Pharmaceutical Chemistry Journal, Vol. 46, No. 11, February, 2013 (Russian Original Vol. 46, No.

11, November, 2012)

MOLECULAR-BIOLOGICAL PROBLEMS
OF DRUG DESIGN AND MECHANISM
OF DRUG ACTION
BIOLOGICAL ACTIVITY OF ORGANOGERMANIUM
COMPOUNDS (A REVIEW)

L. G. Menchikov1 and M. A. Ignatenko2

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 46, No. 11, pp. 3 – 6, November, 2012.

Original article submitted February 9, 2011.

Data on the main biologically active organogermanium compounds that were synthesized in the past 5 – 10
years were reviewed. The dietary trace element germanium is necessary to ensure normal functioning of the
body. Therefore, practically all water-soluble stable organogermanium compounds exhibit biological activity
and attract the attention of researchers.
Keywords: germanium compounds, biological activity

The chemical element germanium (Ge) was predicted by
D. N. Mendeleev in 1871 and later discovered by C. Winkler
in 1886. Germanium is a key trace element in living organ-
isms. A deficiency of it causes several diseases, including
oncogenic ones [1]. The biological activity of Ge compounds
was discovered long ago, e.g., the antitumor activity of its in-
organic compounds was observed already in 1928 [2]. How-
ever, this area began to develop vigorously only in the mid-
dle of the 1960s when the first water-soluble organogerma-
nium compounds, Ge sesquioxides, were synthesized.
Germanium sesquioxides were first discovered by Rus-
sian researchers in 1965 via hydrolysis of the addition prod-
ucts of HGeCl3 to 1,3-enones, in particular, methylmethac-
rylate [3, 4].
COOMe COOMe
HGeCl3 + H2C C Cl3GeCH2CH
CH3
CH3
H2O
(O1,5GeCH2CHMeCOOMe)n
This reaction was expanded further to incorporate other
compounds with a double bond. The most well known exam-
ple was bis(2-carboxyethylgermanium)sesquioxide,
(O1.5GeCH2CH2COOH)n, the addition product of HGeCl3
and propionic acid that was subsequently hydrolyzed [5, 6].
This compound has a polymeric structure [7]. The physiolog-
ical activity of this compound (known also as Ge-132,
CEGS) was studied the most [8]. This Ge sesquioxide was
applied broadly in medical practice, especially for multi-drug
cancer therapy [8, 9]. Its spectrum of biological activity
turned out to be extremely expansive and, besides the anti-
tumor effect, it exhibited also analgesic, anti-inflammatory,
antioxidant, immunomodulating, and antiviral action. Its
hypotensive and neurotropic properties are well known. It is
a hepatoprotector and radioprotector and exhibits low toxic-
ity [10].
The vigorous development of the chemistry of organo-
germanium compounds as potential drugs and the active
study of their biological activity began with Ge-132. This
topic was reviewed several times [11-19] and was the subject
of an original monograph [10]. In the present review, atten-
tion is focused on research during the last 10 years.

1
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Germanium sesquioxides
Moscow, 119991 Russia;.
2
Lomonosov Moscow State Academy of Fine Chemical Technology, Mos- Progress in the application of Ge-132 to oncological
cow, 117571 Russia; e-mail: mlg@ioc.ac.ru. practice (including clinically proven cases, e.g. total remis-

635
0091-150X/13/4611-0635 © 2013 Springer Science+Business Media New York
636 L. G. Menchikov and M. A. Ignatenko

