Direct liquid chromatography determination of the reactive imine SJG-136 (NSC 694501).
SJG-136 (NSC 694501), 8,8'-[[(propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-methylidene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one], which is being developed as a DNA-interactive antitumor agent, contains highly reactive imines in the diazepinone portions of the molecule. Water or alcohol adds readily to the imino moiety to form the corresponding carbinolamine or its alkyl ether, respectively. This sensitivity to protic substances poses a formidable challenge to the formulation and HPLC assay development for the compound. After studying the solution chemistry of SJG-136 and its potential interaction with various stationary phases, two reversed-phase liquid chromatographic assays for the compound have been developed. A direct assay that separates SJG-136 from its water or methanol adducts and an indirect assay that quantifies SJG-136 as its dihydrate adduct are reported. The latter method, which is more practical for drug development, has been validated. It is reproducible (R.S.D.<2%), linear (r2=0.9999) and accurate (within 98-102% recovery), with a lower detection limit of 2.5 ng.
Cheung
Andrew
A
SRI International, Analytical Chemistry Department, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Struble
Elaine
E
He
Jingyi
J
Yang
Chun
C
Wang
Euphemia
E
Thurston
David E
DE
Liu
Paul
P
D001570:Benzodiazepinones / Q000032:analysis* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003432:Cross-Linking Reagents / Q000032:analysis / Q000737:chemistry; D004355:Drug Stability; D007097:Imines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011758:Pyrroles / Q000032:analysis* / Q000737:chemistry*
C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); D001570:Benzodiazepinones; D003432:Cross-Linking Reagents; D007097:Imines; D011758:Pyrroles