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Mechanistic investigation of charge-remote and charge-driven fragmentation processes in 2,5- diphenyl-3,4-ethylenedioxythiophene diamidines

RATIONALE: Diphenylfuran diamidines represent an important class of DNA minor groove binders of high therapeutic interest as antitumor and antibacterial agents. This study aimed to investigate fragmentation patterns in mass spectra of four diamidine derivatives with significant antitumor activity, in order to gain more insight into the structures and stability of their putative biological metabolites. METHODS: Compounds were investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS) using low-energy collision-induced dissociation (CID). Density functional theory calculations were performed to confirm the main fragmentation paths. RESULTS: The most abundant ion present in mass spectra is the doubly protonated molecule, whereas singly protonated molecules are present to a lesser extent. In the simplest compound, 2, 5-bis(4-amidinophenyl)-3, 4- ethylenedioxythiophene, the main fragmentation path was loss of ammonia, followed by loss of HCN where possible. The fragmentation of the N-alkyl derivatives (N-isopropyl-, N-isobutyl-, N-cyclopentyl-) includes competition between loss of alkene and the corresponding amine, followed by loss of another alkene and formation of fragment ions present in the pathway of the parent compound. CONCLUSIONS: The primary sites of fragmentations of investigated compounds are amidine groups, while breaking the core 3, 4-ethylenedioxy-thiophene ring system does not take place. Fragmentation of the singly protonated molecule [M + H]+ occurs primarily on the charged side of the molecule, but a charge-remote process is energetically viable. The fragmentation mechanism of the alkyl derivatives revealed that singly and doubly protonated molecules cleave to the singly and doubly protonated molecules of the parent compound. Once formed, they are gradually transformed into nitrile.

amidines ; tandem mass spectrometry ; density functional theory

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