JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2006; 19: 512–517
Kinetic and mechanistic studies on sulfamate esters:
Models of enzyme inhibitorsy
*
Cheryl J. A. McCaw and William J. Spillane
Department of Chemistry, National University of Ireland, Galway, Ireland
Received 22 August 2005; revised 3 November 2005; accepted 15 November 2005
ABSTRACT: Many compounds containing a sulfamate moiety, such as NH2SO2O— are now known to be medicinally
important. However, very little is known about their mechanisms of reaction even under non-biological conditions. In
this work the various types of elimination mechanisms that may occur have been probed by studying the kinetics of the
reactions of model sulfamate substrates with amines (bases) that act as models for the enzymes involved. The principal
¨
mechanistic tool employed has been Bronsted plots and both ‘normal’ rectilinear and two types of biphasic plots have
been found for the decomposition of the esters in acetonitrile (ACN). The mechanisms operating are seen as being of
the E2 and E1cB types. Copyright # 2006 John Wiley & Sons, Ltd.
¨
KEYWORDS: sulfamate esters; 667-Coumate; emate; Bronsted biphasic plots; aminolysis mechanisms; enzyme inhibitors
INTRODUCTION
interested, as these compounds have been shown to
inhibit various unrelated enzymes. There are several
drugs already in the market or in clinical trials containing
the sulfamate moiety (Fig. 1).
Topiramate 6 is an anti-epileptic drug which is fast and
3
effective and in clinical use at present. Although the
Sulfamate esters have been used as herbicides, sweeteners
and pharmacological intermediates for many years. In
recent years interest in compounds that contain the
sulfamate functional group has increased enormously as
awareness has risen of their important medical appli-
cations.1
Sulfamic acid 1 itself, the parent of the sulfamate
moiety, possesses pharmacological applications. Its O-
substituted derivatives 2, N-substituted compounds 3, and
the O,N-di/trisubstituted compounds 4 and 5 respectively,
are all biologically active (Scheme 1).1
Compound 1 is well known as a standard strong acid
and both it and its salts are extensively used in the
electrochemical industry. It is itself a potent inhibitor of
the zinc enzyme, carbonic anhydrase (CA), which
regulates the reversible hydration of carbon dioxide to
bicarbonate. The O-substituted derivatives 2 have shown
good inhibitory activity against unrelated enzymes such
as the CAs and the steroid sulfatases (STSs), which
regulate the formation of estrone from estrone sulfate.
The N-substituted compounds 3, have found application
as sweeteners,2 whilst the O,N-di/trisubstituted com-
pounds 4 and 5 show a wide range of biological
activities.1 In this study it is the O-substituted derivatives
2, the sulfamate esters, in which we are particularly
mechanism of action is not yet fully understood,4 the
sulfamate moiety has been shown to be crucial for this type
of biological action.3 An interesting side effect of 6 was that
it caused weightloss in some patients, and thus it is now
under investigation as an anti-obesity drug.1 This devel-
opment is exciting due to the widespread and increasing
problem of obesity in the Western world. Avasimibe 7 is an
anti-atherosclerotic sulfamate, restricting loss of elasticity
of, and arterial wall thickening. It works by inhibiting acyl
coenzyme A:cholesterol acyltransferase (ACAT).1 This
was a breakthrough discovery in 1994 and is now in clinical
phase III trials, showing low toxicity and low incidence of
side effects.5 There are many other sulfamate drugs under
investigation as anti-arthritic and anti-cholesterol agents.
With the increasing number of bacteria resistant to
traditional antibiotics and the increasing threat of HIV,
AIDS Hep B and C etc., there is also a great amount of
research ongoing in the development of antibiotic and anti-
viral sulfamates.1
The particular area of interest to this work is that of anti-
cancer sulfamates. There are two different inhibitory
activities of interest, that of STS inhibitors and that of CA
inhibitors. STS isresponsiblefor the hydrolysisofalkyland
aryl steroidal sulfamates therefore having a pivotal role in
regulating the formation of biologically active steroids.
These steroids support the growth of hormone-dependent
cancers such as breast and prostate cancers. The enzyme
inhibiting properties of these type 2 sulfamates prompted
*Correspondence to: W. J. Spillane, Department of Chemistry, N.U.I.,
Galway, Ireland.
E-mail: William.spillane@nuigalway.ie
ySelected paper presented at the 10th European Symposium on Organic
Reactivity, 25–30 July 2005, Rome, Italy.
Contract/grant sponsors: NUI Galway and Galway County Council;
James Hardiman N.U.I. Galway Library Fund.
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 512–517