We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Progress in the medicinal chemistry of silicon: C/Si exchange and beyond

    Shinya Fujii

    *Author for correspondence:

    E-mail Address: fujiis@iam.u-tokyo.ac.jp

    Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

    &
    Yuichi Hashimoto

    Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

    Published Online:https://doi.org/10.4155/fmc-2016-0193

    Application of silyl functionalities is one of the most promising strategies among various ‘elements chemistry’ approaches for the development of novel and distinctive drug candidates. Replacement of one or more carbon atoms of various biologically active compounds with silicon (so-called sila-substitution) has been intensively studied for decades, and is often effective for alteration of activity profile and improvement of metabolic profile. In addition to simple C/Si exchange, several novel approaches for utilizing silicon in medicinal chemistry have been suggested in recent years, focusing on the intrinsic differences between silicon and carbon. Sila-substitution offers great potential for enlarging the chemical space of medicinal chemistry, and provides many options for structural development of drug candidates.

    Papers of special note have been highlighted as: • of interest

    References

    • 1 Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control 10(5), 361–369 (2003).
    • 2 Fu H, Fang H, Sun J et al. Boronic acid-based enzyme inhibitors: a review of recent progress. Curr. Med. Chem. 21(28), 3271–3280 (2014).
    • 3 Brook MA. Silicon in Organic, Organometallic, and Polymer Chemistry. John Wiley & Sons, NY, USA (2000).
    • 4 Franz AK, Wilson SO. Organosilicon molecules with medicinal applications. J. Med. Chem. 56(2), 388–405 (2013).
    • 5 Lukevics E, Ignatovich L. Comparative study of the biological activity of organosilicon and organogermanium compounds. Appl. Organomet. Chem. 6(2), 113–126 (1992).
    • 6 Mills JS, Showell GA. Exploitation of silicon medicinal chemistry in drug discovery. Expert Opin. Investig. Drugs 13(9), 1149–1157 (2004).
    • 7 Showell GA, Mills JS. Chemistry challenges in lead optimization: silicon isosteres in drug discovery. Drug Discov. Today 8(12), 551–556 (2003).
    • 8 Gately S, West R. Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffolds. Drug. Dev. Res. 68(4), 156–163 (2007).
    • 9 Fujii S, Miyajima Y, Masuno H, Kagechika H. Increased hydrophobicity and estrogenic activity of simple phenols with silicon and germanium-containing substituents. J. Med. Chem. 56(1), 160–166 (2013). • Systematic investigation of the physicochemical properties of various silyl and germyl functionalities.
    • 10 Van Hattum AH, Pinedo HM, Schlüper HMM, Hausheer FH, Boven E. New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer. Int. J. Cancer 88(2), 260–266 (2000).
    • 11 Bom D, Curran DP, Kruszewski S et al. The novel silatecan 7-tertbutyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J. Med. Chem. 43(21), 3970–3980 (2000).
    • 12 Daud A, Valkov N, Centeno B et al. Phase II trial of karenitecin in patients with malignant melanoma: clinical and translational study. Clin. Cancer Res. 11(8), 3009–3016 (2005).
    • 13 Curran DP, Du W. Palladium-promoted cascade reactions of isonitriles and 6-iodo-N-propargylpyridones: synthesis of mappicines, camptothecins, and homocamptothecins. Org. Lett. 4(19), 3215–3218 (2002).
