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Computational Study of the addition of Methanethiol to 40+ Michael Acceptors as a Model for the Bioconjugation of Cysteines
Computational Study of the addition of Methanethiol to 40+ Michael Acceptors as a Model for the Bioconjugation of Cysteines
- Source :
- The Journal of Organic Chemistry, Dipòsit Digital de la UB, Universidad de Barcelona
- Publication Year :
- 2021
- Publisher :
- American Chemical Society, 2021.
-
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.
- Subjects :
- Anions
Bioconjugation
Immunoconjugates
010405 organic chemistry
Organic Chemistry
Tiols
Methanethiol
010402 general chemistry
Triple bond
01 natural sciences
Combinatorial chemistry
Article
0104 chemical sciences
Ion
Adduct
Addition reactions
chemistry.chemical_compound
chemistry
Thiols
Reaccions d'addició
Cysteine
Sulfhydryl Compounds
Maleimide
Conjugate
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The Journal of Organic Chemistry, Dipòsit Digital de la UB, Universidad de Barcelona
- Accession number :
- edsair.doi.dedup.....5974db250a40615af15cefaee78d5168