O S and NSilylation

O-Silylation of hydroxyl-group-containing drugs leads to prodrugs with an enhanced lipophilicity.18,26,33 36 They are more rapidly transported across the lipid barrier followed by hydrolysis liberating the parent drug. The rate of the hydrolysis can be regulated by the substituents at the silicon atom. Under acidic conditions the hydrolysis rate diminishes in the order:34,37,38

Me3Si > Me2EtSi > Et3Si > t-BuMe2Si > TxMe2Si > i-Pr3Si > t-BuPh2Si

If the silylating agent R4—nSiXn contains more than one functional group at the silicon atom (n > 1), two to four residues of the biologically active substance can be introduced to one silicon atom.7,9,33,39 43 In the case of polyhydroxy

compounds heterocyclic siloxa derivatives have been obtained. Biologically active siloxa heterocycles have been prepared also by intramolecular cyclization.50 52

O-Silylation can be used not only for the modification of hydroxyl group containing biologically active organic compounds but also for the modification of organic derivatives of aluminium,53 germanium,54,55 titanium56 and phosphorus.57

In many cases such a modification increases the activity of the parent drug7,9,22,26,36,46,48,58 68 or prolongs the duration of its action.7,9,18,22,26,69 71 Reduction of toxicity has also been observed.7,9,63,71,72

As a result, the anabolic agent Silabolin® (1), an O-trimethylsilyl derivative of 19-nortestosterone, has been developed and registered in Russia.72 It exhibits high anabolic potency, long duration of action, lower toxicity than other anabolic steroids and good tolerability.72

The introduction of an organosilicon substituent into the molecular framework of a drug can generate some biological properties not inherent in the initial drug. Thus, for example, the introduction of dimethyl(tert-butyl)silyl groups into the anti-tumour drug methotrexate (2a) yields silylated methotrexate (2b) which exhibits an activity against experimental allergic encephalomyelitis and, in contrast to 2a, prevents serious paralysis and mortality in animals.73 It can be assumed that the activity of 2b is due to the increase of lipophilicity and to the ability to pass across the blood-brain barrier.

It has been found that, in contrast to uridine (3a), 5-O-tert-butyldimethyl-silyluridine (3b) exhibits anti-tumour activity suppressing the growth of human lung fibrosarcoma cells, HT-1080.63 Some growth inhibition of human breast

(MCF-7), central nervous system (SF-268) and NCI-H40 lung cancer has been observed for 3'-O-silatranylthymidine (4).74

Silylation of hydroxyl groups of (/3-D-ribofuranosyl)-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) nucleosides led to a new family of highly specific non-nucleoside reverse transcriptase inhibitors designated as TSAO.75 98 Several hundreds of silyl derivatives of these nucleoside analogues have been synthesized, their human immunodeficiency virus type 1 (HIV-1)-inhibiting activity has been tested and structure-activity relationships have been established.

The introduction of bulky tert-butyldimethylsilyl group at the C-2' position of the ribose moiety led to the appearance of a slight anti-HIV-1 activity. The C-5' silyl group increased the activity but the presence of tert-butyldimethylsilyl group at both C-2' and C-5' positions is necessary for high anti-HIV-1 activity.76,78,83,94,98 A larger thexyldimethylsilyl substituent is also accepted at the 5' position with only a marginal loss of activity.83 The presence of the unique 3-spiro group having a D-ribo configuration is also a prerequisite for anti-viral activity.77,84,85

The prototype compound is [2',5'-bis-O-(tert-butyldimethylsilyl)-^-D-ribofur-anosyl]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)thymine (TSAO-T, 5a). The thymine moiety of TSAO-T can be replaced by a number of other pyrimidines, purines and 1,2,3-triazoles without a marked decrease of anti-viral activity.76,78 81,87 Urea derivatives, which can mimic to a large extent both the shape and the electrostatic potential of a thymine ring, can effectively replace this nucleic base.88 Also, the dihydrouracil TSAO derivatives retained pronounced anti-HIV-1 activity.88 The oxalyl group in the position 4'' of the 3'-spiro moiety was important for the anti-HIV-1 activity against both wild type and TSAO-resistant strains.95 The most selective compound is the 3-N-methyl derivative 5b but the introduction of a 3-hydroxypropyl group at the N-3 (compound 5c) led to a 2-6-fold improvement in anti-viral potency.93 Several TSAO derivatives bearing, at the N-3 position of the thymine, an L-amino acid,90 (E)-hydroxypro-penyl or vinyl group (5d) showed some activity against HIV-2 in addition to their inhibitory effect on HIV-1.97


