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Antimetabolites of Coenzyme Q. Their Potential Application as Antimalarials

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Volume 13
-
Number 9
September 1974
Pages 559 - 618
International Edition in English
Antimetabolites of Coenzyme Q. Their Potential Application as Antimalarials
By Thomas H. Porter and Karl Folkers[*]
Malaria is transmitted to man by the bite of the female Anopheles mosquito, man acting as
the intermediate host, and the mosquito as the definitive host for the plasmodia. Plasmodia
are found to have become resistant to certain chemotherapeutic agents. A new fundamental
approach to malaria chemotherapy is based on the biochemical rationale of inhibition of
the electron transfer mechanism in the metabolism of plasmodia by antimetabolites of coenzyme
Q , which is essential for electron transfer. Coenzyme Q refers to 2,3-dimethoxy-5-methyl-l,4benzoquinones with isoprenoid chains of varying length on C-6. In this progress report a series
of synthetic antimetabolites are presented together with a discussion of their action in current
pharmacological tests.
1. Malaria4till a Widespread Disease
Malaria, a disease of the blood system caused by protozoa
of the genus Plasmodium, is perhaps the most worldwide of
all human diseases. According to a new treatise by Sfeck"'
at least one-tenth of the human race suffers from malarial
disease each year despite all attempts both therapeutically
and prophylactically to control the disease. It is still the most
devastating of the infectious diseases of man. The millions
of infections and many hundreds of thousands of deaths that
occur each year demonstrate that malaria constitutes a global
problem that has not yet been eliminated[''.
Malaria is transmitted to man by the bite of the female Anophrlrs mosquito, man acting as the intermediate host, and
the mosquito as the definitive host for the plasmodia. Control
of malaria has been effected by the public health measures
of eradication of the mosquito vector by chemical agents
and destruction of breeding areas; numerous chemotherapeutic agents have been developed for treatment of the illness.
In chemotherapy, two natural product antimalarials which
have withstood the test of time and have proved effective
are quinine ( 1 ) and febrifugin ( 2 ) . However, because of the
I'[
Prof. I>r. K . Folkers and Dr. T. H. Porter
institute for Biomedical Rescarch
The University of Texas a t Austin
Austin. Texas 7x712 ( U S A )
Angen. Chem. internat. Edit
Val. 13 (1974) J No. 9
threat of restricted quinine supplies during the World Wars,
these drugs have gradually been replaced by synthetic chemotherapeutic agents such as chloroquine (31, primaquine ( 4 ) .
aniodiaquine /S), proguanil ( 6 ) . and pyrimethamine 17).
I Lj
Between about 1948 and 1950 the resistance of plasmodia
to certain chemotherapeutic agents became a significant problem following the discovery in Malaya of the resistance of
Pfasmodiirm jukipurum and Plasmodizrm ciuax to proguanil
16) (cf. Ref. [?I). Since then the resistance to other important
antimalarials has been reported from many other countries
of the world, including Africa and South America.
As certain strains of plasmodia have been found to be resistant
to conventional antimalarial drugs, such as chloroquine (3)
and primaquine ( 4 ) [ 3 - s 1new approaches to malaria chemotherapy have had to be sought by many investigators. One
new and fundamental approach is based on the biochemical
rationale of an inhibition of the electron transfer mechanism
in the metabolism of plasmodia; this approach forms the
main theme of the present progress report.
559
2. Early Research on Naphthoquinones as Antimalarials
As early as 1942, as the result of a screening program in
the search for new antimalarial agents, hydrolapachol ( 8 )
and two structurally similar quinones ( 9 ) and (10) were found
to possess antimalarial activity against P. lophurae in ducks.
These results stemmed largely from the prodigious researches
carried out by Fieser and LeJ37er and their respective coworkers on quinones, particularly the naphthoquinones[‘. ’I.
(Si, R
(9).
&OH
= (CHd-CH(CH3);!
= (CHZ)E<(~-C~HI,)Z
OH
R
0
activity of these naphthoquinones was the result of antagonism
of vitamin K. Such a concept appeared reasonable, for it
was known that vitamin K participates in the metabolism
of many microorganisms, although the presence of vitamin
K in plasmodia had still not been established, and apparently
not even sought for.
(lo), R
=
(cH~),
c)
Emerging from all this effort were, inter alia, clinical data
on two naphthoquinones ( 9 ) and ( l o ) ,which showed antimalarial activity in manIb1. In the case of ( 9 ) , it was stated
that “two patients left the hospital in perfect condition with
no parasites in the blood .._or without relapse”[61.For ( l o ) ,
it was said that the “effect was not satisfactory, but enough
to show ... definite antimalarial activity in man”’”].
In 1943, Buuer found that some of these 2-alkyl-3-hydroxy-l,4naphthoquinones were also effective prophylactic agents
against malaria in chickensf8- In].Administration of such
quinones, in adequate dosage prior to and for about five
days after the inoculation of chickens with sporozoites of
P. gullinaceurn, provided complete protection. In further investigations it was established that these naphthoquinones destroyed the exoerythrocyticforms of the malarial parasite which
were in the reticuloendothelial cells of chicks infected with
P. gaUinaceumf9~“1.
Research on the mode of action of these quinone antimalarials
waslimitedduring the 1940’s,althouth certaindatadid indicate
interference with cell respiration. About 1945, Wendell“ ‘I found
that 2-alkyl-3-hydroxy-l,4-naphthoquinoneswere indeed
potent inhibitors of respiratory systems. At concentrations
of ca. 1 x
mol/l, 2-(3-cyclohexylpropyI)-3-hydroxy-l,4naphthoquinone (10) reduced the respiration of parasitized
erythrocytes by about 50% in blood drawn from a duck
infected with P. lophurae. The results of these studies also
indicated that these compounds interfere with carbohydrate
metabolism and cause accumulation of lactic acid in the
organism.
Smith et a/.[”’31 reported that 2-(3-cyclohexylpropyl)-3-hydroxy-I ,4-naphthoquinone (10) produced a hemorrhagic syndrome and hypoprothrombinemia in young rats, and that
the development of these symptoms was prevented by simultaneous administration of vitamin K. These authors’ data
also implied the existence of a form of vitamin K in plasmodia.
It was not until after these studies on naphthoquinone antimalarials that coenzyme Q (ubiquinone) ( 1 2 ) was discovered,
and its widespread presence in living systems and its role
in cell respiration, e. g. in succinate-dehydrogenase- and
NADH-dehydrogenase-coenzyme Q[*’ enzyme systems, was
established (cf. Ref. {14]).
