ADVANCES IN THE CHEMISTRY OF BIOLOGICALLY ACTIVE ORGANOSILICON COMPOUNDS

45 ADVANCES IN THE CHEMISTRY OF BIOLOGICALLY ^CTIVS ORGANOSILICON CCKi-OUNDS M. G. Voronkov Institute of Organic Chemistry, Siberian Division of Academy of Sciences of the USSR Irkutsk, USSR ABSTRACT Recent advances in the field of synthesis, study of physiological effect, and practical application of biologically active organosilicon compounds made by the research group under the author's guidance and by other scientists are considered. The latest data on the presence of silicon in living matter and on its role in vital processes are discussed as well·

We live in the world of silicon which is (together with oxygen) the principle element of inanimate nature on the Earth/1/. Silicon compounds, both inorganic (silicate building materials, glass, ceramics, etc.) and organic (silicones) are used in all branches of human practice. Therefore, no wonder that we are in a constant contact with silicon compounds which also come into our organism in drinking water (in soluble form) and in inspired air (a3 minute parts of silicon-containing dust). And, finally, man ingests daily about 0.5 g of silicon in food (silicon is present in nutrition products especially of vegetable origin) /2/. Herbivorous animals ingest in food several tens greater quantities of silicon /2/. Despite this, silicon does not seem to accumulate in the organism (its content in a human body does not exceed several grams) and produces no effect upon it. All these facts led scientists to the conclusion which was later reflected in many text-books and classical manuals, about the biological inertness and uselessness of silicon. As an example, I should like to quote a statement of not unknown English scientist H. Sherman:"The only known physiological effect of these elements (silicon and fluorine - M.V.) is injurious, and although they are always present in the organism, their presence is likely due to their random ingestion"/3/. An appreciable blow at this prevailing conviction was striken by a finding made in the laboratory of the present author· Ten years ago we showed that within a new and at that time unstudied class of organosilicon compounds with general formula RSi ( O C ^ C ^ T Q N called by us "silatranes" there were substances with very high and specific biological activity. These substances were 1arylsilatranes (H s aromatic substitutent) which exhibited a strong analeptic effect and were highly toxic for warm-blooded animals (for some of them L D C Q S 0*1 1 mg/kg)/1/. High toxicity of 1-arylsilatranes (Table 1) was further confirmed in a number of laboratories in the USSR, the GDH / V and the USA /5Λ The American company "M & T Chemicals,Inc.V5/ put on the market a new

46

Table 1 S i l a t r a n e RSl(OCH2CH2)3N T o x i c i t y f o r White Mice ( i / p ) *

H p-CH 3 C 6 H 4 C H 6 5 dC-C4H3S p-ClC6H4 m-ClC6H4 C2H5SCH

H C6H50 CH2(CH2)4CH

LD

R

50· mg/kg 0.20 0.33 0.75

BrCH2 p-0 2 NC 6 H 4 0 P -C1C 6 H 4 0

1.7 4.4 16 100 200 150

C H CH 6 5 2 CH30 5 f -CH 3 -2 f - (CH3)2CHC6H30 C2H50 Alkyl CK2=CH

^50» mg/kg

400 700 1050 1120 2100 4000 3000 3000 3000

For 3 t 5 - d i z a e t l i y l - 1 - p i i e n y l s i l a t r a n e and 1-ph.enyl-2c a r b o s i l a t r a n e LD 50 1 4 . and 8.1 mg/kg, r e s p e c t i v e l y

47

rodenticide, l-(p-chlorophenyl)silatrane · It is noted for its rapid and complete inactivation in the organisms of poisoned rodents. That is why their corpses are not harm­ ful for other animals. Besides, when getting on the skin of man, solid 1-arylsilatranes do not produce toxic effects. The striking biological action of 1-arylsilanes was pointed out by us time and again /1,6,?/ and reported at both the First and Second Symposia on Organosilicon Chemistry /8,9/· However, it should be noted that not only 1-aryl- but some of 1-heteryl- and 1-aralkylsilatranes as well as certain carbofunctional derivatives of 1-alkylsilatranes. 1-arylsilatranes induce a high activation of the background bio-electrical activity of the cortex and some subcortial structures of the brain as well. The toxicity of silatranes ranges greatly depending on the nature of R substituent (Table 1), the most toxic sil­ atranes being highly selective species. For example, pchlorophenyl silatrane is 50 times less toxic for monkeys than for sparrows /5/. We have received also less toxic silatranes which have a narcotic or depressing effect and exhibit other kinds of physiological action. A wide range of biological activity of silatranes mainly due to the nature of the R substituent at the silicon atom and their high permeability through the cell membranes possibly resulted from the high dipole moment and spheric shape of the silatrane system make silatranes rather promising object of pharmacological and biochemical studies. We have begun the present communication with the biological activity of silatranes which have no analogs among organic compounds first of all, because its dis­ covery in 1963 convinced us that many silicon compounds had to possess a specific biological activity and that a number of derivatives of this element could play a significant role in vital processes. This all made us start extensive experimental studies which confirmed completely our hypothesis. The preliminary results were reported in the monograph "Silicon and Life" /1/ by , M.G. Voronkov, G.I· Zelchan and E.J. Lukevits, published in 1971. The book deals also with a thorough analysis of highly scattered data in the world literature concern­ ing the silicon content of microorganisms, plants and animals, the possible role of this element in their life activity as well as the biological action of silicon compounds· What is the importance of the problem "Silicon and Life" and what is its present state? What aspects of this problem have been already investigated and what remains to be seen? I would like to begin with cosmic aspects. Is it possible that somewhere in the Universe there exists a "silicon-based life" instead of a "carbon-based life"? The authors of science-fiction used to give an affirmative answer. However recent science does not 11

