Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffolds

Gately, Stephen; West, Robert

doi:10.1002/ddr.20177

Cited by 151 publications

(59 citation statements)

References 80 publications

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“…Because the original carbon-based drug has been tested thoroughly, the corresponding silicon analog may be able to shortcut the discovery part of drug development. Some silicon-containing drugs are currently being evaluated in clinical trials (Bains and Tacke, 2003;Gately and West, 2007), and it will be interesting to follow the outcome of those studies with respect to pharmacodynamic properties and safety compared with the original molecule.…”

Section: Discussionmentioning

confidence: 99%

“…The use of organosilicon chemistry in drug design has been reviewed previously (Tacke and Linoh, 1989;Bains and Tacke, 2003;Showell and Mills, 2003;Mills and Showell, 2004;Pooni and Showell, 2006;Gately and West, 2007). Carbon and silicon both are group 14 elements and are similar in that they form four covalent bonds with many other elements.…”

Section: Introductionmentioning

confidence: 99%

“…One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al, 2008). The present study will focus on a thorough investigation of both phase I and II metabolism of sila-haloperidol compared with those of haloperidol.The use of organosilicon chemistry in drug design has been reviewed previously (Tacke and Linoh, 1989;Bains and Tacke, 2003;Showell and Mills, 2003;Mills and Showell, 2004;Pooni and Showell, 2006;Gately and West, 2007). Carbon and silicon both are group 14 elements and are similar in that they form four covalent bonds with many other elements.…”

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confidence: 99%

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In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Johansson¹,

Weidolf²,

Popp³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:The neurotoxic side effects observed for the neuroleptic agent haloperidol have been associated with its pyridinium metabolite. In a previous study, a silicon analog of haloperidol (sila-haloperidol) was synthesized, which contains a silicon atom instead of the carbon atom in the 4-position of the piperidine ring. In the present study, the phase I metabolism of sila-haloperidol and haloperidol was studied in rat and human liver microsomes. The phase II metabolism was studied in rat, dog, and human hepatocytes and also in liver microsomes supplemented with UDP-glucuronic acid (UDPGA). A major metabolite of haloperidol, the pyridinium metabolite, was not formed in the microsomal incubations with silahaloperidol. For sila-haloperidol, three metabolites originating from opening of the piperidine ring were observed, a mechanism that has not been observed for haloperidol. One of the significant phase II metabolites of haloperidol was the glucuronide of the hydroxy group bound to the piperidine ring. For sila-haloperidol, the analogous metabolite was not observed in the hepatocytes or in the liver microsomal incubations containing UDPGA. If silanol (SiOH) groups are not glucuronidated, introducing silanol groups in drug molecules could provide an opportunity to enhance the hydrophilicity without allowing for direct phase II metabolism. To provide further support for the observed differences in metabolic pathways between haloperidol and sila-haloperidol, the metabolism of another pair of C/Si analogs was studied, namely, trifluperidol and sila-trifluperidol. These studies showed the same differences in metabolic pathways as between sila-haloperidol and haloperidol.Haloperidol was developed in the late 1950s and was found to be a potent neuroleptic agent (Janssen et al., 1959). Haloperidol is a dopamine (D 2 ) receptor antagonist and is still used in the treatment of schizophrenia, although it may cause severe extrapyramidal side effects, including parkinsonism and tardive dyskinesia (Levinson, 1991;Casey, 1995). The pyridinium metabolite of haloperidol has been proposed to contribute to these neurotoxic side effects because it structurally resembles 1-methyl-4-phenylpyridinium (commonly referred to as MMP ϩ ), an inducer of Parkinson disease-like symptoms (Subramanyam et al., 1991a;Dauer and Przedborski, 2003).In the search for analogs of haloperidol, a silicon analog (silahaloperidol) was synthesized, where the quaternary R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom (R 3 SiOH). The synthesis and the physicochemical and pharmacological properties of sila-haloperidol have been reported previously (Tacke et al., 2004a(Tacke et al., , 2008. As a minor part of an extensive study of sila-haloperidol, including synthesis and pharmacological properties, three major phase I metabolites in human liver microsomes (HLMs) were tentatively identified. One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al., 2008). Th...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Johansson¹,

Weidolf²,

Popp³

et al. 2010

Drug Metabolism and Disposition

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show abstract

“…In this context, silicon chemistry is being used as a novel source of chemical diversity in drug design (see reference [1] for reviews). The group 14 elements carbon and silicon show many similarities, one being that they readily form four covalent bonds with themselves and many other elements.…”

Section: Introductionmentioning

confidence: 99%

Novel Silicon‐Containing Analogues of the Retinoid Agonist Bexarotene: Syntheses and Biological Effects on Human Pluripotent Stem Cells

et al. 2011

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Twofold sila-substitution (C/Si exchange) of the clinically used RXR-selective retinoid agonist bexarotene leads to disila-bexarotene, which displays pharmacological potency similar to that of the parent carbon compound, as shown in a HeLa-cell-based RXR assay. Formal exchange of the SiCH₂CH₂ Si group in disila-bexarotene with a SiCH₂Si or SiOSi moiety leads to the disila-bexarotene analogues 8 and 9. The silicon compounds 8 and 9 were synthesized in multistep syntheses, starting from HC≡C(CH₃)₂SiCH₂Si(CH₃)₂C≡CH and HC≡C(CH₃)₂SiOSi(CH₃)₂C≡CH, respectively. The key step in the syntheses of 8 and 9 is a cobalt-catalyzed [2+2+2] cycloaddition reaction that affords the 1,3-disilaindane and 2-oxa-1,3-disilaindane skeletons. Disila-bexarotene and its analogues 8 and 9 were studied for their biological effects relative to all-trans retinoic acid in cultured human pluripotent stem cells. The parent carbon compound bexarotene was included in some of these biological studies. Although the silicon-containing bexarotene analogues disila-bexarotene, 8, and 9 appear not to regulate the differentiation of TERA2.cl.SP12 stem cells, preliminary evidence indicates that these compounds may possess enhanced functions over the parent compound bexarotene, such as induction and regulation of cell death and cell numbers. The biological data obtained indicate that bexarotene, contrary to the silicon-containing analogues disila-bexarotene, 8, and 9, may partially act to induce cell differentiation.

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“…[29] Sila-amidation of certain pharmacological agents has shown to increase potency and selectivity. [33,34] Silicon substitution onto the L-NAC molecule should lead to more lipophilic compounds of type 6, [34 -36] better able to penetrate across the gut wall and cell membranes. [36] This may result in improved pharmacological properties, [37,38] including bioavailability, metabolism and/or pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of lipophilic sila derivatives of N‐acetylcysteineamide, a cell permeating thiol

Zakai

Bikzhanova

Staveness

et al. 2009

Applied Organom Chemis

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N-acetyl-L-cysteine (L-NAC) is a potent antioxidant that can reduce levels of reactive oxygen species. N-acetyl-cysteine-amide, the amide form of L-NAC, has recently been reported to be more lipophilic and permeable through cell membranes than NAC, and to be able to traverse the blood-brain barrier. In this communication we report the synthesis and characterization of highly lipophilic sila-amide derivatives of L-NAC that may show enhanced cell penetration and bioavailability.

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Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffolds

Cited by 151 publications

References 80 publications

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Novel Silicon‐Containing Analogues of the Retinoid Agonist Bexarotene: Syntheses and Biological Effects on Human Pluripotent Stem Cells

Synthesis of lipophilic sila derivatives of N‐acetylcysteineamide, a cell permeating thiol

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