Organogermanium compounds: balancing act between an anticancer drug and a herbal supplement

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Chapter: Essentials of Inorganic Chemistry : The Carbon Group

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


Germanium sesquioxide

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) Na2H2PO2H2O, 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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