sion of lung cancer [20]) stimulated firstly a comprehensive tivity. Furthermore, it could be concluded based on a study of
study of other types of physiological activity of Ge-132 itself the activities of derivatives of acrylic acid
and, secondly, the synthesis of its derivatives and the study (O1.5GeCH2CH2COOR)n compared with those of
of their properties. methacrylic acid derivatives (O1.5GeCH2CHMeCOOR)n
The high effectiveness in multi-drug cancer therapy in [29 – 32] that the former exhibit substantially greater activity
the post-operational period was demonstrated during a study (the antitumor activity turned out to be greater by an average
of Ge-132 [21]. This compound was also proposed for treat- of two times).
ment of burns [22], several cardiovascular diseases [23, 24],
and hepatitis [25, 26]. It was shown that it stimulates and Germatranes
normalizes liver function [27]. It was also established that
the observed antitumor activity of Ge-132 could in several Another group of biologically active Ge compounds are
cases be secondary (in particular, the antitumor effect could 1-germa-2,8,9-trioxa-5-azatricyclo[3.3.3.01,5]undecane and
be a result of an increased NK activity and increased humo- its derivatives (germatranes) [19, 33]. These compounds are
ral immunity [28]). stable owing to the hypervalent Ge atom with a transannular
A large number of various derivatives of Ge-132, mainly bond to N.
its esters, were synthesized and studied. Thus, several quino-
line esters were synthesized [29]. It was shown that introduc- O
tion of quinoline substituents as the ester increased the anti-
R Ge N
tumor activity of the derivatives. The compound 2-carboxy-
ethylgermanium sesquioxide b-(8-quinoline ester) showed O O
the greatest activity (inhibition of PC-3M prostate adenoma
cell growth by up to 78%). The new germatranes included benzyl- and bromo-
benzyl-substituted (R = CH2C6H5, CH2C6H4Br) germatranes
(O1,5GeCH2CH2COO )n
[34]. These exhibited low toxicity (LD50 > 1000 mg·kg–1)
and a broad spectrum of neurotropic activity. In particular,
N the bromobenzyl-substituted germatranes improved memory
processes.
It was found among several new Ge sesquioxide deriva- Germatrane derivatives with cinnamic
tives [30, 31] with anthraquinone and naphthalene substitu- [R = CH(C6H4OH)CH2COOH] [35] and caffeic
ents that introduction of anthraquinone and naphthalene es- [R = CH(C6H3(OH)2)CH2COOH] [36, 37] acids were also
ters also increased substantially their antitumor activity com- synthesized. They had low toxicity and good antitumor activ-
pared with Ge-132. The naphthyl ester showed the greatest ity. The caffeic acid derivatives turned out to be more active
than the cinnamic acid derivatives.
activity (IC50 = 4.8 mmol/L, K562 human myeloid leukemia
cells).
Other Ge compounds
(O1,5GeCH2CH2COO )n
Other classes of compounds incorporate Ge as R3Ge sub-
stituents (usually as trimethylgermyl) in organic compounds
with known physiological activity. As a result, their synergic
activity was detected in several instances.
Another sesquioxide that showed high antitumor activity Thus, the amide of trimethylgermylpropionic acid and an
was g-thiocarbamidopropyl Ge sesquioxide [32], for which amino-analog of ascorbic acid was synthesized. It exhibited
the inhibition in trials (at concentration 50 mg/mL) was 92.9, antioxidant properties and was proposed also for treating
84.9, and 70.9% for KB cells (human epidermal cancer atopic dermatitis [38, 39].
cells), HCT (human colon cancer cells), and Bel (hepato- Me OH
Me H
cellular carcinoma cells), respectively. Ge N O
O
S Me
O1,5Ge(CH2)3NHCNH2 O
n HO OH

However, Ge-132 in these same trials was active only for
HCT (inhibition 31.4%) whereas it was inactive for the other two.
It can be seen by comparing data for various Ge
sesquioxide derivatives [29 – 32] that the acids themselves
are less active than their esters with respect to cytostatic ac-
Another compound with a trimethylgermyl group is
6-O-[3-(trimethylgermyl)propyl]-b-D-glucopyranoside. It
was more active than Ge-132 owing to its high solubility in
water. It stimulated interferon production [40] and was sig-
nificantly less toxic than Ge-132.
Biological Activity of Organogermanium Compounds 637

