Silicon-based drugs versus carbon-based analogues

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Chapter: Essentials of Inorganic Chemistry : The Carbon Group

Silicon chemistry has been of interest as a source for the design of novel pharmaceutically active compounds.

Silicon-based drugs versus carbon-based analogues

Silicon chemistry has been of interest as a source for the design of novel pharmaceutically active compounds. Why is it possible to introduce a silicon group or replace a carbon centre by silicon and what are the resulting changes? Carbon and silicon are both group 14 elements exhibiting similarities and differences:

Valency: Silicon and carbon both possess four valence electrons as they show an analogous electron configuration (C: [He]2s22p2; Si: [Ne]3s23p2).

Coordination number: Unlike that of carbon, the chemistry of silicon is influenced by the availability of its 3d orbitals to be involved in additional bonding interactions. Silicon is therefore capable of increasing its coordination number from 4 to 6 and thus forming isolatable penta- and hexacoordinated silicon-based compounds. Nevertheless, for silicon a coordination number of 4 (sp3 hybridisation) is favoured especially over coordination numbers 2 (sp hybridisation) and 3 (sp2 hybridisation). Consequently, the formation of double and triple bonds is disfavoured in contrast to carbon-based reaction centres.

Bond length: Silicon has a larger covalent radius than carbon, resulting in the formation of longer bonds than carbon–carbon bonds (typical C—C bond length = 1.54 Å), silicon–silicon bonds (typical Si—Si bond length = 2.33 Å) and silicon–carbon bonds (typical Si—C bond length = 1.89 Å). As a result, silicon-containing compounds show higher conformational flexibility and therefore steric arrange-ments different from analogous carbon-based compounds. Differences in interaction with proteins and consequently alterations of pharmacodynamics and pharmacological profiles have been observed.

Electronegativity: Silicon is more positive than the neighbouring carbon (electronegativity according to Pauling: Si = 1.90, C = 2.55), resulting in different bond polarisation of analogous carbon–element and silicon–element bonds. As a result, chemical reactivity and bond strength can differ significantly. This can provide improved or altered potency if carbon moieties are switched to silicon-based ones within pharmacophores, especially if hydrogen bonding is involved in the mode of action (Figure 5.4).

Lipophilicity: In general, silicon-based compounds demonstrate an enhanced lipophilicity in comparison to their carbon-analogous due to their different covalent radii. This provides an interesting opportunity for exploitable pharmacokinetic potential in drug design, for example, for drugs that are prone to hepatic metabolism. Silicon-based compounds involved in hepatic metabolism have been observed to exhibit an increased half-life when compared to their carbon analogues. Increased lipophilicity is also believed to be useful in the design of drugs that are supposed to cross the blood–brain barrier. Therefore silicon analogues with their increased lipophilicity can be very interesting drug candidates.

Currently, there are only a small number of silicon-containing compounds under investigation for pharma-ceutical use. Silicones are the only silicon-based compounds widely used in medicine. These oligosiloxanes and polysiloxanes have no carbon analogues and they are widely used for plastics, implants, catheters and many other applications.

The limitations of novel organosilicon compounds are very often attributed to insufficient funding and poor evidence of demonstrated efficacy. There is also an on-going debate about the toxicity of silicon-based therapeutics. So far, no increased systematic toxicity of silicon-containing compounds in comparison to their carbon-analogous has been detected.

Nevertheless, several organosilicon compounds have made it to clinical trials. In the following sections, a couple of interesting examples ranging from steroids being used by bodybuilders to anticancer and antispastic drugs under development are presented.


Introduction of silicon groups

A convenient method to introduce a silicon group is through the so-called silylation. A hydrogen atom that is bonded to a heteroatom (sulfur, nitrogen or oxygen) is exchanged by a silyl group (see Figure 5.5).

Carbon silylation, that is, the introduction of a silicon group next to a carbon centre, is also used for the design of novel drugs. This approach potentially allows changing the properties of the novel drug candidate significantly. It can lead to enhanced blood stability, increased cell penetration and altered pharmacokinetics. Several compounds have entered clinical trials, including the muscle relaxant silperisone (Figure 5.6) .


1. Silabolin

The anabolic compound silabolin is an example of a drug in which this silylation approach has been used. Silabolin is an injectable steroid containing a trimethylsilyl group, and was and still is used as an anabolic preparation by bodybuilders. It is known to have a relatively low androgenic activity like the natural anabolic hormone testosterone. Silabolin was officially registered in the (former) USSR as a domestic anabolic drug. It is believed to influence the protein synthesis in humans. Silabolin itself is a white powder, which is sparingly soluble in ethanol but not soluble in water . Its propensity to cause heart and liver defects is under discussion and its effectiveness is being critically discussed amongst bodybuilders (Figure 5.7) .


2. Silperisone

Tolperisone is a centrally acting muscle relaxant used, for example, in the treatment of acute muscle spasms in back pain. Previous in vitro and in vivo studies in mice have demonstrated that silperisone may have the potential to reduce both central nervous system depressing and motor side effects. Phase I clinical trials were conducted with doses up to 150 mg/day. 

