Organosilicon Entities as Prophylactic and Therapeutic Agents

Garson, Lorrin R.; Kirchner, Lucille K.

doi:10.1002/jps.2600600802

Cited by 41 publications

(8 citation statements)

References 56 publications

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“…Numerous attempts have been made to extract and identify organic Si compounds from tissues, but in no case has a pure substance been isolated and chemically characterized (6,7). Si "esters" of lipids such as cholesterol, lethicin, and choline have been described after extraction of tissues by ethanolether.…”

Section: Discussionmentioning

confidence: 99%

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A Bound Form of Silicon in Glycosaminoglycans and Polyuronides

Schwarz

1973

Proc. Natl. Acad. Sci. U.S.A.

295

121

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Silicon was found to be a constituent of certain glycosaminoglycans and polyuronides, where it occurs firmly bound to the polysaccharide matrix. 330-554 ppm of bound Si were detected in purified hyaluronic acid from umbilical cord, chondroitin 4-sulfate, dermatan sulfate, and heparan sulfate. These amounts correspond to 1 atom of Si per 50,000-85,000 molecular weight or 130-280 repeating units. 57-191 Silicon (Si) is essential for growth and general development (1). In all-plastic isolators that exclude the element from the environment (2, 3), growth of rats is reduced by 30-35% when Si-deficient aminoacid diets are fed, and bone deformations develop. Dietary supplements of silicate prevent these symptoms. Similar findings have been reported for chicks (4). Si, moreover, is needed in rats for normal pigment formation in the enamel of incisors (5).Even though it has been known for years that Si occurs in small, varying amounts in all animals, very little concrete evidence exists about its functional significance and biochemical behavior (6, 7). In mammals, Si occurs most abundantly in connective tissue and related structures. While amounts in blood and parenchymal organs are relatively low, the Si content of skin, cartilage, ligaments, and other tissues of mainly mesodermal origin frequently exceeds 100 ,g/g dry wt (8)*.In extensive experiments with cartilage and bovine-nasal septum we found Si to be strongly bound -to the organic matrix of these tissues. During attempts to identify the binding site of Si we discovered that certain glycosaminoglyeans, * Reported Si amounts vary greatly, depending on the analytical methods used. A large number of results (9, 10) obtained before development of suitable methods (11,12) and the advent of plastic laboratory ware are much higher than those found more recently (8,13

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Section: Discussionmentioning

confidence: 99%

“…Even though it has been known for years that Si occurs in small, varying amounts in all animals, very little concrete evidence exists about its functional significance and biochemical behavior (6,7). In mammals, Si occurs most abundantly in connective tissue and related structures.…”

mentioning

confidence: 99%

A Bound Form of Silicon in Glycosaminoglycans and Polyuronides

Schwarz

1973

Proc. Natl. Acad. Sci. U.S.A.

295

121

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“…Siliconsubstituted drugs have been synthesized previously and found to be safe; recorded adverse events were reported to be drug mechanism of action-based and not related to silicon [12,13]. Several recent examples of siliconcontaining drugs have been reported [1g, 14,15].…”

Section: Introductionmentioning

confidence: 98%

Novel silicon-containing drugs derived from the indomethacin scaffold: Synthesis, characterization and evaluation of biological activity

et al. 2006

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Synthesis, spectroscopic characterization and in vitro pharmacological and cancer cell growth inhibitory activity studies of new silicon-containing compounds based on the indomethacin scaffold are now reported. Amidation of the indomethacin carboxylate group using amino-functional silanes generated a series of novel lipophilic derivatives of indomethacin. The pharmacological activity of these derivatives tested against human recombinant cyclooxygenase-1 and 2 demonstrated that the silicon-containing derivatives are cyclooxygenase-2 (COX-2) selective. The silicon-containing amides of indomethacin demonstrated in vitro growth inhibitory activity against human MiaPaCa-2 pancreatic carcinoma cells at low μM concentrations. The 3a and 3c derivatives exhibited the most potent in vitro antiproliferative activity, with IC 50 <6.0 μM, compared to unmodified indomethacin having an IC 50 >100 μM.

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“…Importantly, there does not appear to be an ''element-specific'' change in toxicology as would be expected for other organometallic species like lead and mercury [Tacke and Zilch, 1986]. No special toxicology has been reported for organosilicon compounds, rather there may be an improvement in the toxicology profile when comparing against a carbon analogue [Garson and Kirchner, 1971]. The antihyperlipidemic drug triparanol and a sila-triparanol analogue were shown to possess equivalent antihyperlipidemic potency, but the silicon derivative was far less toxic when studied in a multi-dose toxicological study [Tacke and Zilch, 1986].…”

Section: Resultsmentioning

confidence: 91%

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

Gately

West

2007

Drug Development Research

146

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The strategic replacement of carbon with silicon within biologically prevalidated drug scaffolds can generate focused libraries of pharmaceutically relevant agents with novel, durable and marketable intellectual property. This approach can be cost-effective and of lower developmental risk because known drugs have recognized pharmacology and toxicity profiles, proven safety in humans, and established manufacturing and formulation methods. The change in shape, charge, and lipophilicity that can result from the addition of silicon can favorably alter the biological activity and toxicology of the parent drug. Silicon-containing derivatives of indomethacin are COX-2 selective, suggesting they will not be associated with the classical toxicities associated with nonselective inhibition of the cyclooxygenases. The silicon-indomethacin derivatives also demonstrated superior anti-cancer activity at clinically achievable concentrations when tested in vitro against a human pancreatic cancer cell line, MiaPaCa-2, and a panel of 14 human multiple myeloma cell lines. Bioorganosilicon chemistry represents an attractive approach for emerging biopharmaceutical organizations seeking to rapidly develop a portfolio of novel pharmacological agents that have the potential for enhanced therapeutic and pharmacological benefit. Drug Dev Res 68: [156][157][158][159][160][161][162][163] 2007 r2007 Wiley-Liss, Inc.

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Organosilicon Entities as Prophylactic and Therapeutic Agents

Cited by 41 publications

References 56 publications

A Bound Form of Silicon in Glycosaminoglycans and Polyuronides

A Bound Form of Silicon in Glycosaminoglycans and Polyuronides

Novel silicon-containing drugs derived from the indomethacin scaffold: Synthesis, characterization and evaluation of biological activity

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

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