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    ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS FOR ACE, FXIa, AND CHYMASE

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    Genre
    Thesis/Dissertation
    Date
    2013
    Author
    Duong, Hoan Quoc
    Advisor
    Sieburth, Scott McNeill
    Committee member
    Davis, Franklin A.
    Andrade, Rodrigo B.
    Cannon, Kevin C.
    Department
    Chemistry
    Subject
    Chemistry, Organic
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/1145
    
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    DOI
    http://dx.doi.org/10.34944/dspace/1127
    Abstract
    Dialkylsilanediols, a novel class of non-hydrolyzable analogues of the tetrahedral intermediate of amide hydrolysis, have been shown to be good inhibitors of the HIV-1 protease, angiotensin converting enzyme (ACE), thermolysin, and the serine protease α-chymotrypsin. Synthesis and biological evaluation of silanediols are therefore a priority in this research. Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers gives silafurans which can be used directly to make chiral β-silyl acids needed for the silanediol peptide mimics. Absolute configuration determination of AIH products remains a challenge. Proton nuclear magnetic resonance (1H NMR) of the Mosher ester derivative was used to confirm the absolute configuration. This has proven to be a simple method to determine the absolute configuration of silicon-containing primary carbinols. Dialkylsilanediols (1.52) are known as good inhibitors of angiotensin converting enzyme (ACE), with inhibition constants from 3.8 to 207 nM. However, the synthesis of these silandiol peptide mimics involved a long synthetic route. A short, asymmetric synthesis of silanediol ACE inhibitors was developed using asymmetric hydrosilylation and addition of a silyllithium to a sulfinimine, 8 linear steps with an 8% over all yield. Specific inhibitors of the FXIa protease could inhibit thrombosis without completely interrupting normal hemostasis, and prevent or minimize the risk of hemostasis complications. Based on the FXIa substrate, the design and synthesis of the first five guanidine-containing silanediol FXIa inhibitors was developed: Ac-Arg-[Si]-Ala-NHMe (4.15), Ac-Ala-Arg-[Si]-Ala-NHMe (4.16), Ac-Leu-Ala-Arg-[Si]-Ala-NHMe (4.17), Ac-Pro-Ala-Arg-[Si]-Ala-NHMe (4.18), and Ac-Arg-[Si]-Ala-Ala-NHMe (4.19). Synthesis of these targets was achieved using our newly developed silyllithium preparation and silyl dianion addition to the Davis sulfinimine, 11 linear steps, gave silanediol precursor 4.60 in 1.7% yield. Inhibition constant of the FXIa inhibitors was good in range of 76 - 980μM. Human heart chymase (HHC), a chymotrypsin-like serine protease present in the left ventricular tissues of the human heart, converts angiotensin I to angiotensin II, raising blood pressure. Although the physiological role of HHC has not been fully elucidated, it may be involved in various pathological states, particularly in cardiovascular diseases. Synthesis of silanediol inhibitors of HHC, therefore, may contribute to the understanding of its physiological functions and a better treatment for cardiovascular diseases. Synthesis of a silanediol chymase inhibitor has been investigated.
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