Hendlin and Cook[151
and Takemari and King“ demonstrated
the inhibition of succinate-dehydrogenase by certain 2-hydroxy-I ,4-naphthoquinones and its reversal by coenzyme
Qin[**I.
Similarly, Howland“71 demonstrated the inhibition
of mitochondria1 NADH-dehydrogenase by 2-alkyl-3-hydroxy-I ,4-naphthoquinones.
Since 1958, it has been known that microorganisms biosynthesize and apparently use vitamin K and/or coenzyme Q in
their oxidative metabolism. Consequently, one could also
assume that vitamin K and/or coenzyme Q are present in
plasmodia, since the occurrence of mitochondria in plasmodia,
particularly in its later stages of development, had already
been documented[’8. l9].
It was predicted that coenzyme Q could exist in plasmodia
as an intrinsic component of metabolism, and that the antimalarial activity of naphthoquinones (81, ( 9 ) , and ( 1 0 ) could,
at least in part, be due to inhibition of coenzyme Q in the
manner of antimetabolites.
3. Discovery of Coenzyme Q8 in Plasmodia
The structural similarity between the compounds (8)-( 10)
and vitamin K (11) formerly implied that the antimalarial
560
[*] These enzymes are also known as “succinoxidase” and “DPNH-oxidase”.
respectively.
[**] The subscript denotes the number n of isoprene units.
Angew. Chem. internat. Edit. J Yo1 13 (1974) J No. 9
The search for the presence of coenzyme Q in plasmodia
was successful; in 1967 Rietz, Skefron, and F o l k u s reported
the occurrence of coenzyme Q 8 and Q g in P. foph~rrae~~*~~'l.
Mass spectral data and reversed-phase paper chromatographic
results showed that CoQx and possibly CoQ9 were present
in parasitized duck blood and could be biosynthesized by
P. lophiirue. Vitamin K was not detected in lipid fractions
by reversed-phase paper chromatography.
Skdton, Lunan, and Folkers, in collaboration with Schnell,
Sirldiytri, ,and Geiman["J, next demonstrated that the [ I "C]coenzymes Qx, Q9,and perhaps Q 7 are biosynthesized from
["C]-p-hydroxybenzoicacid in parasitized blood; the authors
isolated these coenzymes from the blood cells of rhesus monkeys which were parasitized with P. knowlesi. It was then
shown by Skelton e t
that COQXwas biosynthesized
in the blood of rhesus monkeys infected with P. cjxomolgi
and in the blood of mice infected with P. berghei. Again,
the presence of vitamin K in plasmodia could not be detected,
neither by reversed-phase paper chromatography nor by mass
spectral analysis, nor by a labeling method using in t'itro cultures
of P. knowlesi that had been incubated with [I4C]-shikimic
acid, a precursor in the biosynthesis of vitamin K.
Scl?ndl rf nl."'] also demonstrated the biosynthesis of coenzymes QH, QQ, and QI,) in Aotirs blood cultures infected
with P.,fulcipar~rm;but only the CoQ,,) was intrinsic to the
mammalian cells.
With the establishment of the presence and biosynthesis of
coenzyme Qs as the dominant coenzyme Q (compare Ref.
[ 2 5 ] ) in plasmodia and the apparent absence of vitamin K.
it seemed reasonable that such naphthoquinones as (a), ( 9 ) ,
and ( 1 0 ) could actually exert at least part of their antimalarial
activity by interference with the biosynthesis and/or the function of CoQx in the metabolism of plasmodia. Also, it was
now clearly evident that the synthesis of new analogs of coenzyme Q, rather than of vitamin K , opened up a biochemically
valid and previously unexplored approach to new and effective
antimalarials and to other chemotherapeuticals.
4. Synthesis and Antimalarial Activity of Menoctone
In 1967, Fieser and Archer and their respective associates'"'
synthesized additional membersof the 2-(o-cyclohexylalkyl)-3hydroxy- 1,4-naphthoquinone series, including the new naphthoquinone derivative menoctone, 2-(8-cyclohexyloctyl)-3hydroxy-l,4-naphthoquinone ( 1 3 ) , which has since been
extensively investigated as an antimalarial agent both curatively and prophylactically.
0
In mice infected with P. berghei, menoctone showed activity
(T-C=6.2)[*] at 20mg/kg and 4/S cures at 160mg/kg in
the routine one-dose (sc) treatment['". However, at a dose
level of 640mg/kg, menoctone exhibited toxic effects; this
dosage led to only 215 cures and 315 deaths["'.
- - .- .. . . . .
I'[
IT-C) is defined as the change in survival t u n e (in days) of treated
and untreated (controll animals.
Anyrw. Chrm. internat. Edit.
Vol. 13 (1974)
1 No. 9
For comparison: chloroquine ( 3 ) , when it was given orally
at a dose of 5mg/kg once a day for five days to groups
of five mice, consistently cleared the blood of parasites in
all mice for the entire test period of 28 daystLH1.
Similar results
were obtained with menoctone, but at a daily dose rate of
2Smg/kg for five days[*'].
Menoctone was also highly effective prophylactically. In 1968
Berb-herian et
reported that menoctone afforded mice
more protection than primaquine ( 4 ) when the drugs were
administered orally twice daily throughout the course of the
preerythrocytic cycle. Two and a half times as much primaquine had to be given to the mice to afford complete protection
[(number of parasite-free animals/number of surviving animals
on the nth day after infection)= I]. Moreover, oral toxicity
data showed that menoctone (13) was I/! 5 as toxic as primaquine (4).
5. Inhibition of Coenzyme Q Enzymes by Chloroquine ( 3 ) and Menoctone (13)
After having established the presence of CoQ, in plasmodia
it seemed appropriate to test already known antimalarial drugs
and also the extensively studied naphthoquinone, menoctone
( / 3 ) , in cirro to see if they actually d o have antimetabolite
activity for coenzyme Q. Subsequently, both chloroquine ( 3 )
and menoctone ( 1 3 ) were found by Skelton et ~ l . l - ' to
~ ) inhibit
~
the NADH-dehydrogenase coenzyme Q system. Chloroquine
diphosphate depressed NADH-dehydrogenase activity to 70,
60, 50, and 17%)when levels of 25, 50, 100, and lo00 nmoles,
respectively, were added to the intact system supplemented
with 100 nmoles of exogenous CoQ,,. Menoctone proved
to be a far much more potent inhibitor in this in virro system ;
as found by S z ~ r k o w s k a [ ~at' ~levels
,
of I , 10. and 25 nmoles
in an intact NADH-dehydrogenase system in the presence
of 100 nmoles CoQ,,, it depressed enzyme activity to 83, 12,
and 11?(,, respectively. of the CoQ,,-treated control systemf3*!
on mitochondrial electron
Current research by Crunr rt
transport indicates that chloroquine ( 3 ) inhibits oxidation
of reduced coenzyme Qloat a site containing a non-heme iron
protein (MW x 16000). Chloroquine does not, however, inhibit
the oxidation of durohydroquinone; this finding is consistent
with chloroquine competition for enzyme sites with CoQ,,.