5a R = H; 5c R = (CH2)3OH; 5b R = Me; 5d R = CH = CH2


5a R = H; 5c R = (CH2)3OH; 5b R = Me; 5d R = CH = CH2

(S)-4-tert-Butyldimethylsiloxy-2-cyclopenten-1-one, containing the cyclo-pentenone ring of prostaglandine A1, inhibited herpes simplex virus (HSV-1) replication in cell cultures at sub-toxic concentrations. It was also active against acyclovir-resistant strain of HSV-1 but did not affect two laboratory strains of HSV-2.99 At the same time, the O-silyl derivative 6b of podophyllotoxin (6a) showed an unusual 10-fold selectivity for HSV-2 as compared to HSV-1.100 S-Silylation, similarly to O-silylation, can increase the activity101 107 and

1HT 110 11^

lower the toxicity. N-silylation lowers the toxicity of aziridines and nystatine.114 Its N-silyl (Me3Si, Et3Si) derivatives possess a higher fungicidal activity than nystatine itself but the introduction of bulky triisopropylsilyl group at the pyrrole nitrogen atom in 3-pyrrolyl-2,5-dihydro-1H-2,5-pyrrole-dione decreased the anti-bacterial activity against methicillin- and ciprofloxacin-resistant bacterium Staphylococcus aureus 134/94.115

The most investigated field of medical applications of compounds containing Si—N bonds is cancer photodynamic therapy. It is a method for treatment of tumours involving the systematic administration of tumour-localizing photo-sensitizers and their subsequent excitation with visible light (600-800 nm) to produce tumour necrosis.116,117 Silicon phthalocyanines (7),53,118 130 2,3-naphthalocyanines (8)131 139 and tetradibenzobarrelenophthalocyanines140 are suitable for this purpose.


N R- Si R N
8 R = R' R"2SiO

They have a high efficiency of tumour targeting, a large selectivity of accumulation in the tumour, a strong absorption in the red visible region and a high photoactivity.

The photoinduced photokilling of achromic M6 melanoma cells is correlated with an increase in cell-lipid peroxidation and superoxide dismutase activities, a decrease in the concentrations of glutathione and its oxidized form and a reduction of glutathione peroxidase and catalase activities.124

The nature and shape of two axial ligands on the central silicon can modify the lipophilic character of a substance and impede the aggregation in solu-tion.53,119 122,130,135 139 The substituents can be equal (7a,b, 8) or different (7c). The silicon phthalocyanine (7c)53,120,123,125,126 128 has been chosen for clinical trials in cancer photodynamic therapy. This compound combined with red light irradiation also inactivated pathogenic viruses in red blood cells.127

5.2.2 C-Silylation

C-Silylation of drugs has been widely used to design new bioactive agents.6,7,22,29 It can increase the activity141 149 or significantly change the properties of the parent compound.150 155

For example, 17-(triethylsilyl)ethynylestradiol143 and its derivatives144 possess extremely high anti-fertility properties and, at the same time, reduced estrogenic activity. Odour tests of the trialkylsilylated benzyl mercaptans and benzenethiols have revealed that the trimethylsilyl substituent at the benzene ring has a remarkable effect in reducing the foul smell of the parent benzyl mercaptan and benzenethiol.154

The advantage of a C-modification by organosilyl groups lies in the possibility of wide variations of substituents at the silicon atom thus providing the opportunity to obtain libraries of organosilicon compounds representing a broad spectrum of pharmacological activities. Organosilicon amines are one of such class of compounds exhibiting anti-bacterial,6,7,9,21,156 anti-fungal,6,7,9,21 anti-cancer,21,149,156 170 central nervous system,6,7,166,171 176 cardiovascular7,171,177,178 and other activities.6,7

Four organosilicon compounds designed by this approach have entered clinical studies: the muscle relaxants Sandoz 58-112 (9)179 and Silperisone (10),180 183 the long-lasting acetylcholinesterase inhibitor Zifrosilone (11) proposed for the treatment of patients with Alzheimer's disease184 188 and the anticancer drug Karenitecin (12b).149,189

Silylcamptothecins (silatecans), possessing a high anti-cancer activity, obviously demonstrate the importance of C-silylation for the enhancement of the biological activity of known drugs. Camptothecins are potent cytotoxic agents that inhibit DNA topoisomerase I but their clinical utility is limited by the instability of the ¿-lactone ring present in the structure, some side effects and a narrow spectrum of activity.

