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Assessment of the in vitro broad-spectrum antiviral activity of some selected antitumor metallocene and metallocenium complexes.

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Applied OrgunornefullicChemisq ( 1989) 3 49 1-497
0 Longman Group U K Ltd 1989
0268-2605/89/03604491603.50
Assessment of the in vitro broad-spectrum
antiviral activity of some selected antitumor
metallocene and metallocenium complexes
Sarah G Ward,* R Craig Taylor,*t Petra Kopf-Maier,$ Hartmut Kopfs
Jan Balzarini! and Erik De Clercq!
*Department of Chemistry, Oakland University, Rochester, Michigan 48309-4401, USA, SInstitut fir
Anatomie, Freie Universitiit Berlin, D- lo00 Berlin 33, FRG, h t i t u t f i r Anorganische und Analytische
Chemie, Technische Universitiit Berlin, D-1000 Berlin 12, FRG and lRega Institute for Medical Research,
Katholieke Universiteit, Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received 15 March I989
Accepted 26 July 1989
Six neutral metallocenes and six metallocenium
[(TC,H~),T~(~~~~):+][CF~SO;]~
was active towards
the DNA viruses at a concentration that was
salts, all of which have demonstrated antiproliferative properties, were evaluated for their in vitro
ten times lower than the cytotoxicity threshold. (F
broad-spectrum antiviral properties and cytotoxiC5H5)2VC12was weakly inhibitory towards HIV
cities. The metallocenes include the compounds (qreverse transcriptase. All species were ineffective
C5H5)2MC12,where M =Ti, V, Mo, Zr and Hf,
in inhibiting HIV-induced cytopathogenicity in
and (~&H~)~Tibis(hydrogenmaleinate), whereas
human T-lymphocyte MT4 cells.
the metallocenium complexes include the three
Keywords: Metallocenes, metallocenium complexes,
ferrocenium salts, (T-C5H5)2Fe+X-,where X- =
antiviral activity, DNA viruses, RNA viruses, HIV-1
trichloroacetate, tetrachloroferrate0 and picrate,
and three recently discovered antitumor titanocenium complexes, i.e. [ ( T ~ C ~ H ~ ) ~ T ~ ( C H]~ C N ) C ~ +
FeCL], [ ( V - C ~ H ~ ) '~-bipyridyl)2+l
T ~ ( ~ , ~ [CF3SO&,
and [(~-C5H5)2Ti(N-methyl-o-aminothiophenolate+] INTRODUCTION
[J-1. These 12 species were evaluated against DNA
This discovery of the antitumor activity of cisplatin
viruses (herpes simplex virus type 1, type 2 and
[ ~ i s - P t C l ~ ( N H in
~ ) ~1969
l
by Rosenberg and covaccinia virus), and RNA viruses [vesicular
workers' and subsequent developments in this area in
stomatitis virus, Coxsackie virus B4, Sindbis virus,
the past 20 years have helped alter, to a large degree,
Semliki forest virus, parainfluenza virus type 3 and
the bias against inorganic compounds as clinically
human immunodeficiency virus type 1(HIV-l), the
useful chemotherapeutic agents. In addition to cisplatin
etiologic agent of AIDS]. In the case of HIV-1, the
and other platinum-containing complexes, a number
complexes were evaluated for their ability to inhibit
of inorganic complexes of other platinum-group metals
HIV-associated reverse transcriptase activity and
have been shown to exhibit cytostatic properties
HIV-1 induced cytopathogenicity in human Talthough none have yet proven useful in clinical trials.
lymphocyte MT4 cells. Selectivity indexes [ratio
A third group of antitumor active compounds encomof the minimum cytotoxic concentration (dose) to
pass several main-group elements, most notably
the minimum (antiviral) inhibitory concentration
gallium nitrate,2 a number of organogermanium
(dose)] were determined for all complexes and
complexes,2 and some organotin(1V) specie^.^
viruses. In general, the netural metallocenes
Finally, several metallocene and metallocenium
and the ferrocenium salts were only marginally
complexes have been shown to possess tumoractive towards some specific viruses. However,
inhibiting efficacy. These include: (a) the neutral
metallocene dichlorides, ( v - C ~ H ~ ) ~ M
~~
(1)C and
derivatives such as titanocene bis(hydrogen maleinate)
?Author to whom correspondence should be addressed
492
Antiviral activity of metallocene and metallicenium compounds
assessment of their antiviral p ~ t e n t i a l ;there
~
is
(2); (b) ferrocenium complexes, [ (q-CsH5)2Fe+]X-,
virtually no overlap between the two studies.
