title: Mass spectrometry and theoretical studies on N-C bond cleavages in the N-sulfonylamidino thymine derivatives.
abstract: The reactivity of new biologically active thymine derivatives substituted with 2-(arylsulfonamidino)ethyl group at N1 and N3 position was investigated in the gas phase using CID experiments (ESI-MS/MS) and by density functional theory (DFT) calculations. Both derivatives show similar chemistry in the negative mode with a retro-Michael addition (Path A(-)) being the most abundant reaction channel, which correlate well with the fluoride induced retro-Michael addition observed in solution. The difference in the fragmentation of N-3 substituted thymine 5 and N-1 substituted thymine 1 in the positive mode relates to the preferred cleavage of the sulfonyl group (m/z 155, Path B) in N-3 isomer and the formation of the acryl sulfonamidine 3 (m/z 309) via Path A in N-1 isomer. Mechanistic studies of the cleavage reaction conducted by DFT calculations give the trend of the calculated activation energies that agree well with the experimental observations. A mechanism of the retro-Michael reaction was interpreted as a McLafferty type of fragmentation, which includes Hβ proton shift to one of the neighboring oxygen atoms in a 1,5-fashion inducing N1(N3)-Cα bond scission. This mechanism was found to be kinetically favorable over other tested mechanisms. Significant difference in the observed fragmentation pattern of N-1 and N-3 isomers proves the ESI-MS/MS technique as an excellent method for tracking the fate of similar sulfonamidine drugs. Also, the observed N-1 and/or N-3 thymine alkylation with in situ formed reactive acryl sulfonamidine 3 as a Michael acceptor may open interesting possibilities for the preparation of other N-3 substituted pyrimidines.
authors.affiliation: Laboratory of Supramolecular and Nucleoside Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000, Zagreb, Croatia.
authors.forename: Renata
authors.initials: R
authors.lastname: Kobetić
authors.forename: Snježana
authors.initials: S
authors.lastname: Kazazić
authors.forename: Borislav
authors.initials: B
authors.lastname: Kovačević
authors.forename: Zoran
authors.initials: Z
authors.lastname: Glasovac
authors.forename: Luka
authors.initials: L
authors.lastname: Krstulović
authors.forename: Miroslav
authors.initials: M
authors.lastname: Bajić
authors.forename: Biserka
authors.initials: B
authors.lastname: Žinić
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002384:Catalysis; D004355:Drug Stability; D004735:Energy Transfer; D006358:Hot Temperature; D007202:Indicators and Reagents / Q000737:chemistry; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013449:Sulfonamides / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D013941:Thymine / Q000031:analogs & derivatives* / Q000737:chemistry; D014105:Tosyl Compounds / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; D014105:Tosyl Compounds; C009405:tetrabutylammonium; D013941:Thymine