Other important evidence, although indirect, for the inhibition
of coenzyme Q systems by antimalarial naphthoquinones was
found in a study of the changes in P. berghei fine structure
induced by menoctone (13)andprimaquine(4)[331.The initial
mitochondria1 swelling would appear to be followed by generalized degenerative changes in the plasmodia. This finding suggested an initial action of the drugs on the parasite's mitochondria, the apparent CoQ8-containing organelle in which oxidative processes are carried out.
In a study of chloroquine resistance in malaria by Fitch[3"',
the major difference between chloroquine-sensitive and chloroquine-resistant parasites was a deficiency of high affinity binding of chloroquine by cells infected with the chloroquine-resistant parasite. This binding deficiency could explain the reduced
ability of chloroquine-resistant parasites to concentrate chloroquine[355 361 and suggests that chloroquine-resistance is due
to a decrease in the number, affinity, or accessibility of chloroquine receptor sites in the malaria parasite.
561
6. Synthesis of Other Antimetabolites of
Coenzyme Q
At this stage of the investigations, the synthesis of new quinones
as potential antimalarials could be designed upon new knowledge of the existence and role of coenzyme Qs in the metabolism of plasmodia.
New hydroxybenzoquinones based on the structure of coenzyme Q, the 2-alkyl-3-hydroxy-5,6-dimethoxy-1,4-benzoquinones ( 1 4 ) , were synthesized by Catlin et al.[37.3*1by
procedures which permitted considerable structural variation;
the alkyl groups were aliphatic (including isoprenoid moieties).
Catlin et
381 and Pardini et
found the quinones (14)
to be potent inhibitors ofcoenzyme Q enzyme systems. I n t'itro
studies showed that some of these hydroxy-1,4-benzoquinones strongly inhibit succinate-dehydrogenase and NADH-
new and effective prophylactic and curative antimalarials.
Quinones were designed with long side chains to impart lipoid
character and with various ring substituents which could offer
differences in oxidation-reduction potentials, hydrogen bonding, and alkylation sites.
6.1. Alkylhydroxyquinolinequinones
Two series of lipoidal quinones which were examined in this
connection were the 7-alkyl-6-hydroxy- and 6-alkyl-7-hydroxy-5,8-quinolinequinones ( I S ) and [ 16), respectively,
which had previously already been synthesized by Pratt and
Drake[4'.421.In this study, Porter et
synthesized additional new alkylated 5,8-quinolinequinones, namely by alkylation of 6- and 7-hydroxy-5,8-quinolinequinones,with
diacyl peroxides.
0
H3CO
H3c0$0H
R
0
(14)
0
0
dehydrogenase in intact mitochondria1 systems from bovine
heart (Table
or in a system which is extracted for removal
of coenzyme Q10[371.Compound (14c) was more effective
than other phytyl derivatives carrying residues other than
OHf391.The succinate-dehydrogenase system was generally
more sensitive to most of the benzoquinones than was the
NADH-dehydrogenase system, the influence of the alkyl side
chains on the activity being very slight[39!
According to Custelli et ul.[401the quinones ( i 4 a ) and (14c)
are also effective inhibitors of NADH- and succinate-dehydrogenase of intact mitochondria from yeast. CoQ, reversed
the inhibition in NADH-dehydrogenase, but there was little
or no significant reversal in succinate-dehydrogenase. Surprisingly, when CoQ,-deficient NADH-dehydrogenase was
supplemented with 2-hydroxy-5,6-dimethoxy-3-phytyl-1,4benzoquinone (14cj and CoQ,,, there was an unexpected
increase in enzyme activity, indicating some coenzymatic
activity in this particular
It is important to emphasize that the coenzyme Q8 of plasmodia is a lipoidal substance; this is largely because of the
forty carbon atoms in its isoprenoid side chain. Consequently,
one may presume that effective inhibitors of coenzyme Q8
would. of necessity, also have to be lipoidal in nature. For
this reason, the synthesis of several categories of lipoidal
quinones has been undertaken as part of our research toward
In the 7-alkyl-6-hydroxy-5,8-quinolinequinone
series ( I S ) ,
maximum antimalarial activity against blood-induced P . berghei
in mice, according to the procedure of Usdene et ul.[441,
was displayed by compound ( l S a ) with a side chain of 15 carbon atoms. 6-Hydroxy-7-n-pentadecyl-5,8-quinolinequinone
( 1 5 ~showed
) ~ ~1/5
~ cures
~
and an extension of survival time
(T - C)= 13.2 days at 640mg/kg in the routine one-dose treatment (sc) of mice infected with P. berghei. In the 6-alkyl-7-hydroxy-5,8-quinolinequinone (16) series, 6-(8-cyclohexyloctyl)7-hydroxy-5,8-quinolinequinone( M a ) was the most potent
antimalarial; it effected 5/5 cures at 640mg/kg under the same
test conditions.
Most of the 7-aIkyl-6-hydroxy-5,8-quinolinequinones( 1.5)
were also tested on NADH-dehydrogenase and succinatedehydrogenase in bovine heart mitochondria for inhibition
of coenzyme Q["l (see Table 2). The results demonstrated
that a reasonably good correlation existed in this series of
quinones between the concentration of the inhibitor in the
in vitro system and the observed in vivo antimalarial activity
against P. hei-ghri in mice. In succinate-dehydrogenase, the
greatest inhibitions were found in the case of analogs with
7-n-tetradecyl- ( 15 e), 7-n-pentadecyl- ( l S f ) , 7-n-hexadecyl( f 5 g ) , 7-(5-cyclohexylpenty1)- (15 k ) , and 7-(8-cyclohexylocty1)- ( I S ! ) side chains. NADH-dehydrogenase was less sensitive than succinate-dehydrogenase to these analogs; ( I S f ) ,
Table I. In-irfro assay of the inhibitory activity of some 2-alkyl-3-hydroxy-5.6-dime~hox~-1.4-benzoquinones
(141
[a] on NADH-dehydrogenase- and succinate-dehydrogenase-enzyme systems in intact mitochondria1 systems. The
specific activity (S.A.) is defined as the oxygen uptake in patoms O,!min per milligram of mitochondrial protein.
Addition to enryme system
__
~
None
COQIO
CoQlo
CoQIo
CoQlu
CoQlo +
+ 1 1 4 ~ ) R=Fdrnesyl
.