The incorporation of the lipophilic organosilicon substituents into the camp-tothecin structure provides enhanced blood stability, increased cell penetration and improved pharmacokinetics.149,190 199 A series of silatecans were prepared with different triorganylsilyl groups attached to the 7-position. 7-Trimethylsilyl camptothecin was about two times more potent than camptothecin in inhibiting HL-60 human promyelocytic leukaemic cells, 833K teratocarcinoma solid tumour cells and DC-3F hamster lung cells.190 Combination of a 7-trimethylsilyl group with an 11-fluorine provides a compound that is about five times more potent. Combination with a 10-amino group increases the activity 10 times but introduction of all three substituents gives a compound that is more than 20 times more potent than camptothecin.149,190 The influence of the 7-triorganosilyl group decreases in the following order:

7-tert-Butyldimethylsilyl-10-hydroxycamptothecin displays superior stability in human blood when compared with clinically used camptothecins. It is 25 times more lipophilic than camptothecin, and it is readily incorporated into cellular and liposomal bilayers. This silatecan exhibits high cytotoxicity and very high intrinsic potency against topoisomerase I.194 It can effectively cure mice with intracranially implanted human gliomas.192

7-[2-(Trimethylsilyl)ethyl]-20(S)-camptothecin (12b) (Karenitecin) is significantly more potent than other camptothecins. It has a broad anti-tumour activity, superior oral bioavailability, increased lactone stability and lack of multi-drug resistance susceptibility.


In a wide spectrum of human malignant cell lines the Karenitecin exhibits a nanomolar to picomolar activity.196 It is more potent than the parent 7-ethylcamptothecin (12a) and topote-can in experimental human ovarian cancer.198

Silatecans containing a 7-membered lactone ring have been also prepared and shown to be potent topoisomerase I inhibitors that are stable in human blood.193'199

onn 011

C-Silylation of triazole has led to a series of potent fungicides.200 211 Bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane (13) (Flusilazole) is a highly potent ergosterol biosynthesis inhibiting fungicide which has found acceptance world-wide for controlling diseases of cereals' fruits' vegetables and other agricultural products.200 204 It inhibits also the growth of the human pathogenic fungi Trichophyton mentagrophytes (minimal inhibiting concentration 1 mgml-1) and Candida albicans (8 mgml-1).203

13 Flusilazole 14 Simeconazole

2-(4-Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-trimethylsilylpropan-2-ol (14) (Simeconazole) combines a prominent systemic fungicidal activity with a good crop safety.208 210 It is also effective against rice sheath blight by submerged application, rice blast, sharp eyespot and powdery mildew.210

Another potent fungicide for the control of take-all disease of cereal crops caused by the soil-borne fungus Gaeumannomyces graminis has been found through a screening of compounds prepared by C-silylation of aromatic and

010 01

heterocyclic amides. , 4,5-Dimethyl-N-(2-propenyl)-2-trimethylsilyl-3-thio-phenecarboxamide (15) (Silthiopham) had outstanding protectant activity


SiMe3 Silthiopham providing long duration of control of root infection,213 216 and it was selected for marketing in formulation under the trade name Latitude®.

Being in the same group as carbon in the periodic table of elements, silicon differs from the latter in its physicochemical properties (considerably larger covalent radii; lower electronegativity; different electronic energies for their outer electrons; longer bond lengths with hydrogen, carbon and oxygen; and lower bond energies with hydrogen and carbon and higher bond energy with oxygen25). It can be expected that these physicochemical effects may, in principle, result in different biological effects.

In order to compare the biological activity of carbon and silicon analogues having exactly the same chemical structure, with a silicon atom replacing one of the carbon atoms, a large number of sila-substituted drugs have been synthesized and biologically tested.6,7,10,14,15,19,22,29 Two groups of compounds have been found. The main group embraces analogous derivatives of carbon and silicon with close biological activity (bioisosters);7,22,29,217 the second incorporates carbon and silicon structural analogues exhibiting different biological

In the course of these investigations a variety of sila analogues of the muscarinic antagonists have been prepared.22,29 Two of them, hexahydrosila-difenidol (16a) (HHSiD)226 231 and p-fluoro-hexahydrosiladifenidol (16b) (p-F-HHSiD)226,228,231 234 are used worldwide as selective tools for the classification of muscarinic receptor subtypes.22,29

Optically active silanols and hydroxymethylsilanes of this series of muscarinic antagonists have been prepared. Their (R)-enantiomers showed a significantly higher affinity for muscarinic M2 and M3 receptors than the corresponding (S)-antipodes.235

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