Rodenticidal effect of 1-arvlsilatranes (including pchlorophenyl derivative one) was established for the first time in the USSR as early as 1964,

48

leave much for such optimism. In any event, now we may say with confidence that the "silicon-based life" is im­ possible on the planets with environments similar to those on the Barth. But the possibility of the existence of liv­ ing material based on silicon polymer compounds somewhere in farthers corners of the Cosmos, for example, on compa­ ratively cold planets with ammonia atmosphere or, on the contrary, on planets burned by their sun to temperatures ruinous for all life-forms known, cannot be excluded because the Universe is practically infinite not only in space but in its variations as well. But let us come back from heaven to earth· Is it possible for silicon, so abundant in the lithosphère (where the silicon content is 300 times as large as the carbon one,Table 2\ to have no relation to the origin and evolution of life? Of course, not! Natural silicon compounds played a significant role in the origin of life on the earth. First, due to their adsorbtion and catalytic properties they served as matrix on which base the simplest organic molecules taken from the world ocean evoluted to complex protein bodies. The sun and cosmic rays or even impact waves /10/ might play an important role in this process. Rather interesting is a hypothesis confirmed experi­ mentally that the phosphorus comprising the living material originated due to the penetrating radiation affecting the silica via the following nuclear reaction 30 £ i

n t r « , 31 s i _ J l _ 31 Pf

that occurred at the prebiological stage of our planet existence /11/. The optically active quartz forms gave rise to the present asymmetry of natural organic compounds. And, finally, high porous silica and silicates contributed to a greater stability to environmental effects displayed by the microorganisms living in their pores (the same is observed at the present time for the microorganisms inhabiting silicagel pores). In the course of biogenesis on the surface of silice the silicon could not but intrude the protein structure under forma­ tion and was one of the principle elements of living nature and its protoorganisms. This is confirmed by the fact that even nowadays silicon is of great importance for many organisms which are at a lower stage of evolut­ ionary development and are very rich in this element (Table 2 ) . The life-cycle of living material involves about ten milliard tons of silicon! Does not this indicate that silicon is rather an important element of life? Moreover there are all grounds to say that without silicon all the life forms on earth are hardly possible. Many representatives of the simplest life-forms take silicon from the environment using it, first of all, for the formation of shell, test and skeleton. These simplest organisms include foramiferae, diatomea, sponges, algae, etc. The silicon content of the existent so-called prehistoric plants (horse-tails, bryophytes, ferns).

49

Table 2 The C and Si Contents in Nature (parts per million)

Universe Earth crust Sea water River water Soil solution Soil

Carbon Silicon In inanimate nature (6)* (7) 1,000 (II) 276,000 (2) 28 (10) 3 03) 11 (2) 7 (4) 4 (6) 7 (4) 330,000 (2) 20,000 (5) In animate nature (in dry tissues)

Plankton Brown algae Bryophytes Perns Angiosperms Bacteria Annelida Mollusca Crustacea Insects Pisces Mammalia

225,000 345,000 450,000 450,000 454,000 538,000 402,000 399,000 401,000 446,000 475,000 484,000

(2) (2) (1-2) (1) (1) (1) (1) (1) (1) (1) (1) (1)

200,000 1,500 2,000 5,500

(3) (12-13) (6)

(6-7)

200 (9) 180 (14) 150 (13)

1,000 (11-12) 300 (13) 6,000 (7) 70 (15) 120 (15)

Figure in brackets corresponds to the place in the total elementary composition

50

There exist even "silicate bacteria" which inhabite soil and destroy rocks. In the processes of their life activity the "silicate bacteria" release potash, phosphorus, silicon and some trace elements absorbed by plants and this accounts for their application in agriculture as a fine fertilizer /12/. Of special interest are bacteria capable to synthesize in their organisms organosilicon derivatives including the Si-C bonded ones* from inorganic compounds of silicon. The silicate bacteria are possible to be the first living beings appeared on land. It was them who, having destroyed the silicate cover of the earth, prepared the ground for life of higher organisms /7/· It is rather interesting that some bacteria are capable to substitute their phosphorus for silicon. Some plants also exhibit similar ability. This enabled us to advance the hypothesis of the possibility of "non-phosphorous life" where the hereditary information is recorded and realized via the silicon analogues of DNA and ENA. It is most likely that silicic acid is able to replace partially phosphoric acid in nucleic acids which play the main role in the both protein biosynthesis and hereditary character transmission /6,7/· Such partially "silicified" nucleic acids, their possible existence and the role in vita,! processes are under investigation now. We have al­ ready shown that the DNA preparations contain appreciable amounts of silicon. The "non-phosphorous life" suggests also the existence of silicon analogue of adenozinetriphosphate which is an accumulator and distributor of biochemical energy. Silicon compounds also play an important role in the organisms which are. at higher stage of evolutionary development. These include, for example, higher cultural plants (wheat, oats, barley, millet, rice, sugar beet, etc) and many herbs and trees (for instance, fir, larch, palm, bamboo). The silicon contents of these plant species amount to 1.5-2 % of the whole dry plant weight /2/· These and similar plant species which contain relative high proportions of the silicon and intensively assimilate it from soil were even called "siliceous" species. Silicon not only imparts mechanical resistance (for example, to the cereal stalks), but also promotes the important protective functions of the plants. Addition of silicon compounds to culture solutions increases growth of plants as well as their viability, crop capacity and stability to lodging, drought, frost, radiation, and fungal infection, improves assimilation of phosphorus and other nutritious elements from soil. At the same time, the silicon content in soil below normal makes the plants sensitive to fungal and bacterial infections and decreases cropping power. The role of silicon in vital activity of plants is little studied yet. However, it is known that this element is present in plant tissues partly as organo­ silicon compounds (silicic esters of carbohydrates and proteins)/1,2,13/, and partly as mineral compounds (silica, silicic acids and silicates). There were found in plants specific enzymes - "silicazes" which favour the transformation of inorganic compounds of silicon to organic. Silicon in mature pasture plants usually

