Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/186041
Title: | Computational Study of the addition of Methanethiol to 40+ Michael Acceptors as a Model for the Bioconjugation of Cysteines |
Author: | Costa i Arnau, Anna M. Bosch Hereu, Lluís Petit Roig, Elena Vilarrasa i Llorens, Jaume |
Keywords: | Reaccions d'addició Anions Tiols Addition reactions Anions Thiols |
Issue Date: | 29-Apr-2021 |
Publisher: | American Chemical Society |
Abstract: | A long series of Michael acceptors are studied computationally as potential alternatives to the maleimides that are used in most antibody-drug conjugates to link Cys of mAbs with cytotoxic drugs. The products of the reaction of methanethiol (CH3SH/MeSH, as a simple model of Cys) with N-methylated ethynesulfonamide, 2-ethynylpyridinium ion, propynamide, and methyl ethynephosphonamidate (that is, with HC≡C-EWG) are predicted by the M06-2X/6-311+G(d,p) method to be thermodynamically more stable, in relation to their precursors, than that of MeSH with N-methylmaleimide and, in general, with H2C═CH-EWG; calculations with AcCysOMe and tBuSH are also included. However, for the addition of the anion (MeS-), which is the reactive species, the order changes and N-methylated 2-vinylpyridinium ion, 2,3-butadienamide, and maleimide may give more easily the anionic adducts than several activated triple bonds; moreover, the calculated ΔG⧧ values increase following the order HC≡C-SO2NHMe, N-methylmaleimide, HC≡C-PO(OMe)NHMe, and HC≡C-CONHMe. In other words, MeS- is predicted to react more rapidly with maleimides than with ethynephosphonamidates and with propynamides, in agreement with the experimental results. New mechanistic details are disclosed regarding the advantageous use of some amides, especially of ethynesulfonamides, which, however, are more prone to double additions and exchange reactions. |
Note: | Reproducció del document publicat a: https://doi.org/10.1021/acs.joc.1c00349 |
It is part of: | Journal of Organic Chemistry, 2021, vol. 86, num. 10, p. 7107-7118 |
URI: | http://hdl.handle.net/2445/186041 |
Related resource: | https://doi.org/10.1021/acs.joc.1c00349 |
ISSN: | 0022-3263 |
Appears in Collections: | Articles publicats en revistes (Química Inorgànica i Orgànica) |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
721041.pdf | 2.09 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License