Piperazine as a Linker for Incorporating the Nitric Oxide-Releasing Diazeniumdiolate Group into Other Biomedically Relevant Functional Molecules

Synthetic procedures have been devised to exploit the bifunctional amine piperazine (pip) as a linker capable of attaching the nitric oxide (NO)-releasing diazeniumdiolate functional group [N(O)NO]- to a diverse selection of biomedically useful molecules. One of the amino groups bears the diazeniumdiolate, which may be substituted on oxygen as necessary to control its dissociation to NO, while the other is used to provide a site suitable for covalent bonding to the molecule requiring NO donor capability. N,N‘-Disubstituted piperazines of the structure R-pip-N(O)NOE were prepared either by using the nucleophilic character of the amino group or by converting it into an electrophilic moiety for reaction with nucleophilic centers in the molecules to be derivatized. Examples are reported in which E = CH3 and the R groups are bound to the N‘-nitrogen: via amide linkages to the carboxyl groups of the drug ibuprofen and the amino acid derivative N-acetylmethionine; through a urea grouping to the e-amino group of...