51

exists in the form of solid mineral particles of amorphous silica called "opaline phytoliths" /2/· These inclusions reduce the digestability of forages /14,15/ and contribute to the «both dental attrition of cattle and silica urolithiasis /2/. In higher animals and man, silicon is present in only slight amounts (n.10-3% of body weight), although it is contained almost in all tissues and organs· Among the bioelements comprising the organisms of mammals, silicon holds the modest feefteenth place (Table 2) giving way to magnesium, fluorine, iron, and zink. The highest contents of silicon occur in connective tissues, skin (especially in epidermis), lungs, glands (adrenal, thyroid and pancreas, lymphatic nodes), bones, dental enamel, hair. In the organisms of mammals silicon compounds are present in three principal forms. 1. Water-soluble inorganic compounds capable of pass­ ing through cell walls which can be readily eliminated from the organism (orthosilicic acid and ortho- and oliçosilicate ions)· 2· Organosilicon compounds and complexes soluble in organic solvents and containing Si-O-C groups (ortho- and oligo-silicic esters of carbohydrates, proteins, steroids, choline, lipide, phospholipids, nucleic acids, etc«)· 3. Insoluble silico-polymers (polysilicic acids, silica, silicates) which surface is always covered with a chemisorbed layer of organic substances. Silicon is essential for normal functioning of epi­ thelial and connective tissues to which it imparts, in particular, strength, elasticity and impermeability serv­ ing as an agent which sews the ker&tin and collagen macromolecules together. In blood vessels, silicon concentrated mainly ih elastine and, to a lesser degree, in collagen prevents the deposition of lipids, normalizes the perme­ ability of walls and increases their elasticity. Silicon compounds play an important role in many physiological, imaunological, pathological and géronto­ logie al processes. Thus silicon induces the biosynthesis of collagen and the formation of bony tissue. Silicon actively precipitates «here calcification proceeds and seems to induce the formation of preosteal tissue/19/· Where bone fracture has occurred, the silicon content in the area of formation of collagen fibrils and intensive cell growth, is increased as much as 50 times· All this shows the possibility to find certain silicon compounds which would be able to heal bone fractures. Silicon compounds are also of great importance for the growth of hair and nails of man, hair, horns and hoofs of animals and feather of birds. There are some evidences that silicon compounds in­ crease stability of cell membranes, affect lysosomes /24, 25/ and are capable of accumulating in mitochondrions. Most of silicon passing in the alimentary tract is eliminated in the feces. However, a portion of silicon is ingested by absorbing in the duodenum and then enters the blood. The concentration of silicon in blood is controlled by the kidneys which maintain it at a constant level and this results in a wide range of the silicon concentration in the urine. Very low amounts of silicon

52 are excreted in the bile /16-18/. A higher silicon content of the "blood moving from the liver as compared to that moving toward the liver /16/ indicates the synthesis of vitally important organosilicon derivatives occurring in the liver under the conditions of exogenic feeding. The metabolism of silicon in the organism is regulated by the endocrine /26/ and nervous /16/ systems. The hormonal regulation of metabolism of silicon is determined by the sex and age· The steroid and tyreoid hormons also participate in the regulation of metabolism of silicon /26/. The hormons control the intestinal absorbtion of this element. That is why sterilized females of animals display a decreased silicon content of blood and a reduced assimilation in the intestinal tract. The silicon metabolism of animals is also affected by the ablation of adrenals, thyroid glands and pancreas. The reduction of hormonal activity with age seems to be associated with general decrease in the silicon content of organism. Therefore» it does not seem impossible to find organosilicon stimulators of the hormonal metabolism in the future· When nervous system is excited the silicon content of the blood flowing from the brain increases, and when it is inhibited the silicon concentration in the blood drops· This fact shows that one should not exclude the possibility of finding phsychotropic agents among silicon compounds. Of certain interest are evidences indicating that silicon participates in the transmission and enhan­ cement of excitement via nerve fiber /16/ which is possibly related to high toxicity of arylsilatranes. The silicon accumulation in the optic nerve tissue with ttge is likely to be caused by the adaptation mechanism which enhances the light-excited energy weakened while passing through the eye medium altered with age. These data make it possible to hope that there would be found silicon preparations against some eye defects. One can expect that the ability of silicon to parti­ cipate in the metabolism of calcium and some other elements (P, Cl, F, Na, S, Al, Mo, Co) as well as lipids will be used in medicine and Ê&riculture. The metabolism of silicon compounds releases silicic acid which links physiologically important cations (Mg, Cu, Fe, etc.) by the formation of unsoluble silicates and this process may represent one of the mechanisms of physiological activity of silicon compounds. This mav be related to the effect of silicon (well estimated now) on a number of enzyme systems in the organisms of plants and animals. The breakdown of the metabolism of silicon is associated with some diseases such as atherosclerosis, cancer /20/, leprosy, tuberculosis, diabetes, hepatitis, encephalitis /16/, goitre, certain types of dermatites, skin erysipelas, etc. as well as with some processes of senescence /j,21/. Thus, for example, in the case of malicious neoplasm, the silicon content of the tumour is much higher than that of unaffected tissues, the silicon being trasported to the tumour from other organs which become less rich in this element /1,16,20-22/. The liver