+ ( 1 4 6 ) , R=Solanesyl
+ 1 1 4 ~ ) R=Phytyl
.
CoQio
NADH-dehydrogenase
S.A.
S. A
[%]
abs.
["h]
abs.
+
( 1 4 d ) . R=Dihydrophytyl
1 1 4 ~ ) R=,7-CiaH,q
.
Succinate-dehydrogenase
s.A
S.A
abs.
[%]abs.
["/a]
~.~
0.396
0.596
65
100
0.364
60
0.302
0316
50
50
0.406
0.794
0.608
50
100
75
0452
0533
0.309
0.164
0.1 17
85
100
60
30
0.366
0445
80
100
0129
0.096
30
20
20
[a] Addition in each case was 100 nmol of the quinones
562
Angew Chrm. infernat. Edit.
1 Vof. 13
f 1974) 1 No. 9
Table 2 Inhibitory activity of 7-alkyl-6-hydro~y-5.8-q~1no~inequinoncs
l l ) o n the NADH-dehydrogenase-CoQ and succinate-dehydrogenase-CoO en/vme
systems T h e specific activity (S.A.) is defined as the oxygen uptake in patoms Ol:min per 1 mg mitochondria1 protein
.. .. .......
.~
..
R
Conc.
19
32
2.5
4.2
5.1
4.2
5.I
3.2
25
1.9
3.2
6.4
2.9
3.6
190
38
45
64
2.5
3.8
4.5
5.1
A l w [h]
["/.I
[a1
I90
......__
~
NADH-dehydrogenase
.
S. A.
Inhibition
049
0.50
0 37
025
-.
.
0.4I
0.28
0. I7
025
0.14
17
44
66
50
71
~...
.~
..
.
..
.
[h]
.
0 47
>loo
26
50
. ~ . ~
Succinare-debydrogenase
Inhibition
s.A.
Cone.
["O' l
[a1
230
16
16
2.2
2.1
024
0.22
51
I.6
56
1.3 [c]
0.31
0.19
0.085
0.32
0.20
0.33
0.3I
0.28
0.20
0.27
38
58
83
35
60
33
38
43
60
46
024
51
0.22
0.16
77
1.4
1.7
>loo
27
1.3
56
I .9
20
22
27
0.39
0.28
0 25
0.19
0.070
2.2
031
2.7
5.5
2.7
3.6
3.8
44
5.7
2.2
082
I .4
I .6
0.22
0.047
0.34
0.22
0.27
0092
0.027
0.24
0.34
0.29
1.1
1.4
I .6
0.29
020
0.I7
2.7
I60
22
27
0.171
> 100
15
40
48
60
80
14
53
90
26
54
9.5
1.3
41
80
90
40
28
40
63
40
17
1
'
[dl
075
5x
64
065
0.23
0.34
50
28
I .4
> 80
47
80
1.6
2.I
0.25
0.09I
0.29
0.I7
64
0.9
2.2
4.4
0.25
0.0I2
46
97
I .2
1.1
38
[a] nmol inhibitorimg mitochondria1 protein.
[h) Antimetabolite-CoQ,,, index : for a definition see Section 7.The average concentration of Coo,,, i n mitochondria was determined from seberal preparalion\
of mitochondria and found to be ra. 2 nmol/mg mitochondr~alorotein. This value was assumed for the calculation of Also.
[ c ] For 56",,
inhibition.
[d] For 40",,
inhihition
( 1 5 g ) , and ( 1 5 k ) analogs were the most inhibitory. For both
in uitro enzyme systems, the optimum length of the lipoidal
straight side chain for maximum inhibition was 15 or 16
carbon atoms.
Skelton et
found that menoctone (13) and a representative of the 5,8-quinolinequinones, 7-(8-cycIohexyloctyl)-6-hydroxy-5,8-quinolinequinone (1511, inhibit succinate-cytochrome c reductase and the succinate-coenzyme Q reductase
in bovine heart submitochondrial systems and that coenzyme
Q, effects reversal of inhibition. The same substances also
inhibit the succinate-coenzyme Q reductase of intact mitochondria from the human heart.
In another study, Skelton ef ul.1471attempted elucidation of
the mechanism of action of these quinone antimalarials.
Menoctone (13) and the quinolinequinone (151) inhibited
the NADH-cytochrome c reductase system of yeast submitochondrial particles and the succinate-cytochrome c reductase
systems of both yeast and bovine heart submitochondrial
The inhibition could be reversed by addition
of exogenous coenzyme Qh to the systems containing no
added p h o ~ p h o l i p i d l ~ Lineweaver-Burk
~!
double reciprocal
plots indicated that these two quinones act by competitive
inhibition of coenzyme Q enzyme ~ystems[~'J.
6.2. Alkylaminoquinolinequinones and -naphthoquinones
Other categories of quinones newly synthesized as potential antimalarials are 6-alkylamino-5,8-quinolinequinones
Angew. Chem. internal. Edit. f Vol. 13 (1974)
1N o . 9
(17). 6-hydroxy-7-n-tetradecylaminomethyl-5,8-quinoIinequinone (I;$), and the 2-alkylamino-I ,4-naphthoquinones ( 191
Numerous quinones of this type have already been reported[41,42,48- 5 0 1
dNHR
(17a). R =
(
( 1 7 ~ ) .R =
0
0
C
~
I
J
~
~
I t was important to design these new quinone types with
alkyl side chains, so as to impart greater lipoidal character
to the molecule, and with alkyl side chains containing varying
types and numbers of heteroatoms. It was hoped that such
analogs might be more effective antimetabolites of the highly
lipoidal coenzyme Q8 of plasmodia.
A series of fifteen new 6-alkylamino-5,8-quinolinequinones
1 7 ) and 6-hydroxy-7-n-tetradecylaminomethyl-5,8-quinolinequinone (18) were synthesized by Porter et ~ l . ~and
~ ' ~ ,
representative compounds were evaluated for antimalarial
activity against P . herghei in
Three quinones
6-phenethylamin0-5,8-quinolinequinone ( / ? a ) (T- C = 7.3
563
at 640mg!kg), 6-cyclooctylamino-5,8-quinolinequinone(17hi
(T - C = 6.9 at 640 mg/kg), and 6-cycloheptylamino-S,8-quinolinequinone ( 1 7 ~ (T) C=6.5 at 320 mg/kg)-were declared
"active" by the standard criterion of l00(%,increase or greater
in the survival time for antimalarial activity against P. ber-ghei;
all three derivatives were non-toxic at the dose levels tested.
