Aminocyclitol Antibiotics

432 Pages·1980·5.21 MB·English

by  Kenneth L. Rinehart

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98 Aminocyclitol Antibiotics
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Aminocyclitol Antibiotics
Kenneth L. Rinehart, Jr., EDITOR
University of Illinois
Tetsuo Suami, EDITOR
Keio University
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k-1 Based on a symposium jointly
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4, Medicinal Chemistry at the
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125
ACS SYMPOSIUM SERIES
AMERICAN CHEMICAL SOCIETY
WASHINGTON, D.C. 1980
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0 Aminocyclitol antibiotics.
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10. (ACS symposium series; 125 ISSN 0097-6156)
oi: Includes bibliographies and index.
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0 | 1. Antibiotics—Congresses.
98 I. Rinehart, Kenneth L. II. Suami, Tetsuo, 1920- .
st 4, 1 ISIeIr.i eAs.C S/CSJ Chemical Congress, Honolulu, 1979. IV.
u QD375.A44 615'.329 80-10502
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u ISBN 0-8412-0554-X ASCMC 8 125 1-437 1980
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bli Copyright © 1980
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P American Chemical Society
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w0 M. Joan Comstock, Series Editor
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1/ Advisory Board
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10. David L. Allara W. Jeffrey Howe
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0 | Kenneth B. Bischoff James D. Idol, Jr.
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4, Donald G. Crosby James P. Lodge
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Brian M. Harney Raymond B. Seymour
Robert A. Hofstader Gunter Zweig
FOREWORD
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PREFACE
lhe aminocyclitol class of compounds includes some of our longest and
best known antibiotics, streptomycin and neomycin. It also includes
some of the most clinically useful antibiotics, such as gentamicin. Because
of their clinical utility, and in spite of their long familiarity, interest in
the class remains high and, indeed, seems to be increasing. This volume
deals with the current status of structural, synthetic, and biosynthetic
studies.
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00 The aminocyclitol class and its members are defined and described
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5. in Chapter 1, an introduction complete with figures and references to
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01 recent review articles. The longest section of the book follows, devoted
80- to the very extensive recent synthetic efforts directed toward amino
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k- cyclitol antibiotics. Sumio Umezawa discusses his recent preparation of
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1/ neomycin B, the latest in a series of total syntheses that have developed
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10 routes useful for preparing modified aminocyclitol antibiotics with
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doi: 1 rimouptreo vtoed n perwo paemrtiienso. cyIcnl iCtohl aapntteirb i3o, tiTces,t stuhoa tS uinavmoilv dinisgcu mssoesd iafinc aatilotenr noaft iavne
80 | existing antibiotic, describing his own syntheses based on the pseudo-
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4, 1 disaccharide neamine as a starting material. In Chapter 4 Juji Yoshimura
st describes approaches to branched-chain aminocyclitols, employing both
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ug Diels-Alder reactions and nitrosugar cyclizations. Other chapters on
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e: synthetic research also deal with branched-chain aminocyclitols (Kiely
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D and Riordan, Chapter 5) or neamine and its modification (Magerlein,
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o Chapter 10; Ku et al., Chapter 12). The latter chapter also treats
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blic modified kanamycins, as do chapters by Verheyden et al. ( Chapter 13 )
u and Cron et al. (Chapter 14), while Chapter 11 by McAlpine et al. treats
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modified gentamicins and seldomycins. Finally, there are four chapters
on spectinomycin—one (by White et al., Chapter 6) describing the first
total synthesis of spectinomycin, and three (by Thomas et al.; Rosen-
brook and Carney; Foley and Weigele; Chapters 7-9, respectively)
dealing with modification of that antibiotic.
The second major section of the book deals with structural studies
of aminocyclitol antibiotics. In Chapter 15 Takayuki Naito provides and
analyzes a very extensive set of 13C spectra, the most useful spectroscopic
data for aminocyclitols' structural assignments. The two other chapters
in this section (McAlpine et al., Chapter 16 and Shirahata et al., Chapter
17) assign structures to new fortimicins, aminocyclitols with a 1,4-diamino
substitution pattern.
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The final section of the book deals with biochemical studies of the
aminocyclitols. In Chapter 22 Bernard Davis discusses the multiple
mechanisms of action of this class of antibiotics, while Julian Davies
