A Novel Family of Aromatic Diazirines for Photoaffinity Labeling

Abstract

A series of simple methods for modifying diazirines bearing an aromatic ring has been accomplished. This first versatile approach involving direct substitution on the aromatic ring of diazirines has been achieved by means of the aromatic thallation of (alkoxyphenyl)diazirines. Introduction of the thallium moiety was successfully followed by nitration, iodination, or palladium-catalyzed carbonylation to give a family of substituted aryldiazirines useful for photolabeling. For instance, diazirines labeled with a nitro group can be detected by spectrophotometric methods, and those labeled with an iodo group can be useful in tracer experiments. The (methoxyphenyl)diazirines were also found to be stable under certain demethylation conditions, thus providing a potential source of diazirines with modifiable phenol hydroxyl groups. By means of this approach, a spacer arm to link diazirines with ligands was readily introduced. Radioactive diazirines labeled with carbon-14 or tritium were also prepared using this method. All the new diazirines were derived from a pair of simple (methoxyphenyl)diazirines. The ease of derivatization of the (alkoxyphenyl) diazirines described here may offer a practical approach to simplify the time-consuming methods currently used for diazirine synthesis.

Synthesis of Substituted Phenyl Diaziridines and Characterization as Mechanism-Based Inactivators of Human Cytochrome P450 2B6

“…The following compounds were synthesized as described previously: 4-methyoxyphenyl series, 1a, 3a, 4a, 5a (Hatanaka et al, 1994); and 4-methyl thio series, 1d, 3d, 4d, 5d (Findlay et al, 1995).…”

Synthesis of a PbTx-2 photoaffinity and fluorescent probe and an alternative synthetic route to photoaffinity probes

“…The reaction mixture was extracted with ether (3 x 25 ml) and the organic layers were combined and dried over Na2SO4. Evaporation of the solvent, gave a crude yellow oil which was purified by radial chromatography (2 mm plate, 2:1 hexane/CH2Cl2) to give 9 (286 mg, 77%) as a pale yellow oil: Spectroscopic data was consistent with literature 44 . …”

“…Photoaffinity labeling takes advantage of highly reactive intermediates such as nitrenes or carbenes, which are created from functional groups capable of being activated photochemically 44 . Ideally a photolabel should be chemically inert but become reactive when exposed to UV light.…”

Structure-Activity Relationship and Elucidation of the Determinant Factor(s) Responsible for the Mechanism-Based Inactivation of Cytochrome P450 2B6 by Substituted Phenyl Diaziridines

“…1, namely, 3-trifluormethyl-3-(4-methoxyphenyl)diaziridine (1), 3-4-ethoxyphenyl-3(trifluoromethyl)diaziridine (2), 3-trifluoromethyl-3-(3,4-dimethoxyphenyl)diaziridine (3), 3-trifluoromethyl-3-(3,4,5-trimethoxyphenyl)diaziridine (4), 3-trifluoromethyl-3-(3-methyl-4-methoxyphenyl)diaziridine (5), 3-trifluoromethyl-3-(4-(methylthio)phenyl)diaziridine (6), and 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanone (10) were synthesized as described previously (Sridar et al, 2006). 3-(3-Methoxyphenyl)-3-(trifluoromethyl)diaziridine (7) and 3-(trifluoromethyl)-3-phenyl-diaziridine (9) were also synthesized as described previously (Brunner et al, 1980;Hatanaka et al, 1994), and the analytical and spectroscopic analyses were in accord with the published data. 4-Bromphenol-2,3,5,6-d 4 (CAS 152404-44-9) was purchased from C/D/N Isotopes (Pointe Claire, QC, Canada) and methylated according to the reported procedure for the synthesis of 12b (Cho et al,1993).…”