Carboxyethylgermanium sesquioxide

2-Carboxyethylgermanium sesquioxide (1) received much attention in the nineties. The biochemical significance of this crystalline structure consisting of Ge6O6 rings23 will become apparent in discussing organic germanium compounds' ability to scavenge free radicals, protect against radiation, enrich the body's oxygen supply and rid the body of heavy metals. The synthesis is carried out by hydrolysis of an organogermanium trichloride10

CH2=CHR + HGeCl3—> Cl3GeCH2CH2R—>( O15GeCH2CH2COOH)„ R = COOH, COCl, CN 2-Carboxyethylgermanium sesquioxide

A large number of other organogermanium sesquioxides have been synthesized for biological testing.10

2-Carboxyethylgermsesquioxane exhibits acute toxicity for mice and rats with a mean value LD50 = 6000-10 000 mg kg"1 (p.o., i.p.) and 45005700 mg kg"1 (i.v.).24 Subchronic oral toxicity of [(HOOCCH2CH2Ge)2O3]n (in rats 1gkg" day"1 during 6 months) has been reported.25,26 Daily oral administration of 120mgkg"May" of 2-carboxyethylgermsesquioxane, hereafter Ge-132, for 24 weeks showed no toxic effects in mice.27

Oral administration of proxigermanium for a year at 750mgkg" day"1 induced diarrhoea in rats. However, it has been found that a dose of 83mgkg" day"1 is not toxic. Proxigermanium administered in a dose of 15-240mg person"1 has not affected physiological functions in healthy volunteers.28

The compound is not embriotoxic, teratogenic,29 31 mutagenic, carcinogenic or antigenic. , , The oral administration of proxigermanium does not affect fertility at doses 350, 700 and 1400 mg kg"1 day"1 60 days before and at mating in male rats and 14 days before, at and 7 days after mating in female rats.28

The histological investigation revealed no significant renal toxic effects of propagermanium when administered at a high dose for eight weeks. Propager-manium administration was not associated with any alteration in the changes induced by adriamycin or mercuric chloride. This confirms that propagerma-nium may be a safe compound for use by individuals with damaged kidneys.33 On the other hand, case reports on the nephrotoxicity of organogermanium preparations (high doses, long-term administration) have been pub-lished.9,18,20,34 41 One-month oral subacute toxicity of propagermanium has been studied.42

The anti-tumour activity of Ge-132 and its derivatives has been studied. 2-Carboxyethylgermsesquioxane has been revealed to possess anti-tumour,7,8,10,17,43 interferon-inducing10,17,44 46 immunomodulating (normalizing the ratio of T-lymphocyte subpopulations),10,47 53 and anti-viral10,54 properties. The anti-tumour activities of (O15GeCH2CH2COOH)n and (O15GeCH2CH2CO NH2)n7,8 were first reported by Asai.7,8 Mice with the Ehrlich ascites tumour received 20mgml"1 (O15GeCH2CH2COOH)n and 20 and 40 mgml^1 of (O15GeCH2CH2CONH2)n daily for 7 days. The inhibition of the tumour cells' growth was higher than in control by 26, 47 and 31%, respectively. 2-Carboxyethylgermsesquioxane exhibited some anti-tumour activity in adenocarcinoma LA-795, in the Lewis lung carcinoma 3LL,55 58 melanoma B1659 and leukaemia L-121060 and had a limited anti-metastatic effect in mice.56 Complete remission of pulmonary spindle cell carcinoma has been observed after oral administration of germanium sesquioxide.61 In some cases 2-carboxyethylgermsesquioxane reinforces the effect of bleomycine and 5-fluorouracil.62 It has been shown that (O1.5GeCH2CH2COOH)n,63,64 (O15GeCH2CH2COONa)n55 and (O15GeC H2CH2CONH2)n65 prolong life of mice with implanted ascitic hepatomas AH-44 and AH-66 and also of rats with syngenic bladder carcinoma BC47.66

Germanium-132 was not cytotoxic to carcinoma cells growing in vitro and had its anti-tumour effect via the stimulation of host-mediated, immunopoten-tiating mechanisms,14,56,67 leading to the augmentation of natural killer cells' activity and activation of macrophages in mice.56 Carboxyethylgermanium sesquioxide has some preventive effects on the precancerous lesions in rat glandular stomach induced by N-methyl-N'-nitrosoguanidine.68

The Ge-132 administered p.o. activated mouse murine macrophage-mediated tumour cytotoxicity. When Ge-132-activated macrophages were treated with ganglioside in vitro, synergistic activity appeared.69 2-Carboxyethylgermses-quioxane, 2-carbamoylethylgermsesquioxane and a^-dicarboxyethylgermses-quioxane significantly stimulated mouse peritoneal macrophages and human monocytoid cells by oral administration of a single dose of 100mgkg_1.7°

The anti-tumour activity of various organogermanium sesquioxanes [(O15GeCH2CHRCOX)n, R = H, Me, X = OH, NH2]59 and sesquisulphides71 has been studied. The most active was the methacrylic acid derivative (80% life prolongation in melanoma B16 and 72% life prolongation in mice with Lewis lung carcinoma).

