Piperazine as a linker for incorporating the nitric oxide-releasing diazeniumdiolate group into other biomedically relevant functional molecules

Article abstract of DOI:10.1021/jo9901539

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 ε-amino group of a protected lysine; via a carbamate linkage to poly(ethylene glycol); and by replacing the NH₂ nitrogens of nicotinamide and adenosine. Synthesis of analogues in which E = vinyl has been facilitated by introduction of BrCH₂CH₂OSO₂Cl as a novel, efficient bromoethylating agent. Spontaneous NO releasers in the diazeniumdiolated piperazine series include both a fluorescent anion of half-life 5.5 min in which E = Na and R = dansyl and 'MOM-PIPERAZI/NO' (E = CH₃OCH₂, R = H), whose half-life for NO release was estimated as 17 days. The latter agent has made possible the conversion of poly(vinyl chloride) and phosphatidylethanolamine to NO-releasing derivatives. This chemistry should allow introduction of diazeniumdiolate groups into a wide variety of natural products, drugs, polymers, and other molecules whose activities could be beneficially combined with the ability to generate NO for biomedical applications.