Toxicity, silatranes

The most prominent biological feature of silatranes is the remarkable mammalian toxicity exhibited by their 1-aryl derivatives (Table 4). Some of them are several times more toxic than widely known poisons such as hydrocyanic acid and strychnine. At the same time 1-arylsilatranes are almost harmless for cold-blooded animals, plants, and microorganisms. For example, frogs are very resistant to 1-phenylsilatrane (9) doses of 30-40 mg/kg have no effect. 

Remarkable is the fact, that toxicity of silatranes varies within extremely wide limits, being determined mainly by the nature of the substituents R in structure 8 (Table 4). While 1-arylsilatranes are very toxic, 1-alkyl-, 1-vinyl-, and 1-ethinylsila-tranes are practically non-toxic. 1-Alkoxysilatranes have low toxicity and many of them can also be regarded as practically non-toxic. 

Table 5. Oral toxicity of l-(p-ch orophenyI)silatrane for warmblooded animals...

The high toxicity of 1-arylsilatranes is already used commercially in the USA. Marketing of l-(p-chlorophenyl)silatrane (II) as a rodenticide began in 197143 ... 

Numerous other metallatranes have also been tested biologically, but they show much lower effects than the silicon species. The mechanism of the toxic effects of silatranes is not clear in all cases so far. 

Today the toxic effect of silatranes has been thoroughly studied1-3,16-44a b The toxicity of silatranes varies greatly and is mainly dependent on the nature of substituents at the silicon atom. Most toxic of all known silatranes are 1-arylsila-tranes, 4-XC6H4Si(OCH2CH2)3N, where X = CH3, Cl, H (Table 1). These compounds are almost twice as toxic as such well-known poisons as strychnine and hydrocyanic acid. They produce an intensive stimulation of the motor and respiratory centres1-3,30-34,44,when administered at lower than lethal doses... 

Table 2. Oral toxicity of l-(4 -chlorophenyl)silatrane (C. B. Beiter, M. Schwarcz, G. Crabtree, 1971)...

The toxicity of 1-aiylsilatranes is dependent not only on the nature of the substituent but also on the position of the latter in the aromatic ring. Thus, whereas para-methyl and para-chloroderivatives of 1-phenylsilatrane are highly toxic, their meta- and ortho-isomers show a low toxicity compared to them (Table 1). Introduction of the fluorine atom into the methyl group of l-(4-methylphenyl)silatrane decreases its toxicity by one order of magnitude. 

Introduction of methyl groups into the silatrane skeleton of 1-arylsilatranes also reduces considerably the toxicity (LDS0 of 1-phenyl-3,7-dimethylsilatrane is two orders of magnitude lower than that of 1-benzylsilatrane) (Table 1). 

In 1971 M T Chemicals (USA) began marketing 1-para-chlorophenylsilatrane as a new rodenticide under the trade mark RS-15030, 3 ). This first organosilicon pesticide had an advantage over other known toxicants. This highly toxic compound is rapidly inactivated in poisoned rodents, so their corpses are not harmful to other animals. Furthermore, RS-150 penetrates very poorly through the skin (its cutaneous toxicity is 3000 mg/kg for rats)31). Finally, rats do not become resistant to l-(4 -chlorophenyl)silatrane as was the case with other 1-arylsilatranes. Practically complete lack of smell is another important advantage of this preparation and other 1-arylsilatranes. 

Withdrawal of the aromatic substituent in 1-aroxysilatranes from the oxygen atom in a methylene group leads to a sufficient decrease in toxicity (LDS0 of 1-benzyloxysilatrane is 2250 mg/kg). Whereas administration of 150 mg/kg of 1-phenoxysilatrane to white mice produces tonic-clonic convulsions, 1-benzyloxy-silatranes administered at higher doses only cause slight hyperemia. 

Nitrogen-containing 1-alkylsilatrane derivatives (9, 23, 24 and 25) have low toxicity (LDS0 = 1300 - 3000 mg/kg). However, quaternization of the nitrogen atom in 1-aminoalkylsilatranes (32, 33) leads to a sharp increase in toxicity (LD50 is 540 and 240 mg/kg, respectively). l-(3 -Aminopropyl)silatrane (36) is even more toxic (LDS0 = 190 mg/kg). 

The toxicity of l-(3 -halopropyl)silatranes (34,44, 48) is dependent on the nature of the halogen atom and increases in the following order... 

