Optimised synthesis of a nitroCBI hypoxia-activated prodrug with substantial anticancer activity. Issue 22 (31st May 2019)

• Record Type: Journal Article
• Authors: Lee, Ho H.; Dickson, Benjamin D.; Stevenson, Ralph J.; Yang, Shangjin; Tercel, Moana
• Is Part Of: Tetrahedron. Volume 75:Issue 22(2019)
• Page Start: 3001
• Page End: 3007
• Publication Date: 2019-05-31
• Subjects: NitroCBI -- Hypoxia-activated prodrug -- Optimised synthesis; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2019.04.027
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: An optimised synthesis of a hypoxia-activated anticancer prodrug related to the duocarmycin family of natural products is described. The improved 10-step synthesis increases the overall yield from 4.4% to over 40% while requiring just 2 chromatography-based purifications. The most significant improvements optimise the isomer distribution in a key chlorosulfonylation reaction, and facilitate the removal of tin residues from a tributyltin hydride-mediated radical reaction. Improved preparations of two side chains are also reported. The new method provides practical access to sufficient material to support advanced efficacy and toxicology assessments. Graphical abstract: Image 1