Synthesis, Reactivity, Functionalization, and ADMET Properties of Silicon-Containing Nitrogen Heterocycles

Journal of the American Chemical Society
Scott J Barraza, Scott E Denmark

Abstract

Silicon-containing compounds have been largely ignored in drug design and development, despite their potential to improve not only the potency but also the physicochemical and ADMET ( absorption, distribution, metabolism, excretion, toxicity) properties of drug-like candidates because of the unique characteristics of silicon. This deficiency is in large part attributable to a lack of general methods for synthesizing diverse organosilicon structures. Accordingly, a new building block strategy has been developed that diverges from traditional approaches to incorporation of silicon into drug candidates. Flexible, multi-gram-scale syntheses of silicon-containing tetrahydroquinoline and tetrahydroisoquinoline building blocks are described, along with methods by which diversely functionalized silicon-containing nitrogen heterocycles can be rapidly built using common reactions optimized to accommodate the properties of silicon. Furthermore, to better clarify the liabilities and advantages of silicon incorporation, select compounds and their carbon analogues were challenged in ADMET-focused biological studies.

References

Jan 1, 1979·Topics in Current Chemistry·R Tacke, U Wannagat
Jun 1, 1997·Seminars in Cancer Biology·K UedaM Morishima
Oct 6, 1998·Annual Review of Biochemistry·V L Schramm
Jun 6, 2000·Advanced Drug Delivery Reviews·A H Schinkel
Dec 19, 2000·Acta Crystallographica. Section C, Crystal Structure Communications·B VivetA Aubry
Mar 21, 2002·Journal of the American Chemical Society·Florine CavelierMichel Marraud
Jul 18, 2002·Chemical Communications : Chem Comm·Sirik DeerenbergKoop Lammertsma
Feb 7, 2003·Current Topics in Medicinal Chemistry·Edgar JacobyMarcel J J Blommers
Jun 11, 2003·Journal of Clinical Pharmacy and Therapeutics·R B WangE J Lien
Jun 25, 2003·Drug Discovery Today·Graham A Showell, John S Mills
Aug 28, 2004·Expert Opinion on Investigational Drugs·John S Mills, Graham A Showell
Feb 12, 2005·Organic Letters·Guodong Liu, Scott McN Sieburth
Jul 19, 2005·Drug Discovery Today·Robin A E CarrDavid C Rees
Nov 5, 2005·The Journal of Organic Chemistry·Alan R KatritzkyHui Tao
Nov 1, 2006·Mini Reviews in Medicinal Chemistry·P K Pooni, G A Showell
Nov 11, 2006·Bioorganic & Medicinal Chemistry Letters·Matthew J BarnesJulie B H Warneck
Feb 10, 2007·Nature Reviews. Drug Discovery·Philip J Hajduk, Jonathan Greer
Nov 1, 2007·Nature Reviews. Drug Discovery·Paul D Leeson, Brian Springthorpe
Sep 2, 2009·Bioorganic & Medicinal Chemistry Letters·Ted W JohnsonMartin Edwards
Oct 9, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tove JohanssonUlrik Jurva
Jul 31, 2010·Organic Letters·Dácil HernándezTroels Skrydstrup
Mar 19, 2011·Journal of Medicinal Chemistry·Nicholas A Meanwell
Aug 9, 2011·Journal of the American Chemical Society·Jun WangWilliam F DeGrado
Apr 7, 2012·Organic Letters·Cyril FrançoisJacques Maddaluno
Aug 17, 2012·Organic Letters·Swapnil Singh, Scott McN Sieburth
Oct 16, 2012·Journal of Medicinal Chemistry·Annaliese K Franz, Sean O Wilson
Dec 25, 2012·ACS Chemical Biology·Vern L Schramm
Jan 17, 2014·Journal of Chemical Biology·Gillian F WhyteRudiger Woscholski
Jul 8, 2010·ACS Medicinal Chemistry Letters·Dazhong DingJacob J Plattner
Jan 12, 2012·ACS Medicinal Chemistry Letters·John W TomshoStephen J Benkovic
Jul 6, 2014·Chemistry : a European Journal·Thomas BoddaertJacques Maddaluno
Mar 24, 2015·Journal of Medicinal Chemistry·Dennis A SmithLi Di
Dec 1, 2015·ACS Medicinal Chemistry Letters·Gorakhnath R JachakD Srinivasa Reddy
Apr 3, 1998·Angewandte Chemie·Scott McN SieburthLuxuan Guo

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Citations

Aug 7, 2018·Chemical Communications : Chem Comm·Terrance J HadlingtonMatthias Driess
Nov 9, 2018·Chemistry, an Asian Journal·Akira MatsumotoSeijiro Matsubara
Apr 23, 2020·Chemical Communications : Chem Comm·Ryo NinomiyaYoshihiro Ueda
Jun 24, 2019·The Journal of Chemical Physics·Juncheng LeiQian Gou
Nov 4, 2020·Chemical Communications : Chem Comm·Sourish BiswasChristopher Uyeda
Jan 17, 2021·Angewandte Chemie·Elvira RomeroChristian Schnepel
Jul 20, 2021·Journal of the American Chemical Society·Wanshu WangZhenlei Song
Aug 3, 2021·ACS Omega·Shubhranshu Shekhar ChoudhuryHimansu S Biswal
Oct 3, 2018·Journal of the American Chemical Society·Jianbo ZhangSukbok Chang

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