    • 14 Yamakawa T, Kagechika H, Kawachi E, Hashimoto Y, Shudo K. Retinobenzoic acids. 5. Retinoidal activities of compounds having a trimethylsilyl or trimethylgermyl group(s) in human promyelocytic leukemia cells HL-60. J. Med. Chem. 33(5), 1430–1437 (1990).
    • 15 Higginbotham KB, Lozano R, Brown T et al. A Phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 134(12), 1325–1335 (2008).
    • 16 Yamanoi Y, Nishihara H. Direct and selective arylation of tertiary silanes with rhodium catalyst. J. Org. Chem. 73(17), 6671–6678 (2008).
    • 17 Förster B, Bertermann R, Kraft P, Tacke R. Sila-rhubafuran and derivatives: synthesis and olfactory characterization of novel silicon-containing odorants. Organometallics 33(1), 338–346 (2014). • As recent examples of silicon-containing odorants.
    • 18 Friedrich J, Dörrich S, Berkefeld, Kraft P, Tacke R. Synthesis and olfactory characterization of sila-methyl pamplemousse and related odorants with a 2,2,5-trimethyl-2-silahex-4-ene skeleton. Organometallics 33(3), 796–803 (2014).
    • 19 Tacke R, Handmann VI. Derivatives of β-(trimethylsilyl)alanine with SiCH2NH2, SiCH2OH, or SiCH2SH functionality: synthesis of the silicon-containing α-amino acids rac- and (R)-Me2Si(CH2R)CH2CH(NH2)COOH (R = NH2, OH, SH). Organometallics 21(13), 2619–2626 (2002). • As examples of silicon-containing amino acids.
    • 20 Falgner S, Buchner G, Tacke R. Synthesis of rac-2′-(trimethylsilyl)isovaline: a novel silicon-containing α,α-dialkylated α-amino acid. J. Organomet. Chem. 695(24), 2614–2617 (2010).
    • 21 Klapötke TM, Krumm B, Ilg R, Troegel D, Tacke R. The sila-explosives Si(CH2N3)4 and Si(CH2ONO2)4: silicon analogs of the common explosives pentaerythrityl tetraazide, C(CH2N3)4, and pentaerythritol tetranitrate, C(CH2ONO2)4. J. Am. Chem. Soc. 129(21), 6908–6915 (2007).
    • 22 Ohnishi K. PML-RAR-α inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. Int. J. Clin. Oncol. 12(5), 313–317 (2007).
    • 23 Tanaka T, De Luca LM. Therapeutic potential of “rexinoids” in cancer prevention and treatment. Cancer Res. 69(12), 4945–4947 (2009).
    • 24 Tacke R, Müller V, Büttner MW et al. Synthesis and pharmacological characterization of disila-AM80 (disilatamibarotene) and disila-AM580, silicon analogs of the RAR-α-selective retinoid agonists AM80 (tamibarotene) and AM580. ChemMedChem 4(11), 1797–1802 (2009).
    • 25 Büttner MW, Burschka C, Daiss JO et al. Silicon analogs of the retinoid agonists TTNPB and 3-methyl-TTNPB, disila-TTNPB and disila-3-methyl-TTNPB: chemistry and biology. ChemBioChem 8(14), 1688–1699 (2007). • Together with their retinoid X receptor ligands (Reference 28 in this list), suggestive discussions about Si/C-exchange based on x-ray co-crystal analyses were provided.
    • 26 Gluyas JBG, Burschka C, Dörrich S, Vallet J, Gronemeyer H, Tacke R. Disila-analogs of the synthetic retinoids EC23 and TTNN: synthesis, structure and biological evaluation. Org. Biomol. Chem. 10(34), 6914–6929 (2012).
    • 27 Daiss JO, Burschka C, Mills JS et al. Synthesis, crystal structure analysis, and pharmacological characterization of disila-bexarotene, a disila-analog of the RXR-selective retinoid agonist bexarotene. Organometallics 24(13), 3192–3199 (2005).
    • 28 Lippert WP, Burschka C, Götz K et al. Silicon analogs of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology. ChemMedChem 4(7), 1143–1152 (2009).
    • 29 Bauer JB, Lippert WP, Dörrich S et al. Novel silicon-containing analogs of the retinoid agonist bexarotene: syntheses and biological effects on human pluripotent stem cells. ChemMedChem 6(8), 1509–1517 (2011).
