carbon silylation reaction

carbon silylation reactionThe Carbon Group 91
Me
Me
H H
H H
O
O
SiMe3
Figure 5.7 Chemical structure of silabolin
N
Me
Me
HCI
Si
F
Figure 5.8 Chemical structure of silperisone
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].
5.2.1.3 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 [4].
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) [5].
5.2.2 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 [6].
92 Essentials of Inorganic Chemistry
O CI
N
Me
O
Me
O
OH
Figure 5.9 Chemical structure of indomethacin
O CI
N
Me
Me
O
O
HN
R
Si
R
R
n
Figure 5.10 Chemical structure of silicon analogue of indomethacin
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 [1]; two examples are presented in the following:
5.2.2.1 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
The Carbon Group 93
F
O
Si N
HO
CI
Figure 5.11 Chemical structures of sila-haloperidol
caused by problems involving the dopamine regulation in the brain. In general, antipsychotic drugs work by
blocking the dopamine D2 receptors [7].
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) [8]. Nevertheless, 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 [9].
5.2.2.2 Sila-venlafaxine
Venlafaxine is a serotonin and noradrenalin reuptake inhibitor (SNRI) and is used as an antidepressant. Compared to tricyclic antidepressants, it lacks the antimuscarinic and sedative side effects. Nevertheless, treatment
with venlafaxine can lead to a higher risk of withdrawal symptoms [8].
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) [10].
5.2.3 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.
94 Essentials of Inorganic Chemistry
Me
Me
Me
HO
Si
O
N
Figure 5.12 Chemical structure of sila-venlafaxine
N
O
Si
R
O O
Figure 5.13 Chemical structure of silatrane
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 [11] and 2-thienyl-substituted silatranes
[12] have been proposed as rodenticides [1]. These compounds are known for their self-detoxification, resulting in a low hazard for dermal toxicity or long-lasting secondary risk of poisoning (Figure 5.13) [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 [1].
Silicones (oligo and polysiloxanes, see Section 5.1.1) are the most widely used class of silicon-based compounds 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. Simethicone 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.
5.3 Organogermanium compounds: balancing act between an anticancer drug and a
herbal supplement
The first organogermanium compound, tetraethylgermane, was synthesised by Winkler et al. in 1887, but then
it took until the middle of the twentieth century for such compounds to be widely synthesised and examined
(Figure 5.14).
The major uses for germanium compounds include their application as optical materials (60%) and semiconductors (10%), as catalysts or in chemotherapy. Some Chinese herbs and vegetables contain a relatively
The Carbon Group 95
Ge
Ph
Ph
Phreaction time test
reaction formation
reaction paper
reaction paper example
reaction roles
reaction kenneth cole
reaction of photosynthesis
reaction chain
reaction maillard
reaction redox
chain reaction
allergic reaction
allergic reaction rash
chemical reaction
endothermic reaction
exothermic reaction
redox reaction
polymerase chain reaction
maillard reaction
combustion reaction

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