title: Aromatic C-nitrosation of a bioactive molecule. Nitrosation of minoxidil.
abstract: Minoxidil (2,4-diamino-6-(piperidin-1'-yl)pyrimidine N(3)-oxide; CASRN 38304-91-5) is a bioactive molecule with several nitrosatable groups widely used as an antihypertensive and antialopecia agent. Here the nitrosation of minoxidil was investigated. The conclusions drawn are as follows: (i) In the pH = 2.3-5.0 range, the minoxidil molecule undergoes aromatic C-nitrosation by nitrite. The dominant reaction was C-5 nitrosation through a mechanism that appears to consist of an electrophilic attack on the nitrosatable substrate by H(2)NO(2)(+)/NO(+), followed by a slow proton transfer; (ii) the reactivity of minoxidil as a C-nitrosatable substrate proved to be 7-fold greater than that of phenol, this being attributed to the preferred para- and ortho-orientations of the two -NH(2) groups at positions 2 and 4 of the minoxidil molecule, which activate electrophilic substitution in the C-5 position through their mesomeric effect. The N-nitrosominoxidil resulting from the nitrosation could be potentially harmful to the minoxidil users.
authors.affiliation: Departamento de Química Física, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: González-Jiménez
authors.forename: Jorge
authors.initials: J
authors.lastname: Arenas-Valgañón
authors.forename: Emilio
authors.initials: E
authors.lastname: Calle
authors.forename: Julio
authors.initials: J
authors.lastname: Casado
mesh_terms: D000505:Alopecia / Q000188:drug therapy; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D002853:Chromatography, Liquid; D004128:Dimethylnitrosamine / Q000009:adverse effects / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000188:drug therapy; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008914:Minoxidil / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D009573:Nitrites / Q000737:chemistry* / Q000378:metabolism; D015538:Nitrosation; D019800:Phenol / Q000737:chemistry; D011522:Protons; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000959:Antihypertensive Agents; D009573:Nitrites; D011522:Protons; D019800:Phenol; D008914:Minoxidil; D004128:Dimethylnitrosamine