Representative compounds were tested in mitochondria1
NADH-dehydrogenase and succinate-dehydrogenase systems
for inhibition of coenzyme Q. The 6-alkylamino-5,8-quinolinequinones ( 1 7 ) , represented in the assay by seven of the fifteen
compounds, were potent inhibitors in both the NADH-dehydrogenase and succinate-dehydrogenase systems; the inhibition could be completely reversed by CoQ,, (see Table 3)r"l.
Eight new 2-alkylamino-I ,4-naphthoquinones, ( / 9 ) , have also
been synthesized by Porter-et
and tested for antimalarial
activity against P. beryhvi in mice. None of these compounds,
however, showed any significant activity in this test. Significantly, the 2-alkylamino-1,4-naphthoquinones,
represented in
the in ritro assay by seven of the eight new compounds and
three previously prepared derivatives, likewise showed no
important inhibition of either the NADH- or succinate-dehydrogenase enzyme system[521.
Table 4. fiiwii(1 assay of aiitrmalarial activity of 7-alkylthio-5.8-quinolinequinones ( 2 0 ) [a] on mice infected with P hrr!ghri [44] The figures i n
brackets denote the dose ( i n mg,kg) administered in each case.
. - ~. ... ~ ..~
~
~.~
...... .~ .
.~
..~.
.. .
.
.
(:pd.
R
(T-C) [b]
C'tirc\
Dcatha
~ _ ~ _ ~ _
~.~......
~
13.9 ( 3 2 0 )
3 7 (160)
5.9 ( 2 0 )
17.9 ( 160)
1.9 (80)
9.5 ( 160)
0. I ( 160)
2.7 1160)
10.9 (80)
.
~~
.
015 (320)
0:5 (160)
2 / 5 (XO)
3/5 (160)
SJ5 (320)
515 (640)
0/5 (160)
0!5 (160)
015 (80)
.
~
~
. -~~ . ~ .
015 (320)
015 (160)
015 (80)
0/5 (160)
015 (320)
0,'5 (640)
OjS (160)
0i5 (160)
015 (80)
[a] All compounds were administered subcutaneously, in graded doses. t o
groups of five mice.
[b] T-C=changr in survival time. in days, of treated (T) and untreated
animals (C=control).
hydroquinones. These quinones were tested for antimalarial
Of the seven compounds
activity against P. herghei in
tested to date, five showed marked in Giuo antimalarial activity
without apparent toxicity (Table 4).
6-Hydroxy-7-n-octadecylthio-5,8-qu~nolineq~inone
(20d) was
active at 80 mg/kg and totally curative (5/5 cures) at
Table 3 /ii-i.;!r(iassay of the inhibition of coenryme-Q enzyme systems by 6-alkylamino-5.8-quinollnequinone.ri 1 7 )
[a] (after Ref. [31]). The specific activity (S.A.) is dehned as the oxygen uptake in patoms O,!min per 1mg of mitochondrial protein.
Cpd.
S.A.
R
NADH-dehydrogenase
Conc.
Reversal
PI
-~
~ _ ~ _ ~ _
CoQ,,
(17d)
(17r)
(17.1)
f17/1
(17hl
(17i)
(171)
0.582
0.302
0.321
ii-CrHu
II-C~OH~~
~I-C,*H~Y
IJ-CI~HJI
II-C~~H~J
(CH,)IN(~-C~HY),
(CH>)d-C-CeHii
~
0.320
0.328
0.326
0.318
0.320
41
17
17
20
20
14
17
Succinate-dehydrogeiiase
S.A.
C'onu.
[bl
["'.I [.I
0.562
0.292
0.288
0.286
0.290
0288
0.290
0.291
90
97
98
95
95
98
98
~ . - ~
~
~
-
15
10
1I
10
10
9
10
~ . ~ .
[a] Addition of IOOnmol CoQfoin each case
[b] For 50",, inhibition. The concentration of inhibitor is givcn in nmolimg Ihlfochondrial protein.
[ c ] After further addition of 2OOnmol CoQl0.
6.3. Alkylthiohydroxyquinolinequinones
One of our most recent series of quinones, the 7-alkylthio-6hydroxy-5,8-quinolinequinones (20) described by Porter r t
a/.1'"', represent a new structural type of effective antimalarial
quinones, which show little or no toxicity in the prophylactic
assays, and which most likely function as antimetabolites
of the indispensible coenzyme QH of plasmodia. This series
of new antimetabolites of coenzyme Q appears to, be one
of the most promising types of such analogs in our research
on the prophylactic and curative treatment of malaria.
0
TweIve new 7-alkylthio-6-hydroxy-5,8-quinolinequinones
(20) were synthesized by Porter et ul.["l and Wan et ~ l . [ ' by
~]
1,4-addition of appropriate alkanethiols to 6-hydroxy-5,Squinolinequinone and subsequent oxidation of the quinoline564
dose levels of both 320mg/kg and 640mg/kg without toxicity
in the routine one-dose (sc) treatment of mice.
Prophylactically, this compound cured 3/5 chicks at 160 mg/kg
(Table 5 ) in the sporozoite-induced P. gullinaceurn test developed by Rune and
6-Hydroxy-7-oleylthio-S,8-quinolinequinone ( 2 0 h ) , the corresponding C , derivative having
one double bond in the side chain, showed increased in ciao
prophylactic activity with 4/S cures at I S mg/kg. In comparison.
compound ( 2 0 d ) showed only 115 cures at 40 mg/kg. Unsaturation in the side chains appears to enhance in civo prophylactic
activity. The lower homolog of (20d), 6-hydroxy-7-n-tetradecylthio-5.8-quinolinequinone (20h). was totally curative["!
curing 5/5 chicks at a dose of 80mg/kg. The best compound,
7-n-heptadecylthio-6-hydroxy-5,8-quinolinequinone ( 2 0 9 ) ,
cured 5/5 chicks at a dose of IOmg/kg; its effectiveness at
0
0
0
0
Anyew. Chem internal. Edit.
1 Vol. 13 (1974) J No. 9
Tablc 5. 111-m
o assaq of the antimalarial activity of 7-alkylthio-j.8-quinolinequinonesf ? ( I ) [a] on chickens infected
uzith \pororoitcs of 1' g a l i r i i c r ~ e i r r i i [ 5 5 ] The figures given in brackets denote the dose ( i n mgjkg) admm~stered
cach case.
. .
Cpd.
in
~
~.
( 20 ( 1 )
.~
~.~
. ~
.-..
_ .....-..
~
(T- C)[b]
R
. ~.
._._._._.
~.~
11-C1 xH J,
3.5
~.~
H 2~
7.6 120)
11-C I 4
I20Y)
11-Ci7H.x~
(?Or)
11-Cic,H A I
(ZOh)
(CH2)aCH=CH(CH,);CH.~ [c]
9.9 (15)
9.9 (30)
(ZOi)
II-CI Y H A *
0.3 (15)
I 8 (120)
..._.~
_.