No adverse side effects were detected, and the observed plasma levels were deemed to be effective in preclinical trials. Nevertheless, chronic toxicities were observed in animal studies and the research was discontinued (Figure 5.8) .


3. Indomethacin

Indomethacin (see Figure 5.9) is a nonsteroidal anti-inflammatory agent used in pain and moderate to severe inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase) inhibitor and therefore interrupts the production of prostaglandins .

A series of new silicon compounds, based on the structure of indomethacin, have been synthesised and are under investigation as novel anticancer agents. The carboxyl group of indomethacin was reacted with a series of amino-functionalised silanes. The resulting products have been shown to be significantly more lipophilic and more selective to COX-2. Furthermore, in vitro testing has shown an increased uptake of the new compounds at the tumour site. The silane-functionalised indomethacin derivatives exhibited a 15-fold increased antiproliferative effect when tested against pancreatic cancer (Figure 5.10) .


Silicon isosters

The carbon/silicon switch strategy, meaning the replacement of carbon centres by analogous silicon groups in known biologically active reagents, is currently mainly used for the development of novel silicon-based drug candidates .

The idea is that the new silicon-based drug candidates have the same chemical structure, with one carbon atom exchanged by a silicon one. The resulting physiochemical changes include, amongst others, altered bond length and changes in the lipophilicity. These alterations can have a significant effect on the biological activity of these novel silicon-based compounds. A variety of these compounds have been synthesised and tested ; two examples are presented in the following:


1. Sila-haloperidol

Haloperidol is an analogue of the dopamine D2 receptor antagonist and is an older antipsychotic drug. The drug is used in the treatment of schizophrenia, a neuropsychiatric disorder. Schizophrenia is characterised by symptoms such as hallucinations, delusions and disorganised speech. It is believed that schizophrenia is caused by problems involving the dopamine regulation in the brain. In general, antipsychotic drugs work by blocking the dopamine D2 receptors .

Haloperidol is such an antipsychotic drug, which was developed in the 1950s and entered the clinic soon after that. Its use is limited by the high incidence of extrapyramidal symptoms (movement disorders caused by drugs affecting the extrapyramidal system, a neural network which is part of the motor system) . Nev-ertheless, haloperidol may be used for the rapid control of hyperactive psychotic states and is popular for treating restlessness in the elderly.

The silicon analogue, sila-haloperidol, has been synthesised by a sila-substitution of the quaternary R3COH carbon atom of the 4-hydroxy-4-(4-chlorophenyl)piperidin-1-yl group of haloperidol (see Figure 5.11). Chemical analyses have shown that haloperidol and sila-haloperidol both exist as two analogous conformers but with a different conformer ratio for the carbon and silicon analogues. Biological studies have also shown large differences between the metabolic pathways of the silicon and carbon analogues. Radiolabelling studies have shown similar potencies of the silicon and the carbon compounds at the human dopamine hD1, hD4 and hD5 receptors. Sila-haloperidol was significantly more potent with the hD2 receptor, thus giving hope to improved side effects related to the metabolism .


2. Sila-venlafaxine

Venlafaxine is a serotonin and noradrenalin reuptake inhibitor (SNRI) and is used as an antidepressant. Com-pared to tricyclic antidepressants, it lacks the antimuscarinic and sedative side effects. Nevertheless, treatment with venlafaxine can lead to a higher risk of withdrawal symptoms .

The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol, has been synthesised and tested for its biological properties. The hydrochloride salts were examined for their efficacy in reuptake inhibition assays for serotonin, noradrenalin and dopamine. It was concluded that the carbon–silicon switch changed the pharmacological profile significantly in regard to the reuptake inhibition depending on the stereoisomer. (R)-Sila-venlafaxine was found to be consistent with selective reuptake inhibition at the noradrenaline inhibitor (Figure 5.12) .


Organosilicon drugs

There are several classes of silicon compounds with a clinical use or a proposed biological activity that have no apparent carbon analogues. These compounds use the properties specific to silicon, mainly its ability to form molecules with a penta- and hex-acoordinated silicon centre.

Silatranes are silicon compounds in which the central silicon atom is pentacoordinated. Silatranes can be highly toxic depending on the organic rest at the silicon centre. Aryl  and 2-thienyl-substituted silatranes have been proposed as rodenticides . These compounds are known for their self-detoxification, result-ing in a low hazard for dermal toxicity or long-lasting secondary risk of poisoning (Figure 5.13) .

Silatranes substituted with alkyl, alkenyl and other groups are significant less toxic and are under evaluation for a variety of biological or clinical applications ranging from the stimulation of collagen biosynthesis to the proposed use as anticancer agents.

Silicones (oligo and polysiloxanes) are the most widely used class of silicon-based com-pounds clinically. Silicones can be found in plastics, lubricants, catheters, implants and a variety of other medically used items. Silicone fluids, such as simethicone, are known for their antifoaming properties. Sime-thicone is an orally administered suspension containing polysiloxanes and silicon dioxide. It is an antifoaming agent and is used to reduce bloating by decreasing the surface tension in bubbles. Excessive formation of gas bubbles in the stomach and intestines can be painful and can also be of hindrance for any ultrasound examination. Simethicone can be found in antacids and in suspensions given to babies against colic.


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