Synthesis and reduction of (S)-(-)-nicotine-N´-oxide and N,N´- dioxides by rat liver S-9 fraction
Koji Uwai, Hirokazu Sato, Naoe Kazakami, Hisao Matsuzaki, and Mitsuhiro Takeshita*
Tohoku Pharmaceutical University
4-4-1 Komatsushima, Aoba-ku, 981-8558 Sendai, Japan
E-mail:
[email protected]
Dedicated to Professor Keiichiro Fukumoto on the occasion of his 70th birthday
(received 30 May 03; accepted 03 Sept 03; published on the web 19 Sept 03)
Abstract
cis- And trans-Nicotine-N’-oxide (5) and N,N’-dioxide (7) diastereomers were synthesized in good yields from nicotine (1) using m-CPBA. Asymmetric reductions of nicotine N-oxides with rat liver S-9 fraction were investigated.
Keywords: Nicotine, MO calculations, nicotine-N’-oxide, nicotine-N,N’-dioxides, S-9
Introduction
Nicotine (1) is one of the main pharmacologically active constituents of tobacco, and when nicotine (1) is administered it is well absorbed by digestive and respiratory organs as is metabolized to cotinine (2), 5’-hydroxycotinine (3) and 3’-hydroxycotinine (4) by CYP2A6. Nicotine (1) is also metabolized by FMO to trans-nicotine-N’-oxide (5a) (Scheme 1).1,2 The N- oxidation of nicotine (1) shows an interesting stereoselectivity in the formation of cis- and trans- nicotine-N’-oxides (5a and 5b).3 The kinetic properties of the formation of these diastereoisomeric nicotine-N’-oxides (5a and 5b) in rat liver microsomes were only recently reported.4 Interestingly, in humans, the trans-isomer was the major excreted urinary metabolite, while cis-nicotine-N’-oxide (5b), nicotine-N-oxide (6), and the further oxidized product, nicotine-N,N’-dioxide (7) are not found in the urine. To understand these observations nicotine- N-oxides were prepared using m-CPBA and the transition state energies of the reaction intermediates were investigated by an ab-initio MO method. The metabolic reduction of nicotine N-oxides using the rat liver S-9 fraction was also investigated.
