Synthesis of 10, 11-Dihydroxydihydroquinidine N-oxide, a New Metabolite of Quinidine. Preparation and ¹H-nmr Spectroscopy of the Metabolites of Quinine and Quinidine and Conformational Analysis via 2D COSY NMR Spectroscopy

Abstract

The first synthesis of 10,11-dihydroxydihydroquinidine N-oxide [7b], a recently isolated metabolite of quinidine, was accomplished in three steps from 1b. The related congener 7a in the quinine series was also prepared, as well as two other analogues 3a and 4a. In addition, the previously reported human metabolites 2a, 5a, and 6a of quinine [1a] and those 2b, 3b, 4b, 5b, and 6b of quinidine [1b] were synthesized. The chemical shift and coupling constants for all of the metabolites of quinine and quinidine were assigned via 2D COSY 1H-nmr spectroscopy. Moreover, the conformations of these metabolites in solution were found to parallel those of the parent alkaloids, quinine [1a] and quinidine [1b], respectively.

Transformation of Cinchona Alkaloids into 1-N-Oxide Derivatives by Endophytic Xylaria sp. Isolated from Cinchona pubescens.

“…Among the microbial transformation products, 1a, 2a, and 3a were identified as quinine 1-N-oxide, [3][4][5] quinidine 1-N-oxide, [3][4][5][6] and cinchonidine 1-N-oxide, 3,7) respectively, by comparisons of the physicochemical properties including the specific rotations. The physicochemical properties of cinchonine 1-N-oxide (4a) are given here, since Dodin et al 7) reported only 1 H-NMR (in DMSO-d 6 ) and MS spectra for 4a.…”

“…The CHCl 3 -soluble portion was separated by HPLC on Hibar LiChrosorb NH 2 to afford 1a (90% yield) from 1 · HCl, 2a (71% yield) from 2 · HCl, 3a (82% yield) from 3 · HCl, and 4a (52% yield) from 4 · HCl, respectively. Among those transformation products, 1a, 2a, and 3a were identified by comparisons of their physicochemical data (mp, [a] D , 1 H-, 13 C-NMR, IR, and UV) with those of quinine 1-N-oxide, 3-5) quinidine 1-N-oxide, [3][4][5][6] and cinchonidine 1-N-oxide, 3,7) respectively. 4a, which was transformed from cinchonine hydrochloride (4 · HCl), showed similar absorptions to those of 4 in the IR and UV spectra.…”

“…4a, which was transformed from cinchonine hydrochloride (4 · HCl), showed similar absorptions to those of 4 in the IR and UV spectra. (4). From the above findings, it was assumed that 4a might be cinchonine 1-N-oxide, which was previously prepared from 4 by Dodin et al 7) The endophytic fungus Xylaria sp.…”

Enzyme Kinetics for the Formation of 3-Hydroxyquinine and Three New Metabolites of Quinine in Vitro; 3-Hydroxylation by CYP3A4 is Indeed the Major Metabolic Pathway

“…After thawing, the incubation mixture was centrifuged at 1500g for 10 min and 10 to 20 l of the supernatant was injected into the high performance liquid chromatograph. Standard curves with 4 to 5 calibrators were used for quantification of the formed metabolites [3-hydroxyquinine, 2Ј-quininone (provided by Dr. Christie (Diaz-Arauzo et al, 1990)], (10S)-11-dihydroxydihydroquinine and (10R)-11-dihydroxydihydroquinine (synthesized according to Zheng et al (2001). The rates of formation were linear over 45 min of incubation and 0.25 to 2 mg of microsomal protein.…”

NMR Relaxation Measurements on Complex Samples Based on Real-Time Pure Shift Techniques

“…The molecular structure of quinine is given in the top of Figure 3, along with the assigned protons from 1 to 16. [28] A conventional 1D NMR spectrum is acquired in the well-shimmed magnetic field. Numerous multiplet peaks are observed and assigned to corresponding protons ( Figure 3A).…”