344
Notes
Chem. Pharm. Bull. 53(3) 344—346 (2005)
Vol. 53, No. 3
Antioxidant Activity of Propofol and Related Monomeric and Dimeric
Compounds
,a,b
c
b
a
Masahiro OGATA,* Kazuo SHIN-YA, Shiro URANO, and Toyoshige ENDO
a
b
Kyoritsu University of Pharmacy; 1–5–30 Shibakoen, Minato-ku, Tokyo 105–8512, Japan: Shibaura Institute of
c
Technology; 3–9–14 Shibaura, Minato-ku, Tokyo 108–8548, Japan: and University of Tokyo; 1–1–1 Yayoi, Bunkyo-ku,
Tokyo 113–0032, Japan. Received November 15, 2004; accepted December 23, 2004
This study was carried out to investigate the antioxidant activity of propofol (2,6-diisopropylphenol) and its
related compounds, butylated hydroxyanisole (BHA), 2,6-dimethylphenol, 2,6-di-t-butylphenol, and their dimeric
compounds. The degree of antioxidant activity was evaluated based on the degree of peroxidation induced with
Fe-ascorbic acid in egg phosphatidylcholine through the determination of thiobarbituric acid-reactive substances
(TBARS) formed during peroxidation. Their antioxidant activities were in the order of dipropofolꢄdi(2,6-di-t-
butylphenol)ꢄdiBHAꢄdi(2,6-dimethylphenol). Dipropofol, a dimeric compound of propofol, showed the highest
antioxidant activities. Dimeric compounds had higher activities than monomeric compounds, and the 1,1-
diphenyl-p-picryhydrazyl-trapping ability of dimeric compounds was also greater than those of monomeric com-
pounds (4–10-fold). These results suggest that dimeric phenols may increase their antioxidant activities along
with increments in the conjugation system and play a inhibitory role in the propagation of free radical chain re-
actions.
Key words dipropofol; lipid peroxidation; di(butylated hydroxyanisole); dimeric phenol; free radical; oxidation
In recent years, oxygen-derived free radicals have been re- Experimental
Chemicals 2,6-Di-t-butylphenol, 2,6-dimethylphenol, and 2,6-diiso-
propylphenol (propofol) were purchased from Sigma-Aldrich Japan K.K.
Tokyo, Japan). BHA was purchased from Tokyo Kasei Kogyo Co. (Tokyo,
ported to be closely involved in many medicobiologic prob-
lems such as inflammation, cancer, atherosclerosis, ischemia-
(
1—5)
reperfusion injury, etc.
Free radicals can oxidize biomole-
Japan). Egg phoshatidylcholine (PC) was isolated from egg yolk by the pre-
15)
cules such as nucleic acid, proteins, lipids, and carbohy- viously reported method. a-Tocopherol was purchased from E. Merck
(
Darmstadt, Germany). Thiobarbituric acid (TBA), L-ascorbic acid, and
drates, which may generate cellular alteration and ultimately
lead to tissue injury. Almost all organisms are protected from
free radical attack by defense mechanisms. One such mecha-
nism is a preventive antioxidant system that reduces the rate
FeSO4 were purchased from Tokyo Kasei Kogyo Co., Daichi Kagaku
Yakuhin Co., and Kanto Chemical Co. Inc. (all Tokyo, Japan), respectively.
,1-Diphenyl-2-picrylhydrazyl (DPPH) and ethylenediaminetetraacetic acid
1
disodium salt were purchased from Wako Pure Chemical Co. (Osaka,
of radical formation, and another is a system to produce Japan). CHCl , EtOH, pyridine, and BuOH were purchased from Yoneyama
3
Yakuhin Kogyo Co. (Osaka, Japan). Hydroperoxide was purchased from
chain-breaking antioxidants that scavenge and stabilize free
radicals. The free radical production rate may exceed the ca-
Mistubishi Gas Kagaku Co. (Tokyo, Japan).