The sesquioxanes (O15GeCH2CHRCOX)n7273 and (4-RC6H4GeO15)n (R = Hal, CN)74 76 exhibited anti-tumour activity and prolonged the lives of animals with Ehrlich ascites tumour.

Organogermanium sesquioxanes containing uracil or 5-fluorouracil (5-FU) moieties possess an anti-tumour activity against IMC carcinoma in mice.77,78 1-[p-[Bis(/3-chloroethylamino)phenyl]-2-amino-2-carboxyethylgermanium ses-quioxane (LD50 1 76 5mgkg_1) inhibited the growth of sarcoma S-180 by 78% (in mice, i.p.), whereas a 65% inhibition was achieved with 5-FU under the same experimental conditions.79 Some germanyl heterocyclic (indolyl or furyl) amino acid derivatives, such as 1-(3'-indolyl)-2-amino-2-carboxyethylgermsesquioxane, and corresponding sesquisulfide have anti-tumour activity in sarcoma S-180 comparable to that of 5-FU.80

The results of bioassay showed that the organogermanium sesquioxanes containing the a-aminophosphonate group OL5GeCHR'CHR"C(O)NHCH (R)P(O)(OPh)2 exhibit cytotoxicity in vitro.81,82

Preliminary pharmacological investigations of 2-(2-germaoxa-3H-benzofuran-3-yl)-2-acetylaminoglycine and 1-(2-hydroxyphenyl)-2-amino-2-carboxyethyl germanium sesquioxane showed that the sesquioxane derivative had a low toxicity (LD50 >10gkgfor mice) and inhibited the growth of S-180 in mice by 51.6% (orally). The activity of this compound was slightly higher than that of 5-FU under the same experimental conditions.83

Glucopyranosyl derivatives of carboxyethylgermanium sesquioxane such as 2,4-di(O-acetyl)- 1,3,6-tri-O-(carboxyethyl)germanyl-/3-D-glucopyranose showed EAC(Erlich Ascites Carcinoma) growth inhibition in mice (i.p.) by 62%.84

Germsesquioxanes (GeCR1R2CR3HCOX)2O3 (R1, R2, R3 = H or lower alkyl, Ph; X = OH, O-lower alkyl group, amino group or a negative charge) have been proposed as therapeutic agents for brain aging.85 Ge-132 can antagonize the damage of neural behaviour caused by the heavy element lead.86

Germanium-132 can inhibit bone resorption by osteoclasts in a concentration-dependant manner.87 The therapeutic effect of Ge-132 for experimental osteoporosis has been studied using ovariectomized rats maintained on a low calcium-containing diet. Ge-132 prevented decreased bone strength, and affected the femur cortical bone index and bone mineral mass caused by osteoporosis.88 The peripheral quantitative computed tomography measurements of the femur demonstrated that a high correlation existed between the transverse strength and total bone mineral density or bone mineral content.89

Recently, the effects of Ge-132 on the low density lipoprotein oxidation and atherosclerosis in Kurosawa and Kusanagi hypercholesterolemic (KHC) rabbit have been studied.90 Treatment with Ge-132 resulted in decreases in the oxidation rate and in the formation rate of thiobarbituric acid-reactive substances following copper-induced oxidation of low-density lipoprotein. Ge-132 is suggested to possess anti-oxidative properties, but this did not lead to any attenuation of atherosclerotic progression in the KHC rabbits.

The non-enzymic glycosylation (Maillard reaction) of amino acids with glucose has been markedly suppressed in the presence of Ge-132 in the range of 1-10mmoll_1. These results demonstrate the anti-diabetic properties of Ge-132.91 Some derivatives of Ge-132 also inhibit the Maillard reaction.92,93 As protein modification, such as glycation, may play a role in initiating changes that lead to cataract development, the effect of Ge-132 on galactose-induced cataractagenesis has been studied. It has been found that Ge-132 acted as an antiglycation agent and delayed cataract formation. This compound was effective in maintaining Na(+)-K(+)-ATPase.94,95

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