collections: Celebrating the scientific accomplishments of RSC Fellows and 2024 Chemical Science Covers

Chemical Science

Modular synthesis of functional libraries by accelerated SuFEx click chemistry†

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