Biomedical Frontiers of Fluorine Chemistry

352 Pages·1996·35.46 MB·English

by  Iwao Ojima

ACS SYMPOSIUM SERIES 639
Biomedical Frontiers
of Fluorine Chemistry
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http://96-06 Iwao Ojima, EDITOR
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pril 10.1 James R. McCarthy, EDITOR
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MOugu State University of New York at Albany
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by the Division of Fluorine Chemistry and
the Division of Medicinal Chemistry
American Chemical Society, Washington, DC
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
RS 431 .073B55 1996 Copy 1
Biomedical frontiers of
fluorine chemistry
Library of Congress Cataloging-in-Publication Data
Biomedical frontiers of fluorine chemistry / Iwao Ojima, James R.
McCarthy, John T. Welch, editors.
p. cm.—(ACS symposium series; 639)
"Developed from a symposium sponsored by the Division of Fluorine
Chemistry and the Division of Medicinal Chemistry."
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ubs.acs.or9.fw001 IInScBluNd 0es-8 b4ib1l2io-g3r4a4p2h-ic6a l references and indexes.
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http://96-06 21.. OOrrggaannoofflluurooriinnee ccoommppoouunnddss——PShynysthioelsoisg—icaCl oenfgfercets—sesC. ongresses.
10 | k-19 3. Organofluorine compounds—Therapeutic use—Congresses.
0b I. Ojima, Iwao, 1945- . II. McCarthy, James R., 1943-
8, 221/ III. Welch, John T. IV. American Chemical Society. Division of
pril 110.10 FMluedoirciinnea lC Chehmemisitsrtyry. . VVI. .A Smereierisc.a n Chemical Society. Division of
LL on A96 | doi: R61S54'.3311.20—73Bd5c250 1996 96-2478C4IP
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PRINTED IN THE UNITED STATES OF AMERICA
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
Advisory Board
ACS Symposium Series
Robert J. Alaimo Cynthia A. Maryanoff
Procter & Gamble Pharmaceuticals R. W. Johnson Pharmaceutical
Research Institute
Mark Arnold
Roger A. Minear
g University of Iowa
or University of Illinois
pubs.acs.39.fw001 DUnaivveirdsi tBy aokf eTren nessee Omatk Uarrbaamna -NChaalammpaaisgun
http://96-06 Arindam Bose AT&T Bell Laboratories
10 | k-19 Pfizer Central Research Vincent Pecoraro
0b
8, 221/ Robert F. Brady, Jr. University of Michigan
pril 110.10 Naval Research Laboratory George W. Roberts
LL on A96 | doi: MChaermyE dEit. CCoamstpealnliyo n NJoohrtnh CRar.o lSinhaa Sptlaetye University
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H C3, 1 Margaret A. Cavanaugh University of Illinois
UTst 1 National Science Foundation at Urbana-Champaign
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TMAu Arthur B. Ellis Douglas A. Smith
DARDate: University of Wisconsin at Madison Concurrent Technologies Corporation
by on Gunda I. Georg L. Somasundaram
oaded blicati University of Kansas DuPont
wnl Pu Madeleine M. Joullie Michael D. Taylor
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D University of Pennsylvania Parke-Davis Pharmaceutical Research
Lawrence P. Klemann William C. Walker
Nabisco Foods Group DuPont
Douglas R. Lloyd Peter Willett
The University of Texas at Austin University of Sheffield (England)
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
Foreword
IHE ACS SYMPOSIUM SERIES was first published in 1974 to
provide a mechanism for publishing symposia quickly in book
form. The purpose of this series is to publish comprehensive
books developed from symposia, which are usually "snapshots
org in time" of the current research being done on a topic, plus
ubs.acs.9.fw001 ssaormye t hreavti ethwe mpaapteerrias lb oen p tuhbeli sthoepdic .a sF qouri ctkhliys aresa psoonss,i bitle i.s neces
http://p96-063 propoBseefdor tea bal esy mofp coosinutmen-btass eisd rbeovoiekw eisd p fuotr uanpdperro pcorinattreancets,s t htoe
10 | k-19 the topic and for comprehensiveness of the collection. Some
18, 20021/b proaupnerds oaurte t heex cslcuodpeed oaft t hthe ivso lpuominet., Iann dad odtihtieorns, aa rdera fatd odef dea ctoh
pril 10.1 paper is peer-reviewed prior to final acceptance or rejection.
LL on A96 | doi: Terhsi)s aonfo tnhyem soyumsp roesviuiemw, wphrooc ebsesc oims esu tpheer veisdeitdo rb(sy) tohfe t horeg baonoizk .