(Chapter 18) discusses the other side of the picture, the various mecha
nisms by which the target bacteria enzymatically inactivate the amino
cyclitol antibiotics. In Chapter 19 Kenneth Rinehart discusses the
biosynthesis of aminocyclitols and describes a technique based on bio-
synthetic studies that uses mutants to prepare new antibiotics—a tech
nique that is also the subject of the paper by Cléophax et al. (Chapter
21). Finally, the role of mutasynthetic and chemical techniques in
preparing improved clinical candidates in the gentamicin class is assessed
by Peter Daniels in Chapter 20.
Overall, then, the present book and the symposium on which it was
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0 based point to the vigor of current research on aminocyclitol antibiotics,
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pr with both elegant and useful organic chemical syntheses being carried
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12 out, and antibiotics of novel structure being discovered. New insights into
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1 and their biosynthesis is not only being better understood, but is leading
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0 We would like to thank the authors for their continued patience and
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10. cooperation, and Lois Shield and Julia Zvilius for their assistance in
oi: preparing this book.
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1 University of Illinois KENNETH L. RINEHART, JR.
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st Urbana, Illinois 61801
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at Yokohama, Japan
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Aminocyclitol Antibiotics: An Introduction
KENNETH L. RINEHART, JR. and LOIS S. SHIELD
Roger Adams Laboratory, University of Illinois, Urbana, IL 61801
Aminocyclitol antibiotics constitute an important class of
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0 clinically useful therapeutic agents, whose discovery dates from
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ch that of streptomycin in 1944. These compounds, which are less
25. precisely, though widely, also referred to as aminoglycoside anti­
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0 biotics, include some of the most successful commercial antibio­
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8 tics and new members of the class are being added yearly. Nume­
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k-1 rous reviews of aminocyclitols are available (1-8), providing
1/b references to the individual antibiotics. Thus, the present in­
02 troductory section will simply indicate the breadth and diversity
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0. of the class, providing specific references only to the newer
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80 | d contaAinm 2in-doecoyxcylisttorelsp tacamnin bee (daiv 1id,2e,d3- tirnitdoe oax yv-e1r,y3- dlaiargmei ngoro uanpa lwoghi ch
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1 of scyllo-inositol) and a somewhat smaller group containing other
st 4, aminocyclitols. The deoxystreptamine antibiotics can be further
gu grouped according to the number and location of substituents
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A attached to the deoxystreptamine unit. 4,5-Disubstituted deoxy­
e: streptamines include neomycins, paromomycins, lividomycins and
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D 2230-C (Figure 1). These pseudotetra- and pseudopentasaccharides
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o all contain one or more diaminohexoses. Another group of 4,5-
cati disubstituted deoxystreptamine antibiotics consists of pseudotri­
bli saccharides, including ribostamycin, xylostasin, the butirosins
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P and the compounds now referred to (9) as 6'-deamino-6'-hydroxy­
butirosins (formerly BU-1709 E and E), and LL BM408α (10)
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(Figure 2). These compounds are characterized by a di- or mono­
aminohexose and a ribose or xylose substituent and in some mem­
bers of the class the 1-amino group of deoxystreptamine is sub­
stituted by an α-hydroxy-γ-aminobutyryl group.
The 4,6-disubstituted deoxystreptamine antibiotics are
characterized by the presence at C-4 of a 2-aminohexose (usually
modified), together with a second amino (usually a 3-amino) sugar
at C-6. These antibiotics include the kanamycins, tobramycin and
the nebramycins (Figure 3), the seldomycins (V\_,}2) (Figure 4),
as well as the very large group of gentamicins and related com­
pounds (Figure 5), and the dehydro analogs of the gentamicins
0-8412-0544-X/80/47-125-001$05.00/0
© 1980 American Chemical Society
2 AMINOCYCLITOL ANTIBIOTICS
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oi: Journal of Antibiotics
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A CHR
ate: 2-Q R R' R" pl„ R,v
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ation wOH RXYIBLOOSSTTAAMSYINC IN NNHH22 OOHH ΗΗ OΗH OΗH
blic BUTIROSIN A NH2 OH * OH Η
Pu BUTIROSIN Β NH2 OH * Η OH
4-DE0XYBUTIR0SIN A NH2 Η * OH Η
4-DE0XYBUTIR0SIN Β NH Η * Η OH
2
LL BM408a OH OH Η Η OH
R"NH 9 DAH-BUTIROSIN A OH OH * OH Η
HOCHj>o DAH-BUTIROSIN Β OH OH * Η OH
*R"« -C0CH0HCHCHNH
2 2 2
Journal of Antibiotics
Figure 2. Ribostamycin group of 4,5-disubstituted deoxystreptamine antibiotics
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