where the anions X- include trichloroacetate
(C13CO;), picrate (2,4,6- (N02)3C6H20-), and
tetrachloroferrate(II1) (FeC1,) (3);4,5 and (c) some
recently discovered titanocenium complexes of the type
MATERIALS AND METHODS
[ ( V - C ~ H ~ ) ~ T ~ or
X L[ (] Y
V - C ~ H ~ (Y)2,
) ~ T ~where
]
X is
an anionic ligand, L is a neutral mono- or bi-dentate
Metallocene and metallocenium
Lewis base and Y is a non-coordinated anion (4).6
complexes
During the past few years, attention has been focused
The neutral biscyclopentadienyl metal dichlorides,
on the potential antiviral efficacy of various inorganic
(q-CsHs)2MC12,where M =Ti, V, Mo, Zr and Hf,
and organometallic antitumor agents. In particular, it
were
synthesized and purified according to methods
has been shown that cisplatin exhibits antiherpetic
described
in the literature.lo$ Titanocene bis(hydrogen
activity both in vitro and in V ~ V U Also,
.~
several other
maleinate),
l3 the three ferrocenium complexes,
second-generation platinum-containing antitumor
and
the
three
ionic, salt-like titanocenium comagents' as well as some diorganotin species8 are
plexes16-18 were synthesized by methods described
weakly active against herpes simplex virus types 1 and
previously. For the assessment of antiviral activity the
2 in vitro. Since the antitumor metallocene and
six neutral metallocenes were first dissolved in
metallocenium complexes mentioned above represent
dimethylsulfoxide (DMSO) (10 mg ~ m - and
~ ) diluted
a class of agents whose antiproliferative properties
with culture medium to give a range of final concendistinguish them from the other groups of inorganic
trations of 200-0.002 pg crnp3. The concentration of
antitumor agents, it was of interest to examine the
DMSO had no effect either on viral-induced cytopathobroad-spectrum antiviral activity of some representagenicity or cell growth as determined in separate
tive examples in this class. Thus this paper presents
experiments. The cationic ferrocenium complexes were
an assessment of the in vitro antiviral activity of six
in phosphate-buffered saline and diluted with
neutral metallocene compounds, i.e. ( V - C ~ H ~ ) ~ M Cdissolved
~~,
when M = T i , V, Mo, Zr and Hf, and ( V - C ~ H ~ ) ~culture
T ~ medium to give final concentrations in the range
400-0.004 pg cmP3. The three ionic titanocenium
[bis(hydrogen maleinate) ] ; three ferrocenium
complexes were dissolved in DMSO (20 mg ~ m - ~ )
complexes, [ ( V - C ~ H ~ ) ~ F ~where
+ ) X -X- = C13CO;,
and diluted with medium to give concentrations in this
picrate and FeCl,; and three titanocenium complexes,
same range.
[ ( ~ - c ~ H ~ ) ~ T 'i-(b2i ~, 2y r i d y l ) ~ [CF3S0:l2,
+]
[(qC5H5)2TiCl(acetonitrile)+][FeClZ], and [ (q-CsH5)2Ti
(N-methyl-o-aminothiophenolate)+]I-. These comViruses
plexes were evaluated against three DNA viruses,
The origin of the viruses was as follows: herpes
herpes simplex virus type 1, type 2 and vaccinia virus;
simplex virus type 1 (strain KOS) and herpes simplex
and the RNA viruses vesicular stomatitis virus,
virus type 2 (strain G ) , see Ref. 19; vaccinia virus,
Coxsackie virus type B4, Sindbis virus, Semliki forest
virus, parainfluenza virus type 3, and the retrovirus
vesicular stomatitis virus, Coxsackie virus type B4 and
HIV- 1. Titanocene dichloride and the corresponding
Sindbis virus, see Ref. 20; Semliki forest virus (ATCC
VR-67) and parainfluenza virus type 3 (ATCC VR-93),
molybdenum analog have been the subject of a previous
l43I5
Antiviral activity of metallocene and metallicenium compounds
American Type Culture Collection, Rockville, MD,
USA. The virus stocks were grown in primary rabbit
kidney (PRK) cells (herpes simplex virus types 1 and
2, vaccinia virus and vesicular stomatitis virus), Vero
cells (Coxsackie virus B4 and Semliki forest virus),
chicken embryo cells (Sindbis virus), or human
embryonic lung cells (parainfluenza virus). HIV-1 was
obtained from the culture supernatant of an H9 cell line
persistently infected with HTLV-IIIB,21which was
kindly provided by Dr R C Gallo, National Cancer
Institute, Bethesda, MD, USA.