53

proteins of patients suffering from cancer display an in­ creased ability to link silicon /23/· In this connection, the proposed application of silicon compounds for chemo­ therapy of wounds /1,9t31-33/ seems rather promising. In the case of atherosclerosis the silicon content in the connective tissue decreases sharply· This results in the drop of elasticity of arterial walls due to the dis­ appearance of elastin responsible for their resilience and in the increase in wall permeability for lipids. The silicon content of skin, arterial vessels and bony tissue as well as the the ability of organism to assimilate silicon reduce with age (it is more typical for women); thus, this is closely connected with the process of senescence. At the same time, the extracellular and plasmatic silicon content of the organism increases with age /26/. The concentration of silicon in the blood of pregnat women, nursing mothers and new-born children is extremely high. The lack of silicon entering the organism ( man as­ similates daily 20-30 mg of silicon) causes ,fsilicotic anaemia" observed in the case of rickets, scrophulosis, lymphadnopathy, etc. The lack of silicon is associated with a high content of calcium (which is the antagonist of silicon) in drinking water and with the lack of "living" silicon in food, in particular, when refined food is used. At the same time it has been found that administration of mineralized water rich in silicon (for example, well known "Dzhermuk water") is very useful for eldery peole suffering from diseases of the gastrointestinal tract, diabetis and breakdown of metabolism« Chickens fed on silicon-free diet for two weeks dis­ play poor development of feather and skeleton and very thin leg bones. The addition of 0.003 per cent of silicon to the diet increases the growth of chicks by as much as 35 per cent and normalizes the development of feather and skeleton /27Λ A. favourable effect of "soluble silica" upon growth of chicks was also reported by other authors /28/. The addition of "soluble silica" to drinking water at a concentration of 800 mg of Si02 per liter increases body weight gains of male lambs as well as feeding effectivity /29/· Analogous experiments show increased body weight gains of weanling male rats by about 6 %, but decreased gains of females by about 5% /30/. This all suggests that the addition of readily as­ similated silicon preparations to food and drinking water might be very useful not only for young stock, pregnant women, nursing mothers, rachitic children, but also for healthy people, especially of eldery age. The number of examples characterizing the biological importance of silicon may be enlarged. But we have enough of them to come to the conclusion of the necessity of a detailed studs including that on a molecular level, of the role of this element in the living organisms and the search for possible application of silicon compounds for therapy and prophylaxis of many diseases and traumas and *" A significant erfect of silicon on the metabolism calcium is well established now.

of

54

against old age· As early as 1878 Louis Pasteur wrote in one of his letters "There is a great future for the therapeutic application of silica1· · It is now evident that the words of the French genius were prophetic· There are good reasons to suggest that in the nearest future the chemical compounds of silica the presence of which in organisms is not only nornal, but necessary, will become, together with other compounds of silicon (mainly organosilicon compounds} effective medicinal preparations. The attempts to use synthetic silicon compounds as well as some plants with high silicon content (such as horse tail) in medicine (in particular, for the treatment of tuberculosis) were made long ago· Nevertheless, they were not entirely successful. The situation is now quite different. In the French Pharmacopée, for instance, there are listed certain organosilicon preparations applied successively in therapy. Prof. N. Duffaut is much of an initiator and enthusiast in this field in France. While visiting him in Bordeaux in 1968 and discussing the problem with the physicians who had contributed to these studies ( J· Loeper, J. Janet, C.Rager a.o.) we were convinced of the efficacy of "silicon therapy". In France two preparations have begun to be used in therapy; these are "DNR" (the complex of potassium methylsiliconate with salycylic acid or with other oxycarbonic acids) and "RDN" (cyclic ether of dimethylsilanediol and glycerol): 0 CH-Si(OH)„OK.nRCOOH.mH 5 do *· DNR

y O-CH (CEL)d0Si; N * 0-CHCH 2 0H

RDN

They are used in the treatment of cardiovascular diseases, cancer and virus infections. And not without success. Thus, a seven year clinical experiment based on the use of ionionhoresis preparations of DNR type (with 500 patients; resulted in 80% of complete cures of chronic heart disease· Satisfactory results have been achieved in the treatment of rapidly evolving cancer (osteosarcome, cancer of the lungs and prostate) - 400 patients were cured for 8 years· The complex of potassium metlrylsiliconete wi-th penicillin D used in the treatment or myxomatosis have resulted in 85% of complete cures (the both components, if taken separately, having no therapeutic effect in this disease). Thus, the application of organo­ silicon derivatives of antibiotics may possibly extend the spectrum of their activity· On the second meeting in Moscow in 1971 Prof· N. Duffaut shared the hope that his preparations would be used in the treatment of diabetis, cataracts and other diseases· However, the experiments with the organosilicon pre­ parations which the French colleagues had kindly supplied us with indicated, when injected, that they were not sufficiently active and had relatively high toxicity. An intensive search for biologically active organo-

