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The reaction of ionized formamide H(2)NCHO(*)(+) with water leads to an exclusive loss of CO from the complex. This contrasts with the unimolecular reaction of low-energy ionized formamide, which loses exclusively one hydrogen atom. The unimolecular loss of CO is not observed because it involves several H-transfers corresponding to high-energy barriers. Experimental and theoretical studies of the role of solvation by water on the fragmentation of ionized formamide leads to three different results: (i) In contrast with different systems previously studied, in which solvation plays only a role on one or two steps of a reaction, a molecule of water is efficient in the catalysis of the decarbonylation process because water catalyzes all the steps of the reaction of ionized formamide, including the final dissociation of the amide bond. (ii) The catalyzed isomerization of carbonylic radical cations into their carbene counterparts is shown to be an important step in the process. To study this step, a precise probe, characterizing the carbene structure by ion-molecule reaction, is for the first time described. (iii) Finally, decarbonylation of ionized formamide yields the [NH(3), H(2)O](*)(+) ion, which has not been generated and experimentally studied previously. By this method, the [NH(3), H(2)O](*)(+) ion is generated in abundance and with a low internal energy content, allowing one either to prepare, by ligand exchange, a series of other solvated radical cations or to generate covalent structures such as distonic ions. First results on related systems indicate that the conclusions obtained for ionized formamide are widespread.

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Molecular dynamics simulations were performed on both apo and copper forms of the human copper chaperone, Hah1. Wild-type Hah1 and a methionine (M10) to serine mutant were investigated. We have evidenced the central role of residue M10 in stabilizing the hydrophobic core of Hah1 as well as the internal structure of the metal-binding site. When copper(I) is bound, the mobility of Hah1 is reduced whereas mutation of M10 implies a drastic increase of the mobility of apoHah1, stressing the importance of this highly conserved hydrophobic residue for copper sequestration by the apoprotein.

We have developed new force field and parameters for copper(I) and mercury(II) to be used in molecular dynamics simulations of metalloproteins. Parameters have been derived from fitting of ab initio interaction potentials calculated at the MP2 level of theory, and results compared to experimental data when available. Nonbonded parameters for the metals have been calculated from ab initio interaction potentials with TIP3P water. Due to high charge transfer between Cu(I) or Hg(II) and their ligands, the model is restricted to a linear coordination of the metal bonded to two sulfur atoms. The experimentally observed asymmetric distribution of metal ligand bond lengths (r) is accounted for by the addition of an anharmonic (r3) term in the potential. Finally, the new parameters and potential, introduced into the CHARMM force field, are tested in short molecular dynamics simulations of two metal thiolates fragments in water. (Brooks BR et al. J Comput Chem 1983, 4, 1987.1).

Spontaneous and catalyzed isomerizations of the acetamide radical cationThe use of mass spectrometry for the study of peptides (sequencing, cationization, H-D exchanges, etc.) is a rapidly growing field. 1 Therefore, the chemistry of ionized amides, studied by mass spectrometry, is of considerable interest. This letter reports some new findings concerning the unimolecular and bimolecular chemistry of ionized acetamide, mainly focused on spontaneous and catalyzed 1,3-H migrations, resulting in tautomerization of the acetamide radical cation.Among the four possible tautomers 1-4 of ionized acetamide (Scheme 1), only 1 and 2 have been experimentally described, 2 although no definitive proof was given of their structures. Structure 1 was assigned on the basis of direct electron ionization of acetamide, and structure 2 was logically given to the m/z 59 ion from ionized hexanamide, as the most stable fragment resulting from the McLafferty rearrangement.G2(MP2) level).

Highlights ➢ Design, synthesis of Benzosceptrin C-derived compounds as new necroptosis inhibitors. ➢ SAR study on the 54 benzazoles on the TNF-α induced necroptosis in human Jurkat FADD-deficient cells. ➢ Compounds AV123 (12) and MBM105 (67) inhibited RIPK1 with IC50 values of 12.12 and 2.89 µM, respectively. ➢ Potent, non-toxic and selective MBM105 (67) blocked the necroptotic but not the apoptotic cell death.

Four new compounds, (+)- and (-)-ecarlottone (1), (±)-fislatifolione (5), (±)-isofislatifolione (6), and (±)-fislatifolic acid (7), and the known desmethoxyyangonin (2), didymocarpin-A (3), and dehydrodidymocarpin-A (4) were isolated from the stem bark of Fissistigma latifolium, by means of bioassay-guided purification using an in vitro affinity displacement assay based on the modulation of Bcl-xL/Bak and Mcl-1/Bid interactions. The structures of the new compounds were elucidated by NMR spectroscopic data analysis, and the absolute configurations of compounds (+)-1 and (-)-1 were assigned by comparison of experimental and computed ECD spectra. (-)-Ecarlottone 1 exhibited a potent antagonistic activity on both protein-protein associations with K values of 4.8 μM for Bcl-xL/Bak and 2.4 μM for Mcl-1/Bid.