2
ꢀ
Fe - and Ascorbic Acid-Induced Oxidation of Egg PC and Assess-
pacity of the antioxidant defense mechanisms and thereby re-
ment of Antioxidant Activity Lipid peroxidation was assayed based on
6)
16)
sult in substantial tissue injury. Recent studies with regard thiobarbituric acid-reactive substance (TBARS) formation. Mixtures of a
to these aspects have suggested that the antioxidant activities solution of egg PC in chloroform (200 ml; 10 mg/ml) and each sample
(
100 ml) were evaporated to dryness under nitrogen gas. Control and refer-
of various agents such as antiallergic drugs, nonsteroidal, an-
tiinflammatory drugs, and traditional Chinese medicines may
have clinically some beneficial actions.
ence substrates with a-tocopherol 20 mM were also tested for comparison.
Lipid peroxidation was initiated by the addition of FeSO 0.2 mM and ascor-
7—10)
4
bic acid 2 mM. After incubation at 37 °C for 30 min, the reaction was termi-
Propofol (2,6-diisopropylphenol), a novel sedative and nated by the addition of EDTA 5 mM. The oxidation mixture was then mixed
anesthetic agent, is recognized to have potent antioxidant ac- with 3 ml of phosphoric acid and 1 ml of aqueous 0.7% TBA solution and
heated at 98 °C for 45 min. The mixture was extracted with 4 ml of n-butanol
tivity. The characteristics of the hindered phenolic structure
of propofol, which are similar to those of the tocopherols,
and the absorbance was measured at 535 nm with a Hitachi 220A spec-
trophotometer (Hitachi Seisakusho Co. Ltd., Japan). Antioxidant activity
was calculated as follows:
butylated hydroxytoluene (BHT), and butylated hydrox-
yanisole (BHA), might account for the antioxidant activ-
11,12)
AcontrolꢃAsample
ity.
after the onset of ischemia. In recent research, sulfite from
the metabisulfite additive in propofol emulsion was shown to where A represents absorbance.
Propofol can reduce ischemia-reperfusion injury
inhibition (%)ꢁ
ꢂ100
13)
Acontrol
create oxidative environments when the emulsion is exposed
to air during a simulated intravenous infusion. This oxidation
results in propofol dimerization and propofol dimer quinone
Synthesis of Dipropofol Propofol (1 g) was dissolved in CH Cl and
2 2
mixed with CuCl(OH)·TMEDA (16 mg) and allowed to stand at room tem-
perature for 5 h. The reaction product was extracted with AcOEt and evapo-
rated. The reactant was dissolved in ethanol, Na S O (1 g) was added, and
the mixture was heated for 20 min. The precipitate was separated, collected
in a filter, and crystallized from hexane to give dipropofol (950 mg, 95%).
FAB-MS m/z: 355 (MꢀH) . H-NMR (500 MHz, CDCl , d, ppm): 1.32
(
Ar). HR-FAB-MS: C H O , 355.2643; Calcd, 355.2637. mp: 108 °C.
Synthesis of DiBHA BHA (10 g) was dissolved in pyridine (10 g) and
mixed with FeSO (100 mg) and 31% H O (20 gꢂ3) at 60 °C for 30 h. The
14)
2
2
4
formation. Their antioxidant activities, however, are still
unknown.
ꢀ
1
In this study, we examined the inhibitory effects of propo-
fol and its related compounds, the dimeric compounds of
propofol, 2,6-dimethylphenol and 2,6-di-t-butylphenol, on
lipid peroxidation.
3
24H, d, Jꢁ6.7 Hz, 8ꢂCH ), 3.20 (4H, d, Jꢁ6.7 Hz, 4ꢂCH), 7.20 (4H, s, H-
3
2
4
35
2
4
2
2
reaction product was extracted with AcOEt and distilled by steam distilla-
tion. The residue was recrystallized from ethanol to give diBHA (3.52 g,
∗
© 2005 Pharmaceutical Society of Japan