.. . ~
~
.. ~
.....
...
0 / 5 (40)
015 (80)
l i 5 140)
2i5 (80)
315 (160)
3/5 (320)
415 ( 2 0 )
51'5 (80)
515 (320)
515 (101
5!5 (40)
515 (320)
5j5 i 120)
515 (240)
515 (480)
4,s (151
4/5 (30)
5 / 5 (60)
515 (120)
215
515 (120)
5 3 (240)
515 (4x0)
(40)
1.7 (80)
1.7(160)
(ZfJh)
Deaths
Cures
115 (160)
215 (3201
0:s (201
0;s (X0)
0!5 (3201
0!5 110)
015 140)
0!5 (370)
015 ( 120)
0 3 (240)
015 (480)
0,'s (15)
015 (30)
0i5 (60)
0iS ( I20)
0/5 ( 120)
0/5 (240)
015 (480)
~
/a] All compounds were administrred subcutaneously to groups of five mice.
[h] T-('=chiingr in survival time. in days. of treated and nontredted (controll animals.
[c] This compound was declared "active" at this dose level by the standard of loo",, increase in survival time.
ginal antimalarial activity in the murine assay, was a potent
inhibitor of the mitochondrial NADH- and succinate-dehydrogenase enzyme systems.
lower dosages is as yet unknown. This quinone showed no
toxicity at doses from 10mg/kg to 320mg/kg.
The alkylthio-5.8-quinolinequinones ( 2 0 a ) , (ZOc), and ( 2 O d )
and the alkylthio-1.4-naphthoquinone( 2 1 ) showed marked
inhibition of both NADH- and succinate-dehydrogenase mitochondrial CoQ-enzyme systems from bovine heart (Table 6).
The effectiveness of these alkylthio-5,8-quinolinequinones,in
oitro and in cico, may be due to their having a combination
of molecular characteristics for inhibition including electron
transport, relative affinities for binding to functional and/or
biosyntheticsites ofCoQx in plasmodia, and lipoidal character.
6-Hydroxy-7-n-octadecylthio-5,8-quinolinequinone
(20d),the
quinolinequinone which exhibited the greatest in ciro activity
against P. hrrqhri in the mouse, showed more inhibitory
activity in the NADH-dehydrogenase system than the other
two alkylthio-5.8-quinolinequinones ( 2 0 ~ ) and (20c)
tested in the same assay. Surprisingly, 2-n-dodecylthio-3hydroxy-1,4-naphthoquinone (21). which showed only mar-
The screening result^^"^ described herein for micei44i and
chicks[''' are generally based on findings which were obtained
on treatment of animals with only one dose; this method
waschosen for simplicity ofroutineassay ofvery large numbers
of compounds. It is not known what the dosage and drug
T'ible 6 / w IW assay of the inhibitory activity of some 7-alkylthio-5.8-qtiinolinequinon~s I 211) and of a 1.4-naphthoquinone compound I 21 ) o n the C o Q enzyme systems NADH-dehydrogenase and succin;ite-dehydropenase. The
\pecific a c t i L i t y I S A . ) is defined as the oxygen uptake in Fatoms O,.min per 1 mg of mitochondrial protein Reaciion
mixture coniaincd 110 exogenous coenzyme Q.
.
.
N A DH-dehydrogenase
c'pd
R
S. A
C'onc.
[;I1
0.3 I
0.26
0.I 2
0.074
0.3 I
0.30
0 20
0. I4
0. I 3
0
0
15
33
75
100
0.30
0.19
(I. I5
0.074,
26
32
14,
0.3 I
0.22
0 IX
0. I 2
i l l
0.3 1
02I
0.16
0.054
.. .- ...
0
13
16
19
0
30
41
61
. ... . .. .
rai
0
16
63
76
13
. .
~ . -
0
26
51
64
0.27
0.2I
0
Inhibition
r %1
. .
~
.~.
Succinare-dehydrogenase
SA
C'onc.
Inliihilion
..... ~
0
17
[%]
..
13
35
XX
57
0
36
0.I7
17
14,
45
0.12
20
54,
0.10
0.30
0.2i
021
20
0
x.5
13
0.I3
17
17
0
8.5
13
I3
66
0
24
30
56
52
0
0
0 15
0.32
13
I3
20
33
48
83
0.24
0. I4
0.14,
76
34
0
~
~. ~
0
52
0
20
53
37
_
.
.
[a] nmol of inhibitor/mg mitochondria1 protein.
Anguw. C'hrm. inturnat. Edit. j Vol. 13 11974)
No. 9
565
effectiveness would be if the optimum regimen were determined
by the traditional procedures of pharmacology in the case
of the most promising antimetabolites of coenzyme Q for
antimalarial effectiveness.
2-Hydroxy-5,6-dimethoxy-3-n-pentadecyl-l,4-benzoquinone
(141') and the analogous compound (22tl) showed about
90 '%, and 35 '%,inhibition, respectively, in succinate-dehydrogenase-the strongest inhibitions in this series of experiments.
Apparently, the dimethoxy groups are more favorable than
the ethylenedioxy group for the inhibition of enzymes.
6.4.Benzodioxinquinones (Ethylenedioxyquinones)
A new series of coenzyme Q analogs, the b-alky1-7-hydroxy-2,3dihydro-1,4-benzodioxin-5,8-quinones(ethylenedioxybenzoquinones) ( 2 2 ) , have been synthesized by Bowman ei U ~ . [ ~ ' I
on the basis of the minor differences in the electronic and
rotational nature between the ethylenedioxy group and the
two methoxy groups. These differences could fundamentally
affect the oxidation-reduction potential of the 1,4-benzoquinone and, in turn, also the inhibitory activity. Appropriate
isoprenyl or alkyl groups were inserted at C-6 by alkylation.
0
6.5.Alkylthio-2,3-dimethoxy-l,I-benzoquinones
Another new category of 2-alkylthio-5,6-dimethoxy-l.4-benzoquinones, compounds 123) and (2 4 ). have recently been synthesized by Wiklzolm er
as potential antimetabolites of
cbenzyme Q.
0
0
0
The succinate-dehydrogenase and NADH-dehydrogenase systems of intact mitochondria from bovine heart were used
in tests for inhibition of these quinones in cirro (Table 7).
In succinate-dehydrogenase the n-nonyl(22u), n-decyl (22 b),
n-pentadecyl ( 2 2 4 . and farnesyl ( 2 2 9 ) derivatives showed
inhibitions of less than 40';/,; the phytyl (22,f), n-heptadecyl
( 2 2 e ) , and 5-cyclohexylpentyl ( 2 2 0 analogs showed inhibitions ofabout 50 All analogs were less inhibitory in NADHdehydrogenase.
x,.
