The first organogermanium compound, tetraethylgermane, was synthesised by Winkler et al. in 1887, but then it took until the middle of the twentieth century for such compounds to be widely synthesised and examined.
Organogermanium
compounds: balancing act between an anticancer drug and a herbal supplement
The first organogermanium compound, tetraethylgermane, was
synthesised by Winkler et al. in
1887, but then it took until the middle of the twentieth century for such
compounds to be widely synthesised and examined (Figure 5.14).
The major uses for germanium compounds include their application as optical materials (60%) and semi-conductors (10%), as catalysts or in chemotherapy. Some Chinese herbs and vegetables contain a relatively high amount of germanium, for example, ginseng, oats, soya beans and shiitake mushroom. The germanium is presented in organic form with Ge—O bonds being formed .
Germanium dioxide is the oxide of germanium, an inorganic
compound, featuring the chemical formula GeO2. It is formed as a
passivation layer on pure germanium after exposure to oxygen. Germanium dioxide
generally has a low toxicity, but shows severe nephrotoxicity at higher doses.
Germanium dioxide is still offered on the market in some questionable miracle
therapies. Exposure to high doses of germanium dioxide can lead to germanium
poisoning .
In the 1970s, a range of organogermanium compounds were widely
marketed as health supplements and became popular because of the therapeutic
value of germanium. This encouraged a wide range of research looking into the
biological potential of organogermanium compounds. Organogermanium compounds
are generally well absorbed after ingestion. Nowadays, mainly compounds with
antitumour, immune-stimulating, interferon-reducing and radioprotective
properties are being researched. A range of germanium compounds, including
germanium sesquioxide, spirogermanium, germatranes, decaphenylgermanocenes,
germanium(IV) porphyrins and germyl-substituted heterocycles, have been
synthesised and evaluated for their biological activities. Most intensively
investigated for a therapeutical application so far have been germanium
sesquiox-ide and spirogermanium (Figure 5.15) .
Figure 5.15 Chemical structures for germanium compounds investigated for their biological activity. (a) Ger-manium sesquioxide. (b) Spirogermanium. (c) Decaphenylgermanocene. (d) Germanium(IV) porphyrin. (e) Germyl-substituted heterocycles
2-Carboxyethylgermanium sesquioxide (Ge-132) was investigated in
the 1990s to protect the human body from radiation, enrich the oxygen supply,
remove heavy metals and scavenge free radicals. Japanese researchers have shown
that Ge-132 has a variety of biological activities and could be effective in
the treatment of several diseases such as cancer, arthritis and osteoporosis .
Ge-132 is a white crystalline powder, which is insoluble in
organic solvents and soluble in water when heated. The compound does not melt
but decomposes at high temperatures above 320 ∘C. These properties
can be explained by the three-dimensional structure of the Ge-132, which
consists of Ge6O6 rings. The structure is described as an
infinite sheet structure. The carboxylate chains form hydrogen bonds between
neighbouring chains and hold these germanium sesquioxide sheets together.
Synthesis starts with the generation of organogermanium
trichloride, which can be hydrolysed in several steps to form germanium
sesquioxide. Organogermanium trichloride itself can be synthesised by reduc-ing
germanium dioxide, a toxic starting material, with sodium hypophosphite. This
reaction proceeds via a redox reaction, where sodium hypophosphite is oxidised
(oxidation state +1 to +2) whilst GeO2 is reduced (oxidation state
+4 to +2). The resulting trichlorogermane is known to be highly unstable and is there-fore reacted in situ to the relevant organic
germanium trichloride via a so-called hydrogermylation reaction (Figure 5.16) .
Figure 5.16 Synthesis of germanium sesquioxide: (i) Na2H2PO2⋅H2O, concentrated HCl, reflux 80 ∘C, 3.5 h, then 0 ∘C; (ii) rt, 24 h 87%; (iii) H2O, 62% and (iv) hydrolysis
Germanium sesquioxides are generally not known to be embriotoxic, teratogenic, mutagenic or antigenic. Administration over a short term did not reveal any significant adverse effects. Ge-132 contains relatively sta-ble Ge—C bonds, which prevents its fast hydrolysis to the toxic inorganic compound GeO2. Ge-132 has good water solubility and is excreted from the human body within 24 h. Side effects are mainly due to impurities of the pharmaceutical product with GeO2, which can induce renal damage and accumulate in the kidneys, liver and spleen .
Lately, the antitumour activity of Ge-132 has been studied. It
has been revealed that it possesses antitumour and immune-modulating activity.
The first anticancer activity was reported when tested on Ehrlich Ascites
tumour. Furthermore, studies were carried out on Lewis lung carcinoma and other
cancer types. Oral treatment of pulmonary spindle cell carcinoma with Ge-132
showed complete remission of the cancer .
Interestingly, no cytotoxicity was proven when the studies were
carried out in vitro, and it was concluded
that the mechanism works via a stimulation of the host-mediated
immunopotentiating mechanism. Neverthe-less, the precise mechanism of the
anticancer activity of Ge-132 is still not fully understood.
Ge-132 has been scrutinised for a range of biological
activities, and studies suggest that the germanium compound may also exhibit
antiviral, cardiovascular, antiosteoprotic and antioxidant activities [1, 15b,
17]. For example, studies have shown that Ge-132 is able to avert the decrease
in bone strength and loss of bone mineral resulting from osteoporosis .
2-(3-Dimethylaminopropyl)-8,8-diethyl-2-aza-8-germaspiro[4,5]decane
(spirogermanium) was the first organogermanium compound tested as an anticancer
agent on a wide variety of human cancer cell lines, such as ovarian, cervix,
breast, renal cell cancers and others. Preclinical toxicological evaluation in
white mice confirmed the lack of bone marrow toxicity .
Spirogermanium entered clinical trials and
showed good drug tolerance in phase I clinical trials. Phase II clinical trials
revealed consistent neurotoxicity as well as pulmonary toxicities and only
moderate activity against ovarian cancer. The mode of action involved is
believed to be based on the inhibition of protein synthesis and a secondary
suppression of RNA and DNA synthesis (Figure 5.17) .
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