55

silicon compounds carried out under the author s guidance in the Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR in Riga and in the Irkutsk Institute of Organic Chemistry, Siberian Division of the USSR Academy of Sciences, has led to the discovery of silicon deriva­ tives which exhibit antiblastic, antisclerotic, anticoagulative, analeptic, narcotic, psychotropic, antipyretic, ganglion-blocking, bactericidal, fungicidal, zoocidal, insecticidal, chemosterilizing and insect repelling effects (Table 3)· Some substances which greatly intensify growth of connective tissue and hair have been also found/59/. Of special interest are absolutely non-toxic organosilicon compounds ("mival", "migugen") having a specific and effective antitumourous action as it has been shown by the experiments on animals /31/· The mechanism of anti­ blastic activity of these compounds is quite different from that of all earlier known anticancer preparations. The new silicon compounds stimulate the protective react­ ions of the organism and cause the strictly local forma­ tion of collagen thus intensifying the evolution of connective stroma which prevents the evolution of tumourous parenchyma· The antiblastic effect of migugen (MGG-2) is shown in Fig· 8. a - tumourous tissue of Walker carcinoma; b,c,d after the injection of migugen (b - lymphocites, fibroblasts and collagen blocks are seen"; c - large collagen blocks are seen; d - connective tissue capsula which sur­ rounds the cancerous cells undergone pycnotic alteration)· It is interesting that migugen as well as its analogs when used together with known antitumorigenic preparations raise their effectiviness about two-fold. Fig. 9 shc..ô sarcoma 180 tumours of white mice. She The upper line presents the tumours of mice which were not treated (control). The intermediate and lower lines show the tumours of mice treated with "naval" injected per os for 10 days. Treatment was started 48 hours after transplatation of tumour. The dose of 300 mg/kg (150 mg/kg twice a day) gives 99·3 % ingibition (I;. The same dose injected once a day gives 90 % inhibition (II). The action of this preparation is shown in Fig· 10 a and b. An immunostimulating effect of the above mentioned preparations and their analogues holds out a hope of the development of a new method to cure maliceous tumours» that is chemotherapy of cancer. However, nowadays it is difficult to say whether this hope will come true. A final answer to this question will take years of thorough study· We have also found organosilicon compounds which accelerate the processes of connective tissue genesis. There is considerable hope that the organosilicon pre­ parations found which stimulate the evolution of connective tissue in pathogenic processes will prove to be effective drugs in treatment of a number of diseases and traumas associated with functionating of such con­ nective tissues. Fairly assuring results, on the effect of silicon on hair growth gains of animals have been obtained /59/· Fig· 11 shows a "long-haired" guinea-pig resulted from the "mivaF action on the animal with normal hair. It is

n

R^i(OCHRfCH2)3N

Zoocidal activity

Antibacterial activity

RfR"NCH2(CH3)Si(OR)2 R f R H NCH 2 Si(OR) 3 R3SiZNRfRM

R 3 Si(CH 2 ) n CH m (SCN) > m

Vn S i ( N C S ) n

R3SiZNR'R"

R3SiZNR'R"

V n Si(NCS) n

Class of organosilicon compounds

Insect repellent activity

Fungistatic activity

Chemo sterilizing activity

Insecticidal activity

Type of effect

RfRf>R,, s Unsubstituted or substituted saturated, unsaturated or aromatic hydrocarbon or alkoxyl radical; Z = saturated.or unsaturated, substituted or unsubstituted three- or four-carbon chain; X,Y = halogen, OH, OCOR.

RfiiCOCHR'CHpJi

RÊi(OCHRfCH2)3N [R^iCH^(CH 3 ) 2 CH 2 CH2X]"Ύ" [R3SiOCH2CH2N (CHOj+ X~ R3SiCH2CH (COCH3 ) CH^RR · R3SiCSCC(OH)RlRH R3SiOH, R3SiNCO

Stimulation of breathing

Soporific activity

[R3SiCH2N (CH3)2CH2CH2X]+Y"

RèiCOCHR'Cï^N

Class of organosilicon compounds* R^iZNR'R" R 4 _ n Si(0CH 2 CH 2 NR£) n ^ 3 SiOCH 2 CH 2 ) n HH >en

Reducing of blood pressure

Impairment of co-ordination of movement

Type of effect

NEW BIOLOGICALLY ACTIVE OHGANOSILICON COMPOUNDS

Table 3

57

Figure 9

58

Figure 10a

Figure 10b

Figure 11

59

interesting to note that the progeny of these long-haired animals also has long and thick hair(this time without "mival" action). This hereditary transmission of aquirred characters is likely to be caused by a higher silicon content in mother's organism. In this connection the problem of transformation of home cats into Siberian and Angora ones as well as that of mastiffs into Newfoundland dogs does not seem very fantastic. Our experiments are expected to be completed with the preparation of new organosilicon compounds very important for breeding of sheeps and fur-bearing animals. The problem of treatment of hair loss is also under consideration. We are now searching for organosilicon compounds having a favourable effect on the metabolism of calcium and lipids which would be used for prophylaxies and therapy of atherosclerosis. The use of .silicon-containing preparations against atheromatosis also seems promising according to the latest studies carried out by other authors /39Λ A new class of antimicrobial substances of XYZSiC^C^C^NRR 1 type which are distinguished for their wide range of activity and which effectively supress pathogenic microorganisms, including vibrions of cholera /5V, have been found. Among the above mentioned compounds there have been discovered antimicrobial substances which are rather more active than widely used antibiotics such as streptomycin, nistatin, etc., and affect the strains of pathogenic microorganisms resistant to well-known antibiotics· On the basis of compounds of this type containing three or two readily hydrolizing substituents on the atom of silicon, we /&/ and later the American scientists from Dow Corning /35/ have obtained new preparations which have the property of forming a stable antimicrobial coat­ ing on the surface of different materials. Among the compounds of RR'NCi^SiCOB"^ type and their derivatives we have found effective insect-repellents which retain their property to repel bloodsuckers for more than a month· During the latest years it was estab­ lished that 1,3t5i7-tetrasilaadamanthane and its deriva­ tives also possess an insect-repellent action (against mosquitoes) /40/· Triorganylsilanols and triorganylisocyanétosilànes /57/ as well as some silatrane derivatives have been found to display an inhibiting (narcotic) action. Organosilicon compounds affecting coagulative and anticoagulative blood systems have been discovered /7/· Quite interesting is the effect of these preparations on coagulation factor XII (Hagemann s factor;. There are good reasons to believe that they affect the surface of biological membranes. An anticoagulative action of in­ organic compounds of silicon has been reported in the literature /41, 42/. All our investigations, both mentioned and unmentioned here, are now in full swing and, in large part, have not left yet the laboratory walls. We trust that a series of our preparations under investigation will stand clinical test and will hold the proper place among the existing therapeutic substances. In this connection,

60

however, it may arise a question, whether it is too early to report the results of our investigations because they are far from their logical completion· We believe that it is not premature. The aim of the present communication is to draw the attention of broad scientific public to the problem of "Silicon and Life". And it is impossible for our research team (although it is not small; to solve alone this serious, complicated and very important, in our opinion, problem. In this connection * am delighted to note that nowadays the interest attracted to the biologically active organo silicon compounds and to the problem of "Silicon and Life" is increasing over the whole world. This is convinc­ ingly evidenced from the reviews /4,36/ in this field published in 1971 and from about three hundred communicat­ ions appeared aft?er the publication of our book /1/. Among the latest studies on this problem, the finding made in the USA is worth special notice: a considerable depression of male reproductive function of mammals under the effect of phenylmethyl substituted silanes and sil oxanes (Ln particular, heptamethylphenyl- and hexamethyl2,6-cia-diphenylcyclotetrasiloxane) /37 f 38/. These data not only disprove the opinion of the biological inertness of polyorganylsiloxanes, but testify once more to the fact that the organosilicon compounds with especially high bio­ logical activity ought to be searched for among the sub­ stances having a Si-aryl group. These results /37t38/ are in agreement with data of the French scientists /30/ who showed that the per os administration of water sodium silicate to rats reduces the birth-rate by 70-80 per cent. This indicates that effective and harmless contraceptives are possible to be found among organosilicon compounds· Furthermore, this shows the widely used tendency to add sodium silicate to washing agents may have grave consequences. Much attention has been recently given to the synthesis vif steroid organosilicon derivatives /43,44/ which are trialkylsilyl and trialkylsilylmethyl ethers and contain the silicon atom in one of the cycles as well. New organosilicon derivatives of cholesterol have been synthesized /45/ (orthosilicic ester of cholesterol is known to be the first natural organosilicon compound isolated from the organism of animals and man). Organo­ silicon antiradiation agents /46/, coronary vasodilatators (of R3Si(CHp)n0N0£,type) /47/f antiinflammation drugs and analgesics ttrialkylsilylmethyl isothiuronium and guanidinium saltsJ/48/, insecticides (substituted trisilylamines of (R~Si) N(SiRdp CH p X)~ type) /49/, etc. are being searched*. ^ ^ It has been recently shown /50/ that silico-tungstic acid salts inhibite* oncogenous viruses. However, despite the available data on the antitumourous effect of a number of silicon compounds it was also well established that liquid polyorganylsiloxanes had a cancerogenous effect /51, 52/. This finding not only discredited the myth of the absolute biological inertness of silicones, but also put an end to an epidemy browken out among women to change the form and size of the bust by the injection of liquid silicones. However, there is no need for the fair sex to

S. Barsza, 1972

Ant i inf1ammat ant s Insecticides

R-jSiCH^HC (=ΝΗ)ΝΗ2·ΗΝ03

(R3Si)nN(I^SiCI^X)3en

H.F.G. Patient, R.P. Bush, 1971

S. Barsza, 1972

Antiinflammatants, analgesics

S. Barsza, 1972

Dow Corning Corp., R.R. Le Vier, D.K.Bennett, K.J. Olson, a.o., 1972

R3SiCH2SC (=NRf )NHR,,.HC1

Antifertilizing (estrogenic) activity

Authors

Coronary vasodilatators

m

Type of effect

R 3 Si(CH 2 ) n ON0 2

[c 6 H 5 (CH 3 )SiO] n [(CH 3 ) 2 SiÔJ

General formula

NEW CLASSES OP BIOLOGICALLY ACTIVE ORGANOSILICON COMPOUNDS

Table 4

62 lose heart because in this cosmetic operation liquid silicones have given way to harmless in fact foamed silicon resins» The studies of the metabolism of silicon compounds carried out recently by the American scientists /53-56/ are of great importance for the introduction of new medicinal preparations in practice and for the invest­ igation of the mechanism of their action· The compounds of this type undergo in the organism a biological oxida­ tion and oxidizing dealkylation /53/· 5Si-H

—9»

•3iSi-CH3 —** ^Si-C 6 H 5 —*>

5SÎ-0-H —*>

gjSi-0-Sié

?tôi-CH2-0H ^Si-C 6 H 4 -0H

^Si(CH 2 ) n CH 3 —«»

