Saturday, December 24, 2016

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

Wednesday, December 14, 2016

Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors

Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors

Balyn W. Zaro, Landon R. Whitby, Kenneth M. Lum, and Benjamin F. Cravatt*
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
J. Am. Chem. Soc.2016138 (49), pp 15841–15844

The use of a fumarate ester warhead is found to confer greater selectivity than a simple acrylamide warhead for inhibition of Bruton's Tyrosine Kinase (BTK).

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...