The series of alkylthio-1,4-benzoquinonesprepared in this
study provided variation in alkyl side chain length; in addition
one compound having a branched alkenylthio substituent
[ ( 2 3 c ) ]was also prepared. Within the series of 2.3-dimethoxy5-n-octadecylthio-1 .4-benzoquinones ( 2 4 ) several 6-substituents provided potentially significant variation in redox
potential of the new quinones.
In the 6-substituted 2,3-dimethoxy-S-rnethyl- I ,4-benzoquinone ( 2 5 ) , lengthening of the alkylthio side chain-from
Table 7. In-iirro assay of the inhibitory activity or henmdioxinquinones f 2 2 ) and dimethoxybenroqtiinone ( 1 4 5 1
on NADH-dehydrogenase and sriccinate-dehydro~enasein intact mitochondrial systems.
Cpd.
(220)
(22b)
( 22 (,)
f22d)
tl-CqH I 9
n-CiuH2i
(CHI)~-C-COHI
I
n-C, 7 H 3 1
(22e)
n-C, -H,>
(22/)
Phytyl
(22Yl
NADH-dehydrogenase
Conc.
Inhibition
R
Farnesyl
r.1
[".I PI
120
I80
22
24
I00
I 50
26
35
I00
I50
26
45
100
205
34
35
60
100
i 30
64
1.10
IYO
i 30
I90
25
37
33
22
43
59
0
10
61
72
74
79
32
(141)
~___
65
130
I90
-
~
... .
~
.
. .
. .~
. ~ - ~
-.~
~
Succinare-dehydrogenase
Conc.
Inhibition
r "01
ra1
67
10
I30
200
24
24
21
30
34
22
40
60
30
37
37
29
41
50
34
45
I25
I70
250
50
115
150
,
'
I00
I40
205
60
120
I80
64
I90
[bl
23
24
12
86
91
I30
I90
32
65
91
20s
90
.~
-
~.
~
[a] Concentration of inhibitor I S expressed in nmol'mg of mitochondria1 protein
[b] Activity of the enzyme system was determined i n microatoms of oxygen uptake per minute per milligram protein.
The percent inhibition is equivalent to: (specific actisity of test system*speciftcactikity of control system) x IOO",,.
The general methodology has been described [31].
566
Angcw. Chem. internot. Edir.
1 Vof.
13 (1974)
1 No. 9
the n-dodecylthio- to the n-octadecylthio group-furnished
coenzyme Q analogs with increasing lipoidal character.
0
OAc
0
OAC
( 2 8 ~ ) .R = C I ~ H I
(286). R = C t j H i q
f 25 c 1. R = s H 3 7
c,
(2Hu) has been tested prophylactically against sporozoiteinduced P. qcrl/inacrcrm in the chick and was effective, without
toxicity. at dose levels of 30mg/kg (1/5 cures) and 120mg/kg
(4/5 cures).
7. Comparison of Inhibitory Activity by the Antimetabolite CoQlo Index (AIs0)
( 2 6 ~ ) .R = C 1 2 H ? r
(26h). R = C I H H I -
Finally, reductive acetylation of crude 2-alkyithio-3.5.6-trimethoxy- I ,4-benzoquinone, another analog in this series,
afforded the crystalline diacetoxy derivatives ( 2 6 ) of the corresponding hydroquinones.
6.6. Alkylquinoxalinequinones
Recently, Portrr rt a[.1s81have initiated the synthesis of a
new series of 6-alkyl-5,8-quinoxalinequinones ( 2 7 ) , and the
alkylthioquinones were investigated as potential inhibitors of
To facilitate comparison of the inhibitory activities of various
analogs and derivatives it7 ritro, Bo~wtanef a/.1451
have defined
an "antimetabolite CoQ,, index" (AIs0);this corresponds to
the ratio of nmoles of analog per nmoles of CoQlo in the
actual mitochondria1 preparation which causes approximately
50Y,; inhibition of enzyme activity. The inhibitory activities
of these analogs were measured by their effect on the oxygen
uptakeoftheCoQenzymes(determined either by the Warburg
manometric method or by polarographic measurement of
oxygen). For most analogs, inhibition of the CoQ enzymes
was determined at several concentrations so that the concentration at which 50% inhibition was effected could be estimated by extrapolation.
TheantimetaboliteCoQIoindices for some 7-alkyl-6-hydroxy5,8-quinolinequinones (IS) in NADH-dehydrogenase and succinate-dehydrogenase are listed in Table 214? The 7-n-penta-
coenzyme Q and as antimalarial drugs. The groups introduced
as side chains were n-dodecylthio- ( 2 7 a ) and 5-cyclohexylpentyl- (27b). ( 2 7 a ) was inactive against blood-induced P.
berghei in mice at 640 mg/kg and inactive against sporozoiteinduced P. gallinaceurn in chicks at 80 mg/kg.
H3c0
0
OH
H (14)
H3CO
0
Tahle 8. Anlinietaholite C o o , r ) indices of 2-aik~l-3-hydroxy-5.6-dimelhoxy-l.4-henzoquinones ( 1 4 )
~
Cpd.
.~..~
.~ ~.
. ~
.
~
.
..
114~i
II-C)oH2 I
(1411)
(CHz)s-c-ChH 1 1
1141)
(1411
( 1 4 ~ )
(1411
(140)
(141 )
.
~.
. .. ~
.
~
.
.-..-....
NADH-dehydrogenase
A150
Inhibition
R
.~
.... .
.
ll-ci~n2~,
II-CF~H,~
II-CI'IHIG
ii-C~IHi.~
Farnesyl
Phytyl
- . ~
. ~.. .~.
~
~.
.
.
-
[">][ a ]
~~
. ~ -. .~
5n
9
5
57
10
48
io
5n
32
50
48
50
50
ii
17
26
~
~
.
~
-.
.~
Succinate-dehydrogenase
Alru
Inhibition
[ O h ] [a]
.
~.
~
~
. .
I7
55
50
50
8
7
8
so
14
in
10
50
SO
.
50
50
.
._
[a] Actual 50",, inhibitions or approximately i O " , , inhihilions from exrrapolatton or experimental values [45]
6.7. Benzothiazolequinones
A new series of 5-alkyl-6-hydroxybenzothiazole-4.7-quinones
( 2 8 ) have been synthesized by Friedwiun ei
in the continuing program to explore new heterobicyclic quinone systems for potential pharmacological activity. The two new
quinones ( 2 8 ~and
) (28h). containing n-undecyl and n-pentadecyl side chains, respectively. were prepared by a multistep
procedure.
