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Sulfobetaines as novel inhibitors of squalene synthase. A model system for Δ4-3-ketosteroid isomerase.

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Call No.	QP752.C5 O56 1996
Author	Onofrey, Thomas J.
Title	Sulfobetaines as novel inhibitors of squalene synthase. A model system for Δ4-3-ketosteroid isomerase.
Date	1996
Abstract	This thesis describes the synthesis of sulfobetaines having the general structure $\rm RN\sp{+}(CH\sb3)\sb2(CH\sb2)\sb{x}SO\sb{3\sp{-}}$ as novel inhibitors of squalene synthase. Squalene synthase reductively couples two molecules of farnesyl diphosphate to produce squalene, and is the first enzyme in the cholesterol biosynthetic pathway dedicated exclusively to the biosynthesis of cholesterol. The results of biological studies of the inhibitors prepared will also be discussed. The first series of sulfobetaines produced includes compounds 84-86, 94, and 95, in which X of the general structure above was systematically varied from 2 to 6 methylenes groups and R is the natural farnesyl subunit of farnesyl diphosphate. Compound 85 was prepared from known farnesyldimethylamine (91) by nucleophilic ring opening of 1,3-propane sultone (89), while 86 was correspondingly prepared by use of 1,4-butane sultone (90). Compounds 84, 94, and 95 were prepared in two steps by treatment of 91 with the appropriate $\alpha$,$\gamma$-dibromoalkane followed by addition of Na$\sb2$SO$\sb3$. Compound 86, with a four carbon spacer proved to be the best inhibitor of this series, with $\rm I\sb{50}=15$ $\mu$M. Structure activity relationships were then undertaken to determine which moieties are necessary for potent inhibition. Compounds 98-100 were prepared with C$\sb{10}$ geranyl and C$\sb5$ prenyl chains to determine the necessity of the natural farnesyl C$\sb{15}$ chain. Compound 108, lacking the methyl groups on nitrogen, and compound 109, with a carboxylate ion in place of the sulfonate ion were also prepared to determine whether or not a permanently charged nitrogen and the sulfonate moiety, respectively, are important for inhibition. With hopes of increasing the binding of the alkyl subunit of the sulfobetaines to the hydrophobic binding pocket, an aromatic ring was introduced to the alkyl chain. Compounds having the general structure $\rm Ph(CH\sb2)\sb{n}N\sp{+}(CH\sb3)\sb2(CH\sb2)\sb4SO\sb{3\sp{-}}$ were prepared, where n = 1, 2, 6, 8, 9, and 10. These were synthesized by treatment of the appropriate $\alpha$,$\gamma$-dibromoalkane with phenyllithium followed by addition of excess dimethylamine to produce the corresponding amines, which were then treated with l,4-butanesultone to give the desired sulfobetaines. The best inhibitor prepared proved to be 121, where n = 9, which had $\rm I\sb{50}=2$ $\mu$M. Two compounds, N,N-dimethyl-1-(3,7-dimethyl-8-phenyl-2E, 6E-octadienyl)-ammonium-1-(4-butylsulfonate) (137) and N,N,3,7-tetramethyl-9-phenyl-(2E,6E-nonadienyl)-ammonium-1-(4-butylsulfonate) (138), whose structures are based on the best inhibitors of the two preceding series, 121 and 86, were also prepared. Compounds 137 and 138 were prepared in multistep syntheses starting from geranyl acetate (149), which was selectively oxidized to afford an alcohol, subsequently activated as a mesylate, and then coupled with either phenyllithium or benzyl magnesium chloride. The sulfobetaines were then prepared according to standard procedures used previously."
Description	xxii, 201 leaves : ill. 28 cm
Format	application/pdf
Advisor	Spencer, Thomas A.
Subject	Cholesterol -- Synthesis. Enzymes -- Inhibition. Isomerases -- Synthesis.
College	Dartmouth College -- Department of Chemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1419

Title	Page 1
Full Text	I. Sulfobetaines as Novel Inhibitors of Squalene Synthase II. A Model System for A'* 3-ketosteroid Isomerase A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Thomas J. Onofrey DARTMOUTH COLLEGE Hanover, New Hampshire February 1996

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Sulfobetaines as novel inhibitors of squalene synthase. A model system for Δ4-3-ketosteroid isomerase.

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