O9 The authors then revise their papers according to the recom
H C3, 1 mendations of both the reviewers and the editors, prepare
UTst 1 camera-ready copy, and submit the final papers to the editors,
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In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
Preface
JLHE EXTRAORDINARY POTENTIAL OF FLUORINE-CONTAINING biologi
cally relevant molecules in biology, medicinal chemistry, and medical
applications has recently been recognized by researchers who are not in
the traditional fluorine chemistry arena. This emerging new wave of
fluorine chemistry at the biomedical interface is rapidly expanding its
g frontiers. Consequently, it is the right time for us to review the recent
or
acs.001 advances in this field and envision the exciting future developments.
ubs.9.pr Bioactive organofluorine compounds showing promise in
p3 medicinal-medical research in the last five years include (a) enzyme in
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pril 18, 210.1021/ MagDenLt s1, 0e1.7g3.,1 g e(ma mciteacbhinanei sm(a- bgaesmed-d iniflhuiobritionart oedf r iabnoanlougc leooft iddeeo dxiypchyotsidpihnaet)e,
OLL on A996 | doi: ra(eand asultoecgrta)os,i ed)a ,ns hbdoic fwaluilnuotgar moad isdoimec ei(lataar xn aeocnltsisv (tfielturyoo iardosa tla aamnnaotlixoaignfesdn r)oo,g fDe nTDica-x 0ao0gl3e);n (t(a)d, v )Ri taaUmn5tii8vn6ir 6Da8l3
H C13, 1 agents, e.g., fluorodideoxythiacytidine, L-FMAU, WIN-63843, and
UTst fluorodeoxyguanosine; (e) antibacterials, e.g., sparfloxacin, tosufloxacin,
MOugu levofloxacin, and a fluoro-2-pyridone antimicrobial agent, A-86719.1; (f)
A
RTe: antimalarial agents, e.g., mefloquine, artemether, and arteflene; (g) anti
DADat fungal agents, e.g., fluconazole, ICI-D0870, and flutrimazole; (h) central
by on nervous system agents, e.g., fluoxetine hydrochloride, paroxetine (an
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ow sodium (an HMG-CoA reductase inhibitor, i.e., a hypolipidemic drug),
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tolrestat, zopolrestat (an aldose reductase inhibitor, i.e., an antidiabetic
agent); and many others.
Fluorine-containing amino acids and other biomolecules are
extremely useful as probes for investigating biomedical problems. For
example, the recent development of 19F NMR techniques combined with
genetic engineering allow us to use fluorine-labeled amino acids as struc
tural and dynamic probes for the study of membrane-associated proteins.
ix
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
neurotransmission have been substantially advanced by the use of
fluoroamine neurotransmitters and their precursors. Remarkable
developments have been made in the use of tracers labeled with fluorine-
18 (18F) for positron emission tomography (PET) studies in the neurosci­
ences, especially of the brain and the heart in living systems. This power­
ful diagnostic method finds many critical medical applications.
Because of the increasing interest and excitement about the fluorine-
containing compounds relevant to biomedical research, three divisions of
the American Chemical Society (ACS) held three symposia in 1995. The
ACS Division of Fluorine Chemistry asked Iwao Ojima to organize its
symposium entitled "Fluoro-Amino Acids and Peptides in Medicinal
Chemistry" in conjunction with the Division of Medicinal Chemistry at
the 210th ACS national meeting in Chicago. I. Ojima is grateful for the
g
or support of this symposium from Great Lakes Chemical Corporation; F-
acs.001 TECH, Inc.; Asahi Glass Company; Central Glass Company; Merck and
ubs.9.pr Company, Inc.; and Yuki Gosei Kogyo Company. For the ACS Division
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pril 18, 2010.1021/b PMRrocouCdsausrecttlh,s y Ian gncr.da tJeCofuhhlenlmy T iac. acWklsn,eo lIwcnhlce .do;g rAegaslln ieitzhde-edS f iitgnhnaea nls,yc Iminacpl.o c;so ianuntmrdib "uHFtiolouenochsri fsnrte oM imna BrA ioioinr­
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OUTgust This book is designed to be useful to researchers who want to take
MAu advantage of the unique properties of fluorine in biomedical research
ARTate: including rational drug design and syntheses, the use of fluorinep robes
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Do nucleosides, fluorine probes for biochemical problems using 19F NMR,
and fluorine-containing biomolecules in neuroscience including 18F labels
for PET studies. Most of the authors in this book were invited speakers
in the three symposia upon which this book is based; the remaining
chapters were contributed by leading chemists in their fields. This publi­
cation maps out the newest developments in this growing research field
for synthetic chemists, medicinal chemists, biochemists, biologists, and
other biomedical scientists worldwide.
χ
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
The editors and authors sincerely hope that this book stimulates this
growing and exciting field of research at the interface of fluorinec hemis
try, biology, and medicine.
IWAO OJIMA
Department of Chemistry
State University of New York at Stony Brook
Stony Brook, NY 11794-3400
JAMES R. MCCARTHY
Department of Medicinal Chemistry
Neurocrine Biosciences, Inc.
g 3050 Science Park Road
or
acs.001 San Diego, CA 92121-1102
ubs.9.pr
p3 JOHN T. WELCH
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pril 18, 210.1021/ April 4, 1996
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In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
Chapter 1
Recent Advances in the Biomedicinal
Chemistry of Fluorine-Containing Compounds
Kenneth L. Kirk1 and Robert Filler2
1Laboratory of Bioorganic Chemistry, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health,
Building 8A, Room B1A-02, Bethesda, MD 20892
org 2Department of Biological, Chemical, and Physical Sciences,
ubs.acs.9.ch001 Illinois Institute of Technology, Chicago, IL 60616-3793
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UTH Cst 13, 1 has been on material published within the past five years.