(28a), R = n-Cl1Hz1
{&OH
R
N
(28b), R = n-CEHzl
0
Angrw. Chem. internat. Edit. 1 Vol. 13 ( 1 9 7 4 )
J
,
No. 9
decyl- and 7-(5-cyclohexylpentyl)-6-hydroxy-5,8-quinolinequinones (1S.f) and ( 1 5 k ) were the most effective antimetabolites of this series in NADH- and succinate-dehydrogenase.
The antimetabolite CoQ,, indices of eight 2-alkyl-3-hydroxy5,6-dimethoxy- 1,4-benzoquinones ( 1 4 ) have been determined
by Boyentofi, ron Klaiidy, and Fo/krrs'"'' (Table 8). For the
CoQ-NADH-dehydrogenase system. a range of antimetabolite indices of 5-32 were obtained for these inhibitors. The
2-(5-~yclohexyIpentyI)-analog
( I 4 h ) was the most effective
antimetabolite with an index of 5. The farnesyl- and phytylanalogs (140) and ( 1 4 ~had
) indices of 17 and 26. respectively.
The antimetabolite CoQ indices for the CoQ-succinate-dehydrogenase system varied from 5.5 to 14 for all eight analogs;
567
no difference was evident in the case of the farnesyl and
phytyl derivatives.
Ingeneral, these eight analogs were more effective antimetabolites of CoQ in succinate-dehydrogenase than in NADHdehydrogenase, but the difference in sensitivity between the
two systems was small.
8. Application of Coenzyme Q Antimetabotites in the
Therapy of Other Diseases
This demonstrated effectiveness, both curatively and prophylactically, of antimetabolites of coenzyme Q in the treatment
of malaria, with little or no toxicity, may be extended to
the therapy of other diseases. From the above data it can
be concluded that a certain selective toxicity for an antimetabolite of CoQ has been achieved and that further analogs can
besynthesized whichcoiild exhibit even more effective selective
toxicity in chemotherapy. Such selective toxicity can be based
on differential inhibition of pathways. The widespread occurrence of coenzyme Q in nature would suggest its presence
in a number of potential pathogens such as bacteria, fungi,
other protozoa, and helminths. Antimetabolites of coenzyme
Q could destroy these organisms or inhibit their growth.
The criticisin is frequently encountered that an antimetabolite
of a vitamin cannot be useful in man or domestic animals
without serious toxicity to the host, which negates the useful
aspect. Evidence shows that such toxicity to the host does
not necessarily occur. Moreover, the progress described here
on antimetabolites of coenzyme Q demonstrates that useful
therapeutic activity without toxicity is feasible.
Antimetabolites or other vitamins are already in use in the
treatment of diseases. Amproliurn (29)["', a thiamine antagonist, is suitable as a coccidiostat in veterinary medicine;
it is selectively effective against coccidia of the digestive tract
and prevents coccidiosis in chickens without adverse effect
upon growth.
~ '4I \ d ' '
C H . - N R o '
I
N H Z
f30a1, R = H
-
Received: September 25, 1973 [A 12 IE]
German version: Angew. Chem 86, 635 (1974)
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131 R D. Puii~ri1,G. J . Brriiw, A S. A/i,in(g, and J. W Milkr, Bull. W H O
30. 29 (I964).
141 K D. Pmi.r//. G'. J . Brni.n-. A . S. A/i.iny, and J. M! Milkrr, Bull. W H O
31. 379 (1964).
[ 5 ] A Bishop, Parasitology 57, 755 (1967).
.F
C. Chong, W G. Duiiher,
, C. H r r d e / h q p r . H
JlI,
E.
Wi/S(ill,
Hr~inunn,
~v.k k . #M.7:
L~f/.fflcv.
K . E. Hrrmlin, R . .1. Huthuicn\., E. J . Mu/.son, E. E. Moorr. M. B.
uid, and H . E. Zuuyg, J. Amer. Chem. Soc. 70. 3151 (194X).
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[((I] L. Whirmun. J. Infect. Dis. K2, 251 (1948).
[ I I ] W B. W m d d l . Fed. Proc. 5 , 406 (1946).
[I21 C. C. Sinirb, K Frudkin. and M. D. L o c i r y . Proc. Soc. Exp. Blol.
Med 61, 398 (1946).
[I-?]C. C. Smilh, R . Frudkin. and M . D. L a c k \ . Proc.
Med. 64, 45 (I947).
Soc Exp Biol.
[ 141 K . F n l k c ~ s .C. H . Shunk, B. 0.Litin, N . R. Ti-ennrr, D. E. MJ/\,C.
H . tfoffniim, A . C. Pug?, Jr.. and F . R. Koiiiiiszi.. Quinones in Electron
Transport. Ciba Foundation Symposium, Little, Brown and Co., Boston
1 9 6 1 , ~100.
[I51 D. Hrndliii and 1 M . Cook, Biochem. Biophys. Res. Commun. 2. 71
( 19601.
[I61 S. Tukemuri and T. E. King, J. Biol. Chem. 33Y, 3546 ( 1964)
[I?] .I. I.. Howlund, Biochim Biophys. Acta 11)5. 205 (19651.
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[ 2 7 ] This information was kindly made available to us through the Walter
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.
C-NH-CH-COOH
I
(CH2)z-C OOH
/306), R = CH3
Similariy, antifolates have found widespread application in
the treatment of cancer because of their .selective toxicities.
The foolic acid antagonists aminopterin (.?on) and methotrexate (30h), are both used in the treatment of acute leukemia
in childreni"'!
Appreciution is parriciilurl,~expressed to Dr. D a d P. Jacobus
for his sj.mpathetic encoiirugement of the initiation of the basic
resrarch which led fo the establishment of coenzyme Q8 as
intrinsic to the metubolism of plasmodia. For their subseycient
cooperation we wish to thank Dr. Thomas R. Sweeney and
Dr. Erkjar A. Steck o f t h e U S . Army Medical Reseurch and
Dec.dopment Cornmund (Contract No. DADA 17-69-C-9067 ) :
Contribution No. 1202 ,fkom the Army Research Program on
maluriu. WL' also wish to express O L ~ Ythanks to the Robert
568
A. Welch Forintiation, and Dr. Lewis H. Sarett, Merrk Sharp
und Dohme Research Laboratories, New Jersey, for [heir i~ulziuble support of this work.
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45 (1971).
Angew. Chrrn. intsmui. Edii. 1 Vul. 13 ( 1974) 1 No. 9
69s
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potential, thein, application, antimalarials, antimetabolite, coenzyme
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