The next group of biologically active organogermanium compounds are germatranes (3) - tricyclic organogermanium derivatives of triethanolamine (1-germa-2,8,9-trioxa-5-azatricyclo[,5]undecane) containing a hypervalent germanium atom with a transannular bond to nitrogen (bond length 2.01-2.29 A) which is responsible for their chemical stability.122 Several methods for the preparation of germatranes have been elaborated. The reaction of tetra-alkoxy- or trialkoxy-germatranes with triethanolamine occurring under mild conditions in the presence of a catalyst or without catalyst giving 70-90% yield is considered the simplest and most available:123

The acute toxicity of germatranes depends on the substituent at the germanium atom.22 Their mean LD50 at intraperitoneal (i.p.) administration varies from 16.5 to 10 000 mg kg"1.16,124

All furylgermatranes are less toxic than the corresponding thienylderiva-tives.16 The position of the bromine atom and germatranyl group in the thiophene ring dramatically influences the toxicity of the compounds, varying

RBr toluene, A

toluene, A

R = alkyl, aryl, hetaryl Germatranes from the very toxic 5-bromo-2-thienylgermatrane to the non-toxic 3-bromo-4-thienylgermatrane. 2-Isomers belonging to the thiophene series appear to be the most toxic while, in the furan series, the 2-derivatives are less toxic than

3-isomers. Phenylgermatrane125 is two times less toxic than 2-thienylgerma-trane (16.5mgkg_1) but still exhibits high toxicity (35.5mgkg_1). p-Fluoro-phenylgermatrane exhibits a comparable toxicity (LD50 42.2mgkg_1). The introduction of a bromine atom or a methyl group in the para-position of the phenyl ring decreases the toxicity by two times (LD50 65.5 and 70mgkg—\ respectively). p-(2-Thienyl)phenylgermatrane (LD50 324mgkg_1) is less toxic (~9 times) in comparison with the unsubstituted phenylgermatrane. Introduction of methylene-, siloxy- or germoxy-group between the aromatic ring and the germatranyl cage substantially lowers the toxicity of germatranes.22

The high toxicity of phenyl- and thienyl-germatranes can be explained neither by the presence of the tricyclic germatrane ring with a penta-coordinated germanium atom nor by the presence of a ^-electron system in the substituent. Alkylgermatranes (LD50 ranging from 355 to 3000 mgkg-1),22 p-biphenyl-, p-(2-thienyl)phenyl- or 2,2'-bithienyl-germatranes (LD50 282, 324 and 447mgkg—\ respectively) containing the same germatrane system and vinylgermatrane (^-bond) (LD50 5600 mgkg-1)22 have low toxicity or are non-toxic. Hydrolysis of the Ge—C bond decreases the toxicity by more than 500 times. Both the products of the Ge—O bond hydrolysis - germanic acid (LD50 ~2000mgkg—1) and triethanolamine (LD50 1450mgkg—1) - are also less toxic than the starting 2-thienylgermatrane. As the mechanism of arylgerma-trane's biological activity is not known yet, one can speculate that both parts of the molecule, the germatrane system (for binding to the receptor?) and aryl group bound directly to the germanium atom (for toxic bioarylation; 2-thie-nylmethyl- and benzylgermatranes are less toxic 325 and >1000mgkg—1), are important for the expression of high toxicity.

The neurotropic activity of germatranes 3 has been studied.10,11,16,22,126 132 In most cases the heteroarylgermatranes R(CH2)nGe(OCH2CH2)3N with the germatranyl group directly connected to the carbon atom (n = 0) possess a higher toxicity and a higher CNS activity.16 Hydrogermatrane HGe(OCH2CH2)3N exhibits the highest depressant activity (ED50 0.0015mgkg—1) on the CNS.16 Thus, the therapeutic index for this compound is rather high (>200 000). The transition from hydrogermatrane to hydroxygermatrane HOGe(OCH2CH2)3N demonstrated that the CNS-depressant activity is noticeably decreased.16,22 The substitution of the hydroxyl group in the germatranol molecule by a trimethylsiloxy, triphenylsi-loxy or triphenylgermoxy group leads to the complete loss of the CNS-depressant activity. Arylgermatranes were more active than hetaryl derivatives in memory improvement tests. Phenylgermatrane, p-tolylgermatrane, p-fluorophenylethynyl-germatrane, benzylgermatrane, and o- and p-bromobenzylgermatranes completely prevented animals from retrogradal amnesia caused by an electric shock.

4-(Dimethylamino)phenylgermatrane has been studied more thoroughly by its administration into the stomach.16 The neurotropic action of this germatrane is characterized by a serotonin-blocking as well as by M-cholinemimetic and GABA-ergic mechanisms.

The anti-tumour activity of two types of germatranes RGe(OCH2CH2)3N and R3MOGe(OCH2CH2)3N (r = alkyl, aryl, furyl, thienyl, phenyl; M = Si, Ge) has been studied.22 The germatranes R3MOGe(OCH2CH2)3N possess higher cyto-toxicity on HT-1080, MG-22A, B16 and Neuro 2A tumour cells (IC50 0.96.1 mgmr1) than RGe(OCH2CH2)3N (IC50 -100 mgml"1). Hydroxygermatrane had the highest cytotoxic activity on HT-1080 tumour cells. 1-Triphenylgermoxy-germatrane (IC50 3.2 mgml-1) suppressed the growth of melanoma B16 cells three times more effectively than 1-triphenylsiloxygermatrane (IC50 10 mgml-1). 1-Trimethylsiloxy- and 1-trimethylgermoxygermatranes inhibited the growth of Sarcoma 37 in mice more effectively than the parent 1-hydroxygermatrane (by 75, 60 and 40% correspondingly).11 Administration of 3-(1-germatranyl)propionic acid to mice afflicted with Ehrlich ascites tumour caused a 78% increase in survival time.59 Germatranes N(CH2CH2O)3Ge(CHR)2CONH2 (R = H, Ph) showed some activity against IMC carcinoma in mice.133

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