-SSi-O-SiS

The rates of the first three reactions decrease as shown· In all the cases studied no oxidation to C0 p occurs. Trimethylsilanol and hexamethyldisiloxane on the per os or intravenous administration to rats and monkeys are well absorbed by the organism and eliminated almost completely in 24 hours Tin the case of (CHo^SiOH 70-85% urinary, 10-30% pulmonary and less than 1% in feces). Dimethylsilanediol is mainly eliminated in urine and no pulmonary excretion was evident· Metabolic study of octamethylcyclotetrasiloxane and 2,6-cis-diphenylhexamethylcyclotetrasiloxane /56/ has shown that these compounds are well absorbed orally and 80% of the dose is eliminat­ ed in the first 48 hours (60 and 65% in urine, 28 and 20% in feces, and 3·3 e^d 2·8% in expired air, respectively)· These data show that on constant administration of organosilicon medicinal preparations the accumulation of silicon in the organism is out of question. There is no doubt that organosilicon medicinal pre­ parations of the future will include, in addition to silicon compounds (among them,possibly, are preparations of "living" silicon) which have no organic analogues, substances with structures analogous to well-known bio­ logically active organic compounds· These preparations will open quite new ways for the creation of therapeutic agents and pesticides· This will occur, firstly, because the biological activities of isostructural organic and organosilicon compounds are, in a number of cases, either similar or quite different in their effect on the organ­ ism· Secondly, the corresponding organosilicon compounds are frequenrxy e»»ier to synrhesize and cheaper than their organic analogues. We are witnesses to the birth of a new branch of silicon chemistry - the chemistry, biochemistry and pharmacology of biologically active organosilicon compounds, i.e. bio-organosilicon chemistry· Its aims should include a detailed study of the role of silicon in living organisms and in the physiological processes and pathological and gerontological changes occurring in

63

them, the search for new compounds of this element with high and specific biological activity, and the study of the possible practical application of such compounds in medicine, veterinary practice, plant growing and other branches of human activity« But the present state of bio-organosilicon chemistry is, alas, best characterized by Goethe's words "The scient­ ist most frequently has only parts, but has no thread that holds them together! However, we have good reason to hope that as early as the life-time of our generation there will be woven this precious thread which will hold together all numerous facts about the biological role of silicon and the physiological effect of its compounds and will prove a guiding one in the struggle for life and health of man­ kind. The successful development of bio-organosilicon chemistry will not only widen our ideas on the mechanisms of vital processes and the structure of living tissues, but will open new routes in the fight for the health and longevity of man· It will also promote the industrial production of a multiplicity of new synthetic and natural biologically active compounds of silicon which will prove as useful as the widely applied silicates and silicones. In conclusion the author wish to express his profound sense of gratitude to his numerous colleagues and coworkers contributed to the above mentioned studies· The group of leading scientists of the Irkutsk Institute of Organic Chemistry is shown in Pig. 14. Next two photoes show the Institute building and beautiful Lake Baikal near which the Institute is situated.

64

REFERENCES* 1. M.G. Voronkov, G.I. Zelchan, E.J. Lukevits, "Silicon and Life", Publishing House "Zinatne, Riga, 1971· 2. E.J· Underwood, Trace Elements in Human and Animal Nutrition, 3rd Bd., Academic Press, N.Y., 1972. 3· Η. Sherman,' Chemistry of Food and Nutrition, London, 1933. , 577 0 9 7 D 4. E. Bien, Pharmazie, 2£, 224, 5. C.B. Beiter, M. Schwarcz, G. Grabtrie, Soap Chem. Specialties, 1970, April, 38; M & T Chemicals, Inc. Bulletin, 8 pp., 197*; D.R. Bennett, private communication. 6. M.G. Voronkov, Vestn. AN SSSR, 41, No.11, 58 (1972); Za nauku v Sibiri, No.11, 6 (1971). 7. M.G. Voronkov, A.T. Platonova, Khimia i zhizn1, 2, No 2, 16 (1973). 8. M.G. Voronkov, Pure Appl. Chem., 13, 35 0966); 19, 399 (1969). 9. M.G. Voronkov, Chemistry in Britain (1973); Kagaku, 28, 213 (1973). 10. V.T7 Goldanskij, T.N. Ignatovich, M.Yu. Kosygin, P.A. Yampolsky, DAN, 207 0972). 11. M. Akaboshi, K.Kawai, A. Waki, Biochem. Biophys. Acta, 238, 5 (197D; 246, 194 (1971); Radioisotopes, 21, 5Ô6 (1972); Tamp ahu shi t su Kahosan Koso, Bessatsu, 99 (1972). 12. V.G. Aleksandrov, M.I. Ternovskaya, Silikatnye bakterii - effektivnye udobreniya, izd. BINTISKh, M., 1968. 13. P.J. Van Soest, F.E. Lovelace, J. Anim. Sei., 29, 182 (1969). 14. G.S. Smith, A.B. Nelson, E.J.A. Boggino, J. Anim.

S e i . , 23, 466 (1971). 15. P . J · Van Soest, H.P. Jones, J . Dairy S e i . , 51, 1644

(1968). 16. A.I. Kortev, G.N. Dontsov, A.P. Lyasheva, Bioelementy i patologiya cheloveka, Sredne-Uralsk. knizhn. izd., Sverdlovsk, 1972, str. 165-175. 17. M.G. Kolomijtseva, R.D. Gabovich, Mikroelementy v meditsine, "Meditsina", M., 1970. 18. G.A. Babenko, L.P. Reshetnikova, Primeneniye mikroelementov vraeditsine,Kiev, 1971. 19. E.Jf. Carlisle, Science, 162, 2 79 (1970). 20. I.V. Kasfyanenko, O.A. Kulskaya, Mikroelementy u bolnykh rakom i predopukholevymi zabolevaniyami vnutrennikh organov, "Naukova dumka", Kiev, 1972. 21. V.A. Delova, Tr. Donetskogo gos.med.in-ta, 23, 17 (1963). 22. E.N. Ivanova, V kn. Mikroelementy v eksperimente i klinike, Drogobychsk .gos.ped.in-t, Drogobych, 1959, str. 233. References are made only to the literature not cited in the book "Silicon and Life" /1/. For the bibliography on all the questions concerned the reader should refer to this monograph.

