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1 Aminocyclitol Antibiotics: A n Introduction K E N N E T H L. RINEHART, JR. and LOIS S. SHIELD
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Roger Adams Laboratory, University of Illinois, Urbana, IL 61801
Aminocyclitol antibiotics constitute an important class of clinically useful therapeutic agents, whose discovery dates from that of streptomycin in 1944. These compounds, which are less precisely, though widely, also referred to as aminoglycoside anti biotics, include some of the most successful commercial antibio tics and new members of the class are being added yearly. Nume rous reviews of aminocyclitols are available (1-8), providing references to the individual antibiotics. Thus, the present in troductory section will simply indicate the breadth and diversity of the class, providing specific references only to the newer members. Aminocyclitols can be divided into a very large group which contain 2-deoxystreptamine (a 1,2,3-trideoxy-1,3-diamino analog of scyllo-inositol) and a somewhat smaller group containing other aminocyclitols. The deoxystreptamine antibiotics can be further grouped according to the number and location of substituents attached to the deoxystreptamine unit. 4,5-Disubstituted deoxy streptamines include neomycins, paromomycins, lividomycins and 2230-C (Figure 1). These pseudotetra- and pseudopentasaccharides all contain one or more diaminohexoses. Another group of 4,5disubstituted deoxystreptamine antibiotics consists of pseudotri saccharides, including ribostamycin, xylostasin, the butirosins and the compounds now referred to (9) as 6'-deamino-6'-hydroxy butirosins (formerly BU-1709 E and E ), and LL BM408α(10) (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. 1
2
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
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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2
AMINOCYCLITOL ANTIBIOTICS
NH Journal of Antibiotics
Figure 1.
Neomycin group of 4,5-disubstituted deoxystreptamine antibiotics (1)
CH R -Q 2
R
wOH
RIBOSTAMYCIN
NH
XYLOSTASIN BUTIROSIN A
NH
2
2
NH NH
2
BUTIROSIN Β
R"NH
HOCHj>o
9
2
4-DE0XYBUTIR0SIN A 4-DE0XYBUTIR0SIN Β LL BM408a
NH
DAH-BUTIROSIN A DAH-BUTIROSIN Β
2
NH
*R"« -C0CH0HCH CH NH 2
2
pl„
R
Η
Η
OH
Η *
OH
Η
OH
Η
*
Η
OH
* *
OH
Η
Η Η
OH OH
OH Η
Η OH
R'
R"
OH OH OH OH Η
OH
Η OH
Η
OH
OH
*
OH
OH
*
2
,v
2
Journal of Antibiotics
Figure 2.
Ribostamycin group of 4,5-disubstituted deoxystreptamine antibiotics w
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
RINEHART AND SHIELD
Aminocyclitol Antibiotics: An Introduction
CH R 2
R'
_?!
_R^
OH
OH
Η
OH
NH
OH
NH
NH
Η
NH
NH
OH Η
NH NH
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R KANAMYCIN A KANAMYCIN Β
NH
KANAMYCIN C
OH
TOBRAMYCIN NEBRAMYCIN FACTOR 4 NEBRAMYCIN FACTOR 5'
NH
2
NH
2
2
2
2
Η
2
2
Η
2
Η
2
CONH
2
CONH
2
2
Journal of Antibiotics
Figure 3.
Kanamycin group of 4,6-disubstituted deoxystreptamine antibiotics (1)
CH,R
JL J i . SELDOMYCIN FACTOR I 2
OH NH
3 5
NH NH
2
2
2
OH Η OH Η
'R"=
NH
9
NH
9
Journal of Antibiotics
Figure 4.
Seldomycin group of 4,6-disubstituted deoxystreptamine antibiotics (1)
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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AMINOCYCLITOL ANTIBIOTICS
RCHR*
R
R"
1
R
...
R
R
R
R"
2
H
OH
NHCH
2
OH
H
NHCH
H
OH
OH H
H NHCH OH N(CHO)CH
t
OH
CH
3
NHCH NHCH
,v
v
VI
H
OH
OH
OH
NH
A,
H
OH
OH
OH
NH
A
H
OH NH OH
OH
OH
NH
OH OH
OH OH
OH NH
OH
OH
NH
2
OH
OH
OH
OH
CH
3
2
OH
OH
NH
2
OH
CH
3
3
GENTAMICIN A
2
2
v
3
3
OH
A, A
H H
*2 Β
H H
Β,
CH
3
NH
c,
CH
3
NHCH
H
H
NH
2
OH
CH
c,.
H
NH
2
H
H
NH
2
OH
CH
3
NHCH
c
CH
3
NH
2
H
H
NH
CH
3
NH
H
H
NH
NHCH
H
H
NH
OH
4
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R
2
C * 20
C * CCJ
H
G-418
CH
(GENTAMICIN X )
H
2b
e
JI-20B
CH
OH NH
2
3
2
3
3
3
2
S
3
3
3
NHCH NHCH
3
2
OH
CH
3
NHCH
2
OH
CH
3
NHCH
2
OH
CH
3
3
3
NHCH
3
OH
OH
NH
2
OH
CH
3
NHCH
NH
2
OH
OH
NH
2
OH
CH
3
NHCH
NH
2
OH
OH
NH
OH
CH
3
NHCH
•STEREOISOMER OF C * SAG AM ICI Ν
2
2
3
3
3
3
3
at C-6'
Journal of Antibiotics
Figure 5. Gentamicin group of 4,6-disubstituted deoxystreptamine antibiotics (1)
RCHNHR'
Journal of Antibiotics
Figure 6. Sisomicin group of 4,6-disubstituted deoxystreptamine antibiotics (I)
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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1.
RINEHART AND SHIELD
Aminocyclitol Antibiotics: An Introduction
5
(Figure 6), including sisomicin. At the present time the gentamicins are the most commercially important of the aminocyclitol antibiotics. The mono-substituted deoxystreptamines are a considerably smaller and less important group of antibiotics, characterized by a somewhat greater diversity of chemical structure, of which apramycin (T3) (Figure 7), with its diaminooctose, is perhaps the strangest. The destomycins, hygromycin B, and the SS-56 components (Figure 8) also belong to this class, most of the class containing the highly unusual destomic acid (aminoheptonic acid) unit. The latter group also provides a transition in that the deoxystreptamine unit is sometimes N-methylated or hydroxylsubstituted. Thus, the destomycin-SS-56 antibiotