Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more ➡
Download
Standard view
Full view
of .
Add note
Save to My Library
Sync to mobile
Look up keyword
Like this
3Activity
×
0 of .
Results for:
No results containing your search query
P. 1
Journal of Medicinal Chemistry - Volume 6 - Issue 4 (1963)

Journal of Medicinal Chemistry - Volume 6 - Issue 4 (1963)

Ratings: (0)|Views: 1,660|Likes:
Published by jtjdp4

More info:

Published by: jtjdp4 on Aug 16, 2010
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See More
See less

02/22/2013

pdf

text

original

 
Journal of Medicinal Chemistry is published by the American Chemical Society. 1155Sixteenth Street N.W., Washington, DC 20036
Demethylation Studies. IV. The in vitro and in vivoCleavage of Alkyl- and Arylalkyl-p-nitrophenyl Ethers
Robert E. McMahon, Hilman W. Culp, Jack Mills, and Frederick J. Marshall
J. Med. Chem.
,
1963
, 6 (4), 343-346• DOI: 10.1021/jm00340a001 • Publication Date (Web): 01 May 2002
Downloaded from http://pubs.acs.org on April 8, 2009
More About This Article
The permalinkhttp://dx.doi.org/10.1021/jm00340a001provides access to:Links to articles and content related to this articleCopyright permission to reproduce figures and/or text from this article
 
JournalofMedicina1
Chemistry
@
Cop~,rwhl
1965
by
the
American Chemical Society
YOLUME
,
XCMBER
JULY
,
1963
Demethylation Studies.
IV.
The
in
citro
and
in
civo
Cleavage
of
Alkyl- and Arylalkyl-p-nitrophenyl Ethers
ROBERT
.
ALC~\IAHON,
ILKLV
W.CULP,
ACK
11~~5,
SD
FREDERICK
J.
N.UISHALL
Lzlly
Research
Laborcdories,
Indzalmpolzs6,
Indiana
Received
January
4,
963
Tlie oxidative 0-dealkylation of a series
of
alkyl
and
arylalkyl p-nitroplien;\-l ethers
by
rat liver microsomes
has
been studied.
For
saturated alkyl
groups
t,he rat,e tends t,o decrease u-ith increasing bulk
of
t,he
group.
Certain electron donating groups such as ethylene, cyano, and phenyl when at,tached
to
the reactive methyleneincrease the rate
of
reaction. Ring subst,itution of any
type
in the benzyl
group of
p-nitrophenyl benzyl ethertends to reduce the rate.
In
Z'L.~
dealkylation rates correlated wellwith
in
citro
results.This is
thought
to be simply
a
steric effect.
Hiiggiiii,
.Jeiiscii,
aiid
Clei.elaiidl studied the
zn
&o
iuetaholism
of
p-nitroanisole aiid p-iiitropheiietole inthe rat
aiid
foliiid
them to be extensively cleaved top-iiiti*opIiciiol. 17sing. issue hoinogeiiates, they foundthat
both
Iii
er
aiid
kidiiey could rarry out this cleavage.
In
a
study
of
the
zn
rtztro
coiiversioii
of
rodeiiie
to
inor-
pliiiic
iueliml?
fowd
the enzymatic activity responsibleresided
iii
IIVCI.
iiii(8rosoines
and required
SXDI'H
aiid
oxygeii.
rl'lie
methyl
group appeared as
formalde-hyde.
Thus
the reactioii
was
shown to
he
oiieof
the
sev-
rral oxidatii
c
imctioiis that are catalyzed
hy
mamma-liaii
IiL
er
micarosomal eiizyinei
aiid
which possess areqiiireinciit
for
SA4DI'H
aiid
.ixelrod4
alsostudied
zn
zt~o
-dealkylation
of
a
variety
of
riiig
suh-
stituted
aiiiwl~s
iid
plieiietoles
by
the
mi(-rosomal
sys-
teni.
Ailtliou~lihe c.lea\.age
of
a
wide
\.ariety
of
arylalkylctheis ha\-e heeii reported,j
iioiie
have
beeii
in\ estigated
ill
\\-hicsli
he
alkyl group was
other
thaii methyl
or
ctliyl.
In
the
present study the aryl group was held
cnoiistaiit
(p-iiitioplieiiyl) and tlie
iiatm.c>
of
tlie alkyl
grotip
1-ai.ied
oiw
a wide
range.
Experimental
Materials.-Substituted
p-nitrophenyl cthers needed for thisstudy 1vei-e prepared
by
st,andard organic synthesis procedures.Paper chromatography was used to ehox that each ether
\vas
free
of
p-nitrophenol. The preparation
of
C" labeled p-nitro-phenyl benzyl ether will serve
to
illustrate
tlie
method used.
A
mixture of 330 pmoles
of
sodium p-nitrophenoxide and 200pnioles
of
benayl-l-Cl4 chloride in
3
ml.
of absolute ethanol
was
refluxed
16
hr. and then evaporated to dryness. The product
(1)
C. Huggins,
E.
F'.
Jensen, and
A.
S.
Cleveland,
I'roc.
So?.
h'xp.
Bioi.
(2)
J.
Axelrod,
J.
Pham"ol.
Ezptl.
Therap.,
115,
239 (19.55).
(3)
B.
Brodie,
J.
.kxelrod,
J.
R.
Cooper,
L.
Gaudette,
B.
N.
LaUu,
C.
(4)
J.
Axelrod,Biochem.
J.,
63,
fi34
(19%).
(5)
R. T.
TYilliarns, "Detoxication AIeciianisnis,"
Jolin
!Gley
and Sons,.Ired.,
68,
477
(1948).
.\Iitoma, and
S.
Udenfriend,
Science,
121,
603
(1955).
h'ew
I'ork,
N.
Y.,
1959.
1).
321.
was
taken up in etlier and unreacted phenol renioved by estrsc-tion with alkali. The ether solution
was
reduced to dryness
md
the product recrystallized from metli\-lryc.lohexane. The
prnd-
uct weighed 20 nig. (43':t) and melted
at
103-105" (reporteds
106').
Paper chromatography was used to demonstrate that nounreacted p-nitrophenol
or
benzyl-1-C" chloride remained in theproduct.
Methods.
Microsomee.-The livers
of
iiornwl
m:de
rats
were quii~kl~~emoved.
folio
.[-in de ,:.p:taL'cin.
nnd
p':t(.ed in icero!d
0.1
.Ii
phoq)hnte
bu"er.
pH
7.4. ?he livers were weighed,minced,
and
put
into
a (*old Potter-E1veh:eni homogenizer.Phosphate buffer
vas
added in the rat,io of
1:
and the livers werehomogenized with
:I
Teflon pestle
for
1-1.5 min. The pooledhoniogenates ',rere caentrifuged at
20,000/
for
30 niin. in
:t
Spinco
LIiidel
I,
rentiifuge
;it
0".
The
resulting siip-rniitmt
n-~s
henrecentrifuged at
S0,OOO:i
for 30 niin. and an aliquot
of
the clearsupernatant, !ree of visible fat,
was
removed and saved. Theremainder
of
the supernatant
was
decanted and discarded.
The
niic
rosonieswverr
resrispended b>- honiogenizing tlie niicro-some pcllet with suitable volumes
of
huffer
and
S0.000:/
super-nat:tnt to \-ield
:i
final
si
spension containing in each
1111.
tlie
micro-somes froin
200
iiig.
of
liver and 80,0007 supernatant
from
40
ing.
nf
liver
In
T'ilro
Dealkjrlaticns.--Var:.ing
amounts of substratedissolved in 0.2
ml.
of
polyethj-lene
glycol
(PEG
400)
were
pl;tcaedin
20
nil.
beakers
and to this
11-as
added 1
nil.
of
mic*rosome
suspension,
50
pnioles
of
nicotinamide?
50
pmoles
of
niagnesiunivhloride,
10
pnioles
of
glucose-6-phosphate, 0.5pniole
of
S,ZDP,
and sufficient, buffer (pH 7.4) to bring t,he final volume to 3
nil.
In the runs involving inhibitors the inhibitor
was
added with
the
substrate.
Incubations were carried out in a shaker at 37" in an ntmos-phere
of
oxygen for 30 min. The presence
of
oxygen completelyinhibited the activity of the microsomal reductase' and p-nitro-phenol carried through
the
incubation could
be
recovered quan-tit,atively. The incubation
was
stopped
by
t,he addition of
1
nil.
of
10yc
richloroacetic acid and the precipitated protein renioved
by
centrifugat,ion. After adding
1
nil. of 0.T5
.I'
SaOH to 3 nil.of supernatant, unreacted subst,rate
was
removed by extractionwith
5
nil.
of
methylene chloride. Removal
of
unreacted
sub-
strate
was
necessary since
its
presence interfered with the p-nitro-phenol reading. p-Sitrophenol
was
determined spectroplio-tometrically
at
400
mp.
That the product
was
indeed p-nitro-
(6)
C.
liiirupf,
.4nn..
234,
123
(1881).
(7)
J.
R.
Fouts
and
B. B.
Brodie.
J.
Phaimacol.
Ezpll.
Therap..
119,
197
(19,771.
343

Activity (3)

You've already reviewed this. Edit your review.
1 thousand reads
1 hundred reads
J1 liked this

You're Reading a Free Preview

Download
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->