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ARTate: can facilitate interactions of a fluorinated biomolecule with enzyme active sites, receptor
DD recognition sites, transport mechanisms, and other biological systems. In contrast, the
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nlPu modification, in turn, can produce altered biological responses. Strategies based on these
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biochemical tools, and pharmacological and medicinal agents. The development of new
fluorinating agents, and new procedures that modify the reactivities of fluorinating agents,
have contributed greatly to the present rapid pace of advancement in this field.
An understanding of the underlying biochemical mechanisms involved, coupled
with knowledge of the physico-chemical properties accompanying fluorine substitution,
have aided in the rational design of many pharmacological agents and drugs. Fluorinated
analogues also can be excellent probes for biochemical mechanisms. Applications include
the use of chiral and prochiral fluorinateds ubstrates to probe reaction stereochemistry and
examination of effects of electronegative centers on reaction rates. Many 19F-NMR
studies have demonstrated the utility of fluorinel abelled proteins as mechanistic tools.
0097-6156/96/0639-0001$16.00/0
© 1996 American Chemical Society
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
2 BIOMEDICAL FRONTIERS OF FLUORINE CHEMISTRY
In the first part of our review, biochemical aspects of the biomedicinal chemistry
of fluorinated compounds will be covered. Medicinal aspects of this field are then
discussed, with emphasis on drugs that have been recently marketed, or are in the final
phases of testing.
Fluorine-Containing Enzyme Inhibitors.
The dual advantages of fluorine substitution in analogue design — small steric changes
coupled with large electronic changes — has been very advantageous in the design of
enzyme inhibitors. Selected examples of these stragtegies will be given in this section.
g Fluorine as a Deceptor (H* vs. F). Loss of a proton is a frequent event in enzyme-
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10 | k-19 synthesis of thymidine monophosphate from deoxyuridine monophosphate, the substrate,
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ow found in eukaryotes, is important in cell differentiation and regulation of gene expression.
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In a process mechanistically similar to the inhibition of thymidylate by fl5dUMP, 5-fluoro-
2-deoxycytidine (fl5dC) irreversibly inhibits DC-MTase-catalyzed methylation of 2'-
deoxycytidine (dC). In the catalytic cycle, addition of a catalytic SH group on the enzyme
to the 6-position of the pyrimidine ring is followed by transfer of a methyl group from S-
adenosyl methionine (AdoMet) to the 5-position of dC. C-5 proton loss and elimination
of enzyme-SH produces the methylated product. However, in the case of the inhibitor,
the presence of fluorine in fl5dC blocks the final elimination of enzyme-SH and an
irreversible enzyme-inhibitor complex is formed (equation 2) (4-6).
Fluorine-Containing Protease Inhibitors. Proteases not only play important roles in
normal physiologic functioning of mammalian cells and tissues, they also are involved in
a host of pathological processes as well. The development of specific, orally active
protease inhibitor has become an important strategy for potential treatment of such
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.
1. KIRK & FILLER Recent Advances in Fluorine-Containing Compounds3
diverse illnesses as metastatic cancer, malaria, arthritis, sleeping sickness, AIDS, and
others (7). In this work, incorporation of fluorine has been key to the development of
several clinical candidates.
Fluoroketone-Containing Reversible Inhibitors of Elastases. Trifluoromethyl
ketones are potent reversible inhibitors of proteases. The highly electrophilic ketone
associates with the enzyme as a hydrate, a tetrahedral structure that mimics the transition
state of normal bond cleavage. Alternatively, in a slower process, reaction of the free
ketone with an enzyme-associated nucleophile may occur.
Particularly impressive results using trifluoromethyl ketones have been seen in the
development of inhibitors of human leukocyte elastase (HLE). This very destructive
g serine protease, produced by neutrophils, is critical to the body's inflammatory defense
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MAu Research at ZENECA Pharmaceuticals also has produced trifluoromethyl ketone
RTe: œntaining inhibitors that show high selectivity, and, in certain cases, oral bioavailability.
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ow bioavailability, research was undertaken to replace the peptide portions of these inhibitors
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with mimetics. Modeling studies together with X-Ray data available from complexes of
reversibly and irreversibly bound inhibitors and elastase were use to design non-peptide
inhibitors, including a series of pyridone- (14) and β-carboline-containing trifluoromethyl
ketones (75) (3 and 4, respectively).
In related research, increased affinity for the enzyme was realized by appropriate
design of residues on both sides of the site corresponding to the scissile bond of the
natural substrate. As with other protease inhibitors, the "difluorostatone" strategy was
used. Structure 5 is a potent member of a series of inhibitors resulting from this work
(16).
Renin Inhibitors (the "Statine Strategy"). Renin is a highly specific aspartyl
protease, secreted into the circulation by the kidneys, that cleaves the Leu-Val bond of
angiotensinogin to produce angiotensin I, the precursor of the vasoconstricting peptide
angiotensin Π. Over the past 25 years an enormous amount of research has been directed
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1996.