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 pi perazine (pip) as a linker capable of attaching the nitric oxide (NO)-relea sing diazeniumdiolate functional group [N(O)NO](-) to a diverse selection o f biomedically useful molecules, One of the amino groups bears the diazeniu mdiolate, which may be substituted on oxygen as necessary to control its di ssociation to NO, while the other is used to provide a site suitable for co valent bonding to the molecule requiring NO donor capability. N,N'-Disubsti tuted piperazines of the structure R-pip-N(O)=NOE were prepared either by u sing the nucleophilic character of the amino group or by converting it into an electrophilic moiety for reaction with nucleophilic centers in the mole cules to be derivatized. Examples are reported in which E = CH3 and the R g roups are bound to the N'-nitrogen: via amide linkages to the carboxyl grou ps of the drug ibuprofen and the amino acid derivative N-acetylmethionine; through a urea grouping to the E-amino group of a protected lysine; via a c arbamate linkage to poly(ethylene glycol); and by replacing the NH2 nitroge ns of nicotinamide and adenosine. Synthesis of analogues in which E II viny l has been facilitated by introduction of BrCH2CH2OSO2Cl as a novel, effici ent bromoethylating agent. Spontaneous NO releasers in the diazeniumdiolate d piperazine series include both a fluorescent anion of half-life 5.5 min i n which E: = Na and R = dansyl and "MOM-PIPERAZINO" (E = CH3OCH2, R = H), w hose half-life for NO release was estimated as 17 days. The latter agent ha s made possible the conversion of poly( vinyl chloride)and phosphatidyletha nolamine to NO-releasing derivatives. This chemistry should allow introduct ion of diazeniumdiolate groups into a wide variety of natural products, dru gs, polymers, and other molecules whose activities could be beneficially co mbined with the ability to generate NO for biomedical applications.