Introduction of FCH2 and F3C groups into the side chain of 1-alkylsilatranes increases the toxicity more effectively than introduction of trifluoromethyl groups into the silatrane skeleton (Table 6). 

The clinical signs after administration of compounds containing fluorine are almost identical. Death occurs more rapidly with higher toxicity of the compound. Thus, administration of l-(3 -trifluoropropyl)silatrane and l-(3 -fluoropropyl)-3,7,10-trimethylsilatrane at the highest dosage causes immediate death while in the case of l-(3 -trifluoropropyl)-3,7,10-trimethylsilatrane death occurs within 10-15 minutes42-so). 

The immediate cause of death seems to be the result of a paralytic action on the central nervous system, particularly on the respiratory centre. Typical toxic signs of poisoning by fluorine-containing silatranes are hyperexcitation, muscle twitching, spasm of abdominal muscles, tremor, salivation. 

Polyfluoroorganylsilatranes containing an iodine atom at the a-position to the silicon atom are less toxic than l-(3 -trifluoropropyl)silatrane (11) (Table 6). The LDS0 value for CF3CH2CHISi(OCH2CH2)3N is 120 mg/kg and that for C3F7CH2CHISi(OCH2CH2)3N is 180 mg/kg. At the same time, l-(2 -perfluoro-hexyl-l -iodoethyl)silatrane (1) is practically non-toxic (LDso = 3000 mg/kg). 

The toxicity of silatranes is considerably influenced by the nature of the solvent. Thus, the toxicity of silatrane solutions in dimethylsulphoxide is considerably higher than in water and tween. On skin application 1-arylsilatranes in DMSO solutions are fairly toxic as well, but not toxic in the solid state and in aqueous solutions. 

The mechanism of the toxic effect of silatranes is not clear yet. The data of Tables 1—6 show that toxicity depends, first of all, on the substituent at the silicon atom. 

Table 7. Toxicity of polyhedral systems of some silatranes, phosphatranes, heteroadamantanes and bicyclo[2.2.2]octanesa...

The toxic effect and other biological properties of many silatranes are thus associated with their structural peculiarities and are mainly determined, in the author s opinion, by the following factors... 

The study of the antitumorous effect of low-toxic silatranes not affecting healthy organs and tissues and producing a certain antiblastic effect in the tests with animals indicates the necessity of further investigation of this class of organosilicon compounds in order to develop a new type of anti-cancer preparations. 

Silatrane itself (R = H) has an LDM of —100 mg/kg. In general, the aryl- and thienylsilatranes are more toxic, and the alkyl-, alkenyl-, and alkoxysilatranes are less toxic. It was reported that there is a direct relationship between the toxicity and the rate of hydrolysis of the silicon-oxygen bonds, a more rapidly hydrolyzed silatrane being less toxic (86). 

The extreme toxicity of the arylsilatranes has found practical application. (p-Chlorophenyl)silatrane has been marketed in the United States as a rat poison. This compound has the dual advantages of not being dermally absorbed by humans and of being rapidly deactivated in vivo, so that the dead rats are not toxic (7, 87). 

Binary technologies are also acknowledged however, the development of other methods of synthesis is not excluded (the more steps there are involved in synthesis the more difficult it is to control the process). An alternative is to search for compounds either used or synthesized already. From the groups of highly toxic chemicals these could be fluorophosphorylcholines (unstable) or toxic silatrans. In the group of medicaments, there are also highly toxic chemicals... 

Silatrane acrylates are obtained in accordance with Scheme 2. In contrast to silocanes their silatrane analogs present the ctystalline substances that are not susceptible to easy polymerization. Their toxicity and wound cicatrizing effects have been studied. 

Silatranes exhibit a wide range of acute toxicity in mammals as demonstrated in Table 1 by the LD50 values [mice intraperitoneal and peroral (footnote) administration, respectively] of some selected derivatives. The toxicity of silatranes is mainly dependent on the nature of the substituent X at the silicon atom of 26. As a general rule, 1-arylsilatranes, such as 27-30, are the most toxic ones, whereas 1-alkyl- (e.g. 33 and 34), 1-alkenyl- (e.g. 35) and 1-alkoxysilatranes (e.g. 36) are virtually nontoxic (Table 1). The LD50 value of silatrane (38) itself was determined to be 100 mg per kg when administered intraperitoneally. The comparison of the LD50 values (intraperitoneal administration) of 1-phenylsilatrane (27) and its derivatives 31 and 32 is a particularly instructive example... 

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