ANTIVIRAL ASSAYS
Confluent cell cultures in 96-well microtiter trays were
inoculated with 100 CCID50(one CCIDSOcorresponds
to the virus stock dilution that is infective for 50% of
the specific cell cultures under test). After adsorption
of the virus to the cells for 1 h at 37"C, residual virus
was removed from the wells and replaced with cell
culture medium (Eagle's minimum essential medium)
supplemented with 3% fetal calf serum and various
concentrations of the compounds. Viral cytopathogenicity was recorded as soon as it reached completion
in the untreated virus-infected cell cultures, i.e., at 1
to 2 days for vesicular stomatitis virus; at 2 days for
Coxsackie virus and Semliki forest virus, at 3 days for
vaccinia virus, herpes simplex virus and Sindbis virus,
at 5 days for human immunodeficiency virus, and at
6 to 7 days for parainfluenza virus. The antiviral
activity of the compounds was expressed as the
minimum (antiviral) inhibitory concentration (MIC)
(pg ~ m - required
~)
to inhibit viral cytopathogenicity
by 50%. For HIV-1-induced cytopathogenicity in
MT-4 cells,22this activity was expressed as the ED5,
(50%effective dose, or dose required to reduce virusinduced cytopathogenicity by 50 %).
HIV-1 reverse transcriptase assay
The reverse transcriptase assay was carried out with
virus preparations isolated from HIV-I -infected H9 cell
cultures. Inhibition of this enzyme by the test compounds was measured during 60 min, the timeframe
in which the reverse transcriptase activity was linear.
The procedure was based on the method of Balzarini
et al. ,23 with some slight modifications. Briefly,
exogenous poly(rA);oligo(dT) 12-18 served as the
493
temp1ate:primer for the enzyme. The reaction mixture
(50 pL) contained 5 mmol dm-3 dithiothreitol, 300
pmol dm-3 glutathione, 50 mmol dm-3 Tris-HC1
(pH 7.8), 5 mmol dm-3 MgC12, 150 mmol dm-3 KC1,
1.25 pg of bovine serum albumin, 1 pmol dm-3 of
[rneth~l-~HIdTTP(specific radioactivity 30 Ci
mmol-') (5 pCi), 0.01 unit of poly(rA):olig~(dT)~-~~,
0.03% Triton X-100, 10 pL of the compound solution
(containing varying concentrations of the test compounds), and 10 pL of the HIV-1 reverse transcriptase
preparation [partially purified by low centrifugation of
the supernatant of a H9/HTLV-IIIB cell suspension,
followed by filtration (0.45 pm) and ultracentrifugation (1OOOOOg, 2 h)]. The reaction mixture was
incubated for 60 min at 37"C, at which time 200 pL
of ice-cold 5 % trichloroacetic acid was added to stop
the reaction. After an additional 30min at O"C, the
acid-insoluble material was filtered, washed with
water, dried and analyzed for radioactivity. Suramin,
a potent inhibitor of HIV reverse tran~criptase,~~
was
included as a standard.
Cytotoxicity
Measurement of cytotoxicity was based on the
alteration of normal cell morphology. To evaluate this
parameter, confluent cell cultures which had not been
inoculated with virus but treated with various concentrations of the complexes were incubated in parallel
with the virus-infected cell cultures. These cultures
were examined microscopically at the same time as
viral cytopathogenicity was recorded for the virusinfected cells. Disruption of the cell monolayer, e.g.
rounding up or detachment of the cells, was considered
as evidence for cytotoxicity. Cytotoxicity of the
compounds against PRK and Vero cell monolayers was
expressed as the minimum cytotoxic concentration
(MTC) (pg cmP3) required to cause a microscopically
detectable alteration of normal cell morphology.
Cytotoxicity of the compounds against MT-4 cells was
expressed as the dose required to reduce the viability
of the cells by 50% (CD50).
RESULTS AND DISCUSSION
Six neutral biscyclopentadienyl metal complexes, i .e.
five metallocene dichlorides, ( V - C ~ H ~ ) ~(where
MC~~
M = T i , V, Mo, Zr and Hf), and titanocenebis
494
Antiviral activity of metallocene and metallicenium compounds
(hydrogen maleinate) [ (T&H~)~T~(OCOCH=
CHCOOH)z]; three ferrocenium complexes, [(qC5H5)zFe+X- (where X = C13CO;, FeC& and
picrate)] ; and three cationic titanocenium complexes,
i.e. [ ( ~ + , H ~ ) ~ T i ( 2 '-bipyridyl)2f]
,2
[CF3S0;l2,
[(q-C5H5)2Ti(acetonitrile)C1+
] [FeCl;] , and [ ( q C5H5)zTi(N-methyl-o-aminothiophenolate)+]
[I-],
were assessed for their antiviral potential in a number
of virus assay systems.
Neutral metallocenes
The six neutral metallocenes were evaluated against
herpes simplex virus types 1 and 2, vaccinia virus, and
vesicular stomatitis virus in primary rabbit kidney
(PRK) cells (Table l), and against Coxsackie, Sindbis,
Semliki forest and parainfluenza virus in Vero cell
cultures (Table 2). The antiviral effects of these complexes were compared with those of four reference
antiviral agents: (S)-DHPA [(S)-9-(2,3-dihydroxypropy1)adeninel,25 C-c3Ado[3-deazaaristeromycin],26
tubercidinZ7and ribavirin.28 The antiviral and cytotoxic effects of the standard compounds were determined in experiments run in parallel with the title
complexes. A selectivity index29(S.I.) was calculated
for each compound. This parameter, as defined in the
current study, is the ratio of the minimum cytotoxic
concentration (MTC) to the minimum antiviral concentration (MIC) required to inhibit virus-induced cytopathogenicity by 50%,and thus it represents a measure
of the antiviral effectiveness of a given agent. The
results are listed in the final table. As a whole, the
compounds were active against virus replication at
concentrations that approached or coincided with those
that were toxic to the host cells. Thus the selectivity
index was generally close to 1. In some cases it reached
2.0-2.5. The results for (q-C5H5)zTiC12are consistent with those found previo~sly.~
The only other
metallocene common to the two studies,
( v - C ~ H ~ ) ~ Mwas
O C reported
~~,
to be inactive towards
vesicular stomatitis virus.
Ferrocenium complexes
The three ferrocenium complexes, ( T J - C ~ H ~ ) ~ F ~ + X where X- = trichloroacetate, tetrachloroferrate(II1) or
picrate, did not exhibit antiviral activity at
~ . were also less cytotoxic than the
200 pg ~ m - They
neutral metallocenes (Tables 1 and 2).
Table 1 Antiviral and cytotoxic effects of metallocenes and metallocenium complexes in PRK cell cultures.
Minimum (antiviral) inhibitory concentrationa
(pg cm-')
Compound
HSV-I(KOS)
(q-CgHs )2TiC12
(q-CsHs)2Tibis(hydrogen maleinate)
(T-CSH~)ZVC~
(T-CSHS~ M o C I ?
(T-CSHS)2ZrC12
(?-CsH~)2HfC12
[ (a-CsHs )2Fe+ 1 [CI3COF]
[ (q-CsHs )2Fe+ I [FeClC]
[ (q-CsHs )2Fe+ ] [picrate-]
[ (q-CsHs h T i ( b i ~ y ) I~[CF3SOS12
+
[ (9-CsHs hTi(NCCH3 )C1+ ] IFeClT]
[ (q-CsHs ) ~ T ~ ( o - S ( N H C H ~ ) C]I~H$
Tubercidin
(S)-DHPA
Ribaririn
C-c'Ado
> 40
> 100
> 10
> 60
> 50
> 50
> 200
> 400
> 400
20
> 40
> 40
>0.1
> 400
> 400
> 400
HSV-2(G)
Vaccinia
virus
> 40
> 40
> 100
> 100
> 10
> 60
> 10
Vesicular
stomatitis
virus
Minimum cytotoxic
concentrationb
(pg ~ m ) - ~
> 40
> 100
> 100
> 100
> 10
> so
> 30
> 200
> 200
> 200
> 10
> 30
> 50
> 30
> 200
> 200
> 200
20
20
5 200
> 40
> 40
> 40
> 40
> 40
> 60
>so
2 50
2 200
>400
> 400
> 40
>0.1
300
> 400
200
>O.l
40
10
0.7
0.2
70
> 400
7
> 60
50
50
2 200
> 400
> 400
r 200
2 40
5 40
0.4
2 400
2 400
>400
"Required to inhibit virus-induced cytopathogenicity by 50%; average values for two or three experiments. bRequired
to cause a microscopically detectable alteration of normal cell morphology; average of S or 6 experiments.
495
Antiviral activity of metallocene and metallicenium compounds
Table 2 Antiviral and cytotoxic effects of metallocenes and metallocenium complexes in Vero cell cultures.
Minimum (antiviral) inhibitory concentrationa
(pg ~ m ) - ~
Coxsackie
virus B4
Sindbis
virus
Semliki
forest virus
Parainfluenza
virus type 3
50
> 100
> 200
> 10
> 40
> 100
> 100
> 100
>200
> 10
>40
> 100
> 60
> 200
> 200
> 200
> 10
> 40
> 40
> 200
> 10
20
40
260
> 200
>200
> 200
> 40
> 100
> 100
0.07
150
150
70
>60
2 200
> 200
> 200
> 40
> 100
> 100
>0.1
>400
> 200
> 10
> 40
> 100
> 60
>200
> 200
> 200
>40
> 100
> 100
>0.4
>400
100
150
> 400
> 400
>0.1
70
70
2
Minimum cytotoxic
concentrationb
(pg
)
> 100
>200
> 10
> 40
2
100
2 60
2 200
2 200
2 200
2 40
2 200
2 200
0.4
2400
2400
> 200
aRequired to inhibit virus-induced cytopathogenicity by 50%; average values for two or three experiments. bRequired
to cause a microscopically detectable alteration of normal cell morphology; average of 3 experiments.
Titanocenium complexes
Table 3 Anti-HIV-l and cytotoxic effects of metallocenes and
metallocenium complexes in MT-4 cells
Because of the broad-spectrum antiviral activity, albeit
rather weak, of titanocene dichloride, it was of interest
cd50b
to evaluate the relatively new, antitumor, ionic,
(pg ~ m 1 biscyclopentadienyl titanium complexes, i.e. [ (17> 200
C5H5)2Ti(2,2’-bipyridy1)2+]
[CF3SO;12, [ (7> 200
C5H5)2Ti(acetonitrile)C1+][FeCl;] and [ ( v - C ~ H ~ ) ~
8-40
Ti(o-S(NHCH3)C6H$][I-]. Interestingly, the former
> 100
species was active towards the three DNA viruses
> 200
included in this study. It inhibited these viruses at a
>200
52
concentration that was 10-fold lower than the minimum
16
cytotoxic concentration (Table 1). The two other
16
titanocenium complexes were inactive towards the
-c
DNA viruses. None of the titanoceniums showed
155
significant activity against RNA viruses. In general,
> 200
all complexes included in this study were far less
a50% effective dose required to inhibit HIV-1-induced
efficacious as antiviral agents when compared with the
cytopathogenicity in MT-4 cells by 50%. b50% cytotoxic dose
most active of the four standard compounds. Although
required to reduce the viability of MT-4 cells by 50%. c - , Not
tested. (Text reference to Table 3, p. 497.)