Me
Representatives of yet another class, amino-acid
O Ge germanates, were studied as potential immunomodulators [45].
Me
HO O
Me Ge NHCHCH2 N
HO OH
O COOH
HO N
H
Trialkylgermyl-substituted trifluoroacetylfurans (R = 2

Me, Et) were synthesized. Their anesthetic activity and Methionine and glutathione in addition to histidine were
cytotoxicity were studied [41]. Of these, 5-triethylgermyl-2- used as the amino acids. It was shown that all prepared com-
trifluoroacetylfuran (R = Et) exhibited anesthetic activity pounds exhibited good interferon-inducing activity (espe-
(ED50 0.9 mg × kg–1). Both compounds showed low antitu- cially bis-methionine germanate).
mor activity. Organogermanium compounds often have very low solu-
O bility in water [10]. Endowing them with amphiphilic prop-
R3Ge CCF3 erties is yet another route for solving this problem. Surfac-
O tants containing Ge were prepared in several studies [46, 47].
The substituent 2-methyl-3-(triphenylgermanyl)propo- Their antitumor activity was demonstrated for several cell
xycarbonyl was introduced into the known insect-growth types.
Radioprotector properties were found for the known Ge
regulator N-tert-butyl-N,N¢-dibenzoylhydrazine in a search
lactate-citrate [48]. A series of organogermanium com-
for new means of control.
pounds, germadithioacetals of substituted naphthylethylimi-
O O
dazoline derivatives (R = H, Me; R1 = R2 = n-C6H13,
N NH CPh iso-C5H11) [49 – 52] in addition to 2,2¢-oxydiethanethiols
CMe3 (X = O) and 2,2¢-thiodiethanethiols (X = S) [52, 53], were
synthesized in order to create compounds with radioprotector
properties.
OCH2CHCH2GePh3

O Me R1R2Ge SCHRCH2N N

However, the product showed low insecticidal activity

[42] although it exhibited unexpectedly fungicidal activity.
Introduction of a trimethylgermyl group into benz-
othiazolines produced a series of complexes with a Ge—S
bond and a transannular bond with N (R = pyridyl, furyl,
thiophenyl). Their antiandrogenic and biocidal properties
were studied [43]. These compounds showed fungicidal ac-
tivity that was comparable with that of Bavistin and bacteri-
cidal activity that was comparable with that of streptomycin.
Me
S
Me Ge
Me N
Me R
Other classes of synthesized organogermanium com-
pounds include a series of germa-g-lactones (R = Me, Ar).
Their effect on the growth of seven species of pathogenic
bacteria and the inhibition of their ureases were studied [44].
These compounds were especially effective against Proteus
mirabilis and Saccharomyces cerevisiae.
R They include agents for the prophylaxis and treatment of cer-
O tain diseases, e.g., peripheral joints and the backbone [55]
Ge
N with cancer and HIV [57]. Various BAA based on
O O
2
H3C
2
CH2CH2S
X Ge(SCH2CH2NH2 HCl)2
CH2CH2S
Antitumor activity of 2,2¢-oxydiethanethiols was also
studied against seven types of cancer cells. It was shown
that, although these compounds also exhibited pronounced
cytostatic activity, it was markedly less than for the known
cis-platin and etoposide [53].
Heightened interest in biologically active additives
(BAA) containing organogermanium compounds has re-
cently been noted in Russia. Thus, the RF Ministry of Health
registered over ten drugs based only on germatranol [54].
Germanium is an essential trace element that is involved
in global biochemical processes of living cells. This is re-
sponsible for the broad spectrum of biological activity of its
compounds [10]. The number of patents on applications of
organogermanium compounds has risen in the last five years.
and type II diabetes [56], and for normalization of immunity
organogermanium compounds were proposed [58, 59]. Also,
cosmetic agents [60, 61] and agents for the care of skin [62],
hair [63], and contact lenses [64] were developed.
638
In conclusion, we note a critical review of existing infor-
mation on Ge compounds and their biological activity [65].
The basic areas and applications of organogermanium com-
pounds as drugs and the hope and expectations for their ap-
plication are discussed in this article.
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