    • 30 Büttner MW, Nätscher JB, Burschka C, Tacke R. Development of a new building block for the synthesis of silicon-based drugs and odorants: alternative synthesis of the retinoid agonist disila-bexarotene. Organometallics 26(19), 4835–4838 (2007).
    • 31 Barnes MJ, Burschka C, Büttner MW et al. Silicon analogs of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization. ChemMedChem 6(11), 2070–2080 (2011).
    • 32 Toyama H, Nakamura M, Nakamura M, Matsumoto Y, Nakagomi M, Hashimoto Y. Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors. Bioorg. Med. Chem. 22(6), 1948–1959 (2014).
    • 33 Tacke R, Handmann VI, Bertermann R, Burschka C, Penka M, Seyfried C. Sila-analogs of high-affinity, selective ó ligands of the spiro[indane-1,4′-piperidine] type: syntheses, structures, and pharmacological properties. Organometallics 22(5), 916–924 (2003).
    • 34 Tacke R, Bertermann R, Burschka C et al. High-affinity, selective ó ligands of the 1,2,3,4-tetrahydro-1,4′-silaspiro[naphthalene-1,4′-piperidine] type: syntheses, structures, and pharmacological properties. ChemMedChem 7(3), 523–532 (2012).
    • 35 Geyer M, Baus JA, Fjellström O, Wellner E, Gustafsson L, Tacke R. Synthesis and pharmacological properties of silicon-containing GPR81 and GPR109A agonists. ChemMedChem 10(12), 2063–2070 (2015).
    • 36 Fischer M, Burschka C, Tacke R. Synthesis of 4-silacyclohexan-1-ones and (4-silacyclohexan-1-yl)amines containing the silicon protecting groups MOP (4-methoxyphenyl), DMOP (2,4-dimethoxyphenyl), or TMOP (2,4,6-trimethoxyphenyl): versatile Si- and C-functional building blocks for synthesis. Organometallics 33(4), 1020–1029 (2014).
    • 37 Geyer M, Karlsson O, Baus JA, Wellner E, Tacke R. Si- and C-functional organosilicon building blocks for synthesis based on 4-silacyclohexan-1-ones containing the silicon protecting groups MOP (4-methoxyphenyl), DMOP (2,6-dimethoxyphenyl), or TMOP (2,4,6-trimethoxyphenyl). J. Org. Chem. 80(11), 5804–5811 (2015).
    • 38 Seetharamsingh B, Ramesh R, Dange SS et al. Design, synthesis, and identification of silicon incorporated oxazolidinone antibiotics with improved brain exposure. ACS Med. Chem. Lett. 6(11), 1105–1110 (2015).
    • 39 Jachak GR, Ramesh R, Sant DG et al. Silicon incorporated morpholine antifungals: design, synthesis, and biological evaluation. ACS Med. Chem. Lett. 6(11), 1111–1116 (2015).
    • 40 Boehm MF, Fitzgerald P, Zou A et al. Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3. Chem. Biol. 6(5), 265–275 (1999).
    • 41 Hosoda S, Tanatani A, Wakabayashi K et al. Ligands with dual vitamin D3-agonistic and androgen-antagonistic activities. Bioorg. Med. Chem. Lett. 15(19), 4327–4331 (2005).
    • 42 Nakamura M, Makishima M, Hashimoto Y. Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: selectivity switching by C/Si exchange. Bioorg. Med. Chem. 21(7), 1643–1651 (2013).
    • 43 Kajita D, Nakamura M, Matsumoto Y, Makishima M, Hashimoto Y. Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character. Bioorg. Med. Chem. 22(7), 2244–2252 (2014).
    • 44 Daiss JO, Duda-Johner S, Burschka C, Holzgrabe U, Mohr K, Tacke R. N+/Si replacement as a tool for probing the pharmacophore of allosteric modulators of muscarinic M2 receptors: synthesis, allosteric potency, and positive cooperativity of silicon-based W84 derivatives. Organometallics 21(5), 803–811 (2002).
    • 45 Duda-Johner S, Daiß JO, Mohr K, Tacke R. Synthesis and pharmacological characterization of new silicon-based W84-type allosteric modulators for ligand binding to muscarinic M2 receptors. J. Organomet. Chem. 686(1–2), 75–83 (2003).
    • 46 Daiss JO, Albrecht M, Mohr K, Tacke R. A novel silicon-based uncharged allosteric modulator for ligand binding to muscarinic M2 receptors: synthesis and pharmacological characterization. Organometallics 23(25), 6052–6057 (2004).
    • 47 Kajita D, Nakamura M, Matsumoto Y, Ishikawa M, Hashimoto Y, Fujii S. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists. Bioorg. Med. Chem. Lett. 25(16), 3350–3354 (2015).
    • 48 Nakamura M, Kajita D, Matsumoto Y, Hashimoto Y. Design and synthesis of silicon-containing tubulin polymerization inhibitors: replacement of the ethylene moiety of combretastatin A-4 with a silicon linker. Bioorg. Med. Chem. 21(23), 7381–7391 (2013).
    • 49 Nishiyama Y, Nakamura M, Misawa T et al. Structure-activity relationship-guided development of retinoic acid receptor-related orphan receptor gamma (ROR-γ)-selective inverse agonists with a phenanthridin-6(5H)-one skeleton from a liver X receptor ligand. Bioorg. Med. Chem. 22(9), 2799–2808 (2014).
    • 50 Toyama H, Nakamura M, Hashimoto Y, Fujii S. Design and synthesis of novel ROR inverse agonists based on dibenzosilole scaffolds as a hydrophobic core structure. Bioorg. Med. Chem. 23(13), 2982–2988 (2015).
    • 51 Balzarini J, Pérez-Pérez M-J, San-Félix A et al. 2′,5′-Bis-O-(tert-butyldimethylsilyl)-3′-spiro-5′′-(4′′-amino-1′′,2′′-oxathiole-2′′,2′′-dioxide)pyrimidine(TSAO) nucleoside analogs: highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proc. Natl Acad. Sci. USA 89(10), 4392–4396 (1992).
    • 52 Camarasa M-J, Pérez-Pérez M-J, San-Félix A, Balzarini J, De Clercq E. 3′-Spiro nucleosides, a new class of specific human immunodeficiency virus type 1 inhibitors: synthesis and antiviral activity of [2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-xylo- and-ribofuranose]-3′-spiro-5′′-[4′′-amino-1′′,2′′-oxathiole2′′,2′′-dioxide] (TSAO) pyrimidine nucleosides. J. Med. Chem. 35(15), 2721–2727 (1992).
    • 53 Das K, Bauman JD, Rim AS et al. Crystal structure of tert-butyldimethylsilylspiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket. J. Med. Chem. 54(8), 2727–2737 (2011).
    • 54 Chen H, Liu L, Jones SA et al. Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs. Antiviral Res. 97(3), 232–239 (2013).
    • 55 Vernekar SKV, Qiu L, Zhang J et al. 5-Silylated 3′-1,2,3-triazolyl thymidine analogs as inhibitors of West Nile virus and Dengue virus. J. Med. Chem. 58(9), 4016–4028 (2015).
    • 56 Panayides JL, Mathieu V, Banuls LMY et al. Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides. Bioorg. Med. Chem. 24(12), 2716–2724 (2016).
    • 57 Wohl AR, Michel AR, Kalscheuer S, Macosko CW, Panyam J, Hoye TR. Silicate esters of paclitaxel and docetaxel: synthesis, hydrophobicity, hydrolytic stability, cytotoxicity, and prodrug potential. J. Med. Chem. 57(6), 2368–2379 (2014).
    • 58 Chandrasekhar V, Boomishankar R, Nagendran S. Recent developments in the synthesis and structure of organosilanols. Chem. Rev. 104(12), 5847–5910 (2004). • For review of organosilanols.
    • 59 Sieburth SMcN, Chen C-A. Silanediol protease inhibitors: from conception to validation. Eur. J. Org. Chem. 2006(2), 311–322 (2006). • For review of silanediol type transition state analogs.
    • 60 Chen C-A, Sieburth SMcN, Glekas A et al. Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease. Chem. Biol. 8(12), 1161–1166 (2001).
    • 61 Sieburth SMcN, Nittoli T, Mutahi AM, Guo L. Silanediols: a new class of potent protease inhibitors. Angew. Chem. Int. Ed. Engl. 37(6), 812–814 (1998). • Excellent utilization of silanediols in the field of medicinal chemistry.
    • 62 Mutahi MW, Nittoli T, Guo L, Sieburth SMcN. Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogs as inhibitors of angiotensin-converting enzyme. J. Am. Chem. Soc. 124(25), 7363–7375 (2002).
    • 63 Madsen JL, Andersen TL, Santamaria S, Nagase H, Enghild JJ, Skrydstrup T. Synthesis and evaluation of silanediols as highly selective uncompetitive inhibitors of human neutrophil elastase. J. Med. Chem. 55(17), 7900–7908 (2012).
    • 64 Hernández D, Lindsay KB, Nielsen L et al. Further studies toward the stereocontrolled synthesis of silicon-containing peptide mimics. J. Org. Chem. 75(10), 3283–3293 (2010).
    • 65 Madsen AS, Kristensen HME, Lanz G, Olsen CA. The effect of various zinc binding groups on inhibition of histone deacetylases 1–11. ChemMedChem 9(3), 614–626 (2014).
    • 66 Steiling L, Tacke R, Wannagat U. Sila-Pharmaka, 11. Diphenyl(3-piperidinopropyl)silanol, ein Sila-Analogon des Difenidols. Liebigs Ann. Chem. 1979(10), 1554–1559 (1979).
    • 67 Tacke R, Strecker M, Sheldrick WS et al. Sila-Pharmaka, XIX. Sila-Pridinol und Pridinol: Darstellung und Eigenschaften sowie Strukturen im kristallinen und gelösten Zustand. Chem. Ber. 113(5), 1962–1980 (1980).
    • 68 Tacke R, Pikies J, Linoh H, Rohr-Aehle R, Gönne S. Sila-Pharmaka, 36. Sila-Procyclidin: Eine neue Synthese sowie Untersuchungen zur peripheren und zentralen anticholinergen Wirkung. Liebigs Ann. Chem. 1987(1), 51–57 (1987).
    • 69 Waelbroeck M, Camus J, Tastenoy M et al. Thermodynamics of antagonist binding to rat muscarinic M2 receptors: antimuscarinics of the pridinol, sila-pridinol, diphenidol and sila-diphenidol type. Br. J. Pharmacol. 109(2), 360–370 (1993).
    • 70 Lambrecht G, Feifel R, Wagner-Röder M et al. Affinity profiles of hexahydro-sila-difenidol analogs at muscarinic receptor subtypes. Eur. J. Pharmacol. 168(1), 71–80 (1989).
    • 71 Tacke R, Mahner K, Strohmann C et al. Cyclohexyl(4-fluorophenyl)(3-piperidinopropyl)silanol (p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD) and derivatives: synthesis and antimuscarinic properties. J. Organomet. Chem. 417(3), 339–353 (1991).
    • 72 Tacke R, Reichel D, Knopfgans M et al. Biological recognition of enantiomeric silanes: syntheses and antimuscarinic properties of optically active (2-aminoethyl)cyclohexyl(hydroxymethy1)phenylsilanes and related quaternary ammonium derivatives. Organometallics 14(1), 251–262 (1995).
    • 73 Tacke R, Reichel D, Jones PG et al. Pharmacological discrimination between enantiomeric germanes by muscarinic receptors: a study on germanium/silicon bioisosterism. J. Organomet. Chem. 521(1–2), 305–323 (1996).
    • 74 Tacke R, Kornek T, Heinrich T et al. Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: a study on C/Si/Ge bioisosterism. J. Organomet. Chem. 640(1–2), 140–165 (2001).
    • 75 Tacke R, Schmid T, Penka M, Burschka C, Bains W, Warneck J. Syntheses and pharmacological properties of the histaminic H1 antagonists sila-terfenadine-A, sila-terfenadine-B, disila-terfenadine, and sila-fexofenadine: a study on C/Si bioisosterism. Organometallics 23(21), 4915–4923 (2004).
    • 76 Daiss JO, Burschka C, Mills JS et al. Sila-venlafaxine, a sila-analog of the serotonin/noradrenaline reuptake inhibitor venlafaxine: synthesis, crystal structure analysis, and pharmacological characterization. Organometallics 25(5), 1188–1198 (2006).
    • 77 Tacke R, Heinrich T, Bertermann R, Burschka C, Hamacher A, Kassack MU. Sila-haloperidol: a silicon analog of the dopamine (D2) receptor antagonist haloperidol. Organometallics 23(19), 4468–4477 (2004).
    • 78 Tacke R, Popp F, Müller B et al. Sila-haloperidol, a silicon analog of the dopamine (D2) receptor antagonist haloperidol: synthesis, pharmacological properties, and metabolic fate. ChemMedChem 3(1), 152–164 (2008). • Sila-haloperidol is an excellent example of Si/C-exchange to change the metabolic fate of the parent carbon analogs.
    • 79 Tacke R, Nguyen B, Burschka C et al. Sila-trifluperidol, a silicon analog of the dopamine (D2) receptor antagonist trifluperidol: synthesis and pharmacological characterization. Organometallics 29(7), 1652–1660 (2010).
    • 80 Geyer M, Wellner E, Jurva U, Saloman S, Armstrong D, Tacke R. Can silicon make an excellent drug even better? An in vitro and in vivo head-to-head comparison between loperamide and its silicon analog sila-loperamide. ChemMedChem 10(5), 911–924 (2015).
    • 81 Toyama H, Sato S, Shirakawa H, Komai M, Hashimoto Y, Fujii S. Altered activity profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317. Bioorg. Med. Chem. Lett. 26(7), 1817–1820 (2016).
    • 82 Schultz JR, Tu H, Luk A et al. Role of LXRs in control of lipogenesis. Genes Dev. 14(22), 2831–2838 (2000).
    • 83 Houck KA, Borchert KM, Hepler CD et al. T0901317 is a dual LXR/FXR agonist. Mol. Genet. Metab. 83(1–2), 184–187 (2004).
    • 84 Mitro N, Vargas L, Romeo R, Koder A, Saez E. T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett. 581(1), 1721–1726 (2007).
    • 85 Kumar N, Solt LA, Conkright JJ et al. The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-α/γ inverse agonist. Mol. Pharmacol. 77(2), 228–236 (2010).
    • 86 Denmark SE, Kallemeyn JM. Palladium-catalyzed silylation of aryl bromides leading to functionalized aryldimethylsilanols. Org. Lett. 5(19), 3483–3486 (2003).
    • 87 Blunder M, Hurkes N, Spirk S, List M, Pietschnig R. Silanetriols as in vitro inhibitors for AChE. Bioorg. Med. Chem. Lett. 21(1), 363–365 (2011). • Revealed the potential utility of silanetriols as transition state analogs.
    • 88 Puri JK, Singh R, Chahal VK. Silatranes: a review on their synthesis, structure, reactivity and applications. Chem. Soc. Rev. 40(3), 1791–1840 (2011). • For review of silatranes.
    • 89 Voronkov MG. Silatranes: intra-complex heterocyclic compounds of pentacordinated silicon. Pure Appl. Chem. 13(1–2), 35–60 (1966).
    • 90 Horsham MA, Palmer CJ, Cole LM, Casida JE. 4-Alkynylphenylsilatranes: insecticidal activity, mammalian toxicity, and mode of action. J. Agric. Food Chem. 38(8), 1734–1738 (1990).
    • 91 Sculimbrene BR, Decanio RE, Peterson BW, Muntel EE, Fenlon EE. Silatranyl-nucleosides: transition state analogs for phosphoryl transfer reactions. Tetrahedron Lett. 42(30), 4979–4982 (2001).
    • 92 Black CA, Ucci JW, Vorpagel JS, Mauck MC, Fenlon EE. Stereoselective and improved syntheses and anticancer testing of 3′-O-silatranylthymidines. Bioorg. Med. Chem. Lett. 12(24), 3521–3523 (2002).
    • 93 Rink CM, Mauck MC, Asif I, Pitzer ME, Fenlon EE. Syntheses of silatranyl- and germatranyluridines. Org. Lett. 7(6), 1165–1168 (2005).
    • 94 Xiang Y, Fu C, Breiding T et al. Hydrolytically stable octahedral silicon complexes as bioactive scaffolds: application to the design of DNA intercalators. Chem. Commun. 48(57), 7131–7133 (2012).
    • 95 Hansch C, Leo A, Unger SH et al. ‘Aromatic’ substituent constants for structure–activity correlations. J. Med. Chem. 16(11), 1207–1216 (1973).