65

23· A.O. Vojnar. Y kn. Mikroelementy v eksperimente i klinike, Drogobychsk.gos.ped.in-t, Drogobych, 1959, srt.54 24. N.S. Grishko, V kn. Biologicheskaya rol mikroelementov i ikh primenenie v sel'skom khozyajstve i meditsine, L·, 1970, str.42. 25. B· Parazzi, G.C. Secchi, Archiv Environ. Health, 17, 850 (1968). 26. G. Charnot, G. Peres, Ann. Endocrinol., 32, 397 (1971); Lion Medical, 226, 85 (1971). 27. E.M. Carlisle, Science, 128, 619 0972). 28. G.S. Smith, R.H. Robertson, J. Anim. Sei., 31, 218 (1970). 29· G.S. Smith. A.L. Neumann, A.B. Nelson, E.E. Roy, J. Anim. Sei., 34, 839 0 9 7 2 ) . 30· G.S. Smith, A.L7 Neumann, V.H. Glendhill, C.A.Arzola, J. Anim. Sei., JJ6, 271 (1973). 31. M.G. Voronkov, G.A. Grigalinovich, G.I. Zelchan, DAN, 200. 967 (197D. 32· Chem. Eng. News, £0, No 46 (1972). 33. U. Wannagat, Mitt. Techn. Univ. Carolo-Wilhelmina, Braunschweig, 6, No II/III (1971). 34. V.S. Ganin, L.E. Khundakov, L.Ya. Urbanovich, M.G. voronkov, Dokl. Irkutsk.protivochumn.in-ta, 9, 109

( 197D.

35. A.J. Isquith, E.A. Abbott, P.A. Walters, J.R. Malek, W.E. Dennis, G.P. Vogel, J.L. Speier, Third International Symposium on Organosilicon Chemistry, Madison, 1972, p. 34. 36. L.G. Garson, L.K. Kirchner, J. Pharmaceut. Sei., 60, 1113 (197D. ~ 37. Dow Corning Corp. Toxicol Appl. Pharmacol., 21, 12, 15, 29, 45, 55, 68, 80 (1972). ~ 38. E.R. Le Vier, M.E. Jankowiak, Biol. Reprod., 7, 260 (1972). 39· Y· Charnot, D. Desmaris-Belecraz, G. Peres, C.r.Soc. biol., 166, 996 (1972)· 40. J.M. Klosôwski, a.oth., BRD Patent 2123345-5 0971); C A . f 2§» 72649, 72649, 72650, 85918,(1972)· 41. A.L. Yudeles, T.I. Kazantseva, Sb. Bor ba s silikozom, izd-vo AMN SSSR, M., 1953, t.I, str.301. 42. S.S. Baizakova, Sov. zdravookhrenenie Kirgizii, No 3, 30 (1956). 43. W. Hartmann, G. Teichmüller, BRD Patent 2004516 (1970); DDR Patent 74032 (1970); English patent 1229511, 1241443 (1971); C.A., 73, IO9977 (1970); 24, 10296; 25t 36485, 118465 (1971). 44. S. Barsza, USA Patent 3529005 (1970); BRD Patent 2100967 (1971); C.A., 21* 120818 (1970); 25f130018 (1971). 45. S-l. Liu, M.-H. Yang, J. Chin. Chem. S o c , 18, 61 (1971). 46. L.H. Edwards, Mechanistic and Synthetic Studies of Organosilicon Containing Derivatives of Potential Antiradiation Agents, Ph.D., Univ. S. Mississippi, 1969. 47. S. Barsza, USA Patent 3585228 (1969); O.A., 251 49312 (1971); Third International Symposium oh Organosilicon Chemistry, Abstracts of Papers, Madison, 1972, p. 20.

66

48. S. Barsza, USA Patents 3636024, 3637735; C A., 76, 85914, 85915 (1972). 49. H.F.G. Patient, R.P. Bush, English Patent 1241897 (1971). 50. M. Raynaud, J.-C. Shermann, P. Plata, C. Jasmin, G. Mathe, C.r., 272, 347 (1971). 51. J. Maeda, Shika lgaku, 34, 390 (1971). 52. T. Sakahi, N. Tsurumi, 77 Maeda, T. Honda, JAHN, 63, 167 (1972). 53· B.J· Fessenden, R.A. Hartman, J. Med. Chem., 13f 52 (197Ο). 54. D.R. Bennett, J.E. Le Beau, S.J. Gorzinski, W.H.Statt, F.O. Stark, R.M. Lacefield, G.E. Vogel, Third Inter­ national Symposium on Organosilicon Chemistry, Madison, 1972, Abstracts of ^apers, p. 4. 55. D. R. Bennett, W.H. Statt, 12th Ann. Meeting Soc. Toxicol., N.Y., 1973i Abstracts of Papers. 56. J.E. Le Beau, S.J. Gorzinski, 12th Ann. Meeting Soc. Toxicol., N.Y., 1973t Abstracts of Papers. 57· E.J. Lukevits, A.A. Kimenis, M.G. Voronkov, Izv. AN Latv. SSR, No 11, 142 (1970). 58. G.I. Zelchan, M.G. Voronkov, Tezisy dokladov i soobshchenij Vsesoyuznoj·konferentsii "Rezultaty nauchno-issledovetelskikh rebot po sozdaniyu novykh pestitsidov, vnedrenie ikh v proizvodstvo i promenenie v selskom khozyejstve", M., 1972, str. 3-4. 59. Za nauku v Sibiri, N 211 3 0973); Vostochno-Sibirskaya Pravda, N 122, 4 (1973).