[( ~ - C ~ H ~ ) ~ T i ( b i p
[CF3S0;I2
y ) ~ + ] was more inhibitory
towards herpes simplex virus type 1 and 2 than the four
human retrovirus, HIV-1, the etiologic agents of
standards, its S.I. is still relatively low when compared
AIDS.31,32
One of the strategies to combat this disease
with that of the current clinically approved drug for
that has been adopted with some degree of success is
herpes simplex virus infections, i.e. acyclovir .30
to identify agents which specifically inhibit virusFinally, the 12 metallocenes and metallocenium
encoded RNA-directed DNA polymerase (reverse
complexes were assessed for their activity towards the
~
a>
<, approx. unity.
Compound
52.5
><1
><1
52.5
><1
><1
> <1
<1
<1
S l
><1
><1
2 10
<1
<1
<2
1
1
1
<4
>1
1
>I
<I
<1
1
><1
><1
2 10
<I
><1
<1
HSV-2(G)
HSV-l(K0S)
52.5
><1
><1
><1
<1
5 1.6
51
52
52
5 10
<1
<1
<4
2 40
2 100
2 800
Vaccinia
virus
52.5
><1
><1
5 2
<I
5 1.6
5 1
52
52
1
<1
<1
5.7
2 20
22
2 800
Vesicular
stomatitis
virus
Table 4 Antiviral selectivity indexes (S.1.) for the metallocenes and metallocenium complexes
>2
><1
><1
22
22.5
><1
<1
<1
<1
<1
<2
<2
25.1
1
22.7
2 20
Coxsackie
virus
type B4
><1
><I
><1
><I
<1
<1
<1
<1
<1
52
52
25.7
25.7
>2.1
25.7
><la
Sindbis
virus
><1
><1
><1
><1
><1
<1
<1
<1
<1
<1
52
52
1
1
1
1
Semliki
forest
virus
><1
><1
><1
><1
><1
<1
<1
<1
<1
<4
55
55
24
2 20
>5.1
2 200
Parainfluenza
virus
type 3
<4
><1
-
><1
><1
<5
><1
><1
><I
<1
<2
<2
~~
HIV- 1
Antiviral activity of metallocene and metallicenium compounds
transcriptase). For example, the 5 ’-triphosphate of
3 ’ -azido-2 ,3 -dideoxythymidine (AZT) is a potent
and selective inhibitor of HIV- 1 reverse transcriptase. 33 Accordingly, the metallocenes and
metallocenium complexes were investigated for their
activity towards HIV- 1 reverse transcriptase activity
and for their ability to inhibit the cytopathic effect of
HIV in human T-lymphocyte MT4 cells. In the former
experiments, only (r]-C5H5)2VC12
was found to inhibit
HIV- 1 reverse transcriptase activity at a concentration
<200 pg ~ m - ~the, highest concentration tested. Its
50% inhibitory concentration was found to be
141 pg ~ r n - ~(560 pmol dm-3), approximately
25000-fold higher than the IC50 of AZT
5’-triphosphate. None of the complexes was found to
be effective in inhibiting HIV-induced cytopathogenicity in human T-lymphocyte MT4 cells at subtoxic
concentrations (Table 3).
In conclusion, a number of antitumor neutral
metallocenes and ferrocenium complexes demonstrated
only marginal antiviral activity when evaluated against
a select number of DNA and RNA viruses. Of the three
titanocenium complexes, [ (q-C5H5)2 T i ( b i ~ y ) ~ + l
[CF3S03I2had distinct activity against DNA viruses,
especially the two selected strains of herpes simplex
virus and vaccinia virus. Selectivity Indexes are given
in Table 4.
Acknowledgements The authors thank Professor Dr V Thewalt,
Ulm, Germany, for providing a sample of the titanocenium bipyridyl
complex and gratefully acknowledge the excellent technical assistance
of Anita Van Lierde, Frieda De Meyer and Ann Absillis. R C T
would like to thank Oakland University for a research retraining leave
during the academic year 1987-88. S G W and R C T would like
to express their gratitude to E D C for providing laboratory space
and supplies to carry out this research at the Rega Institute.
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selected, metallocenium, spectrum, metallocene, broad, activity, complexes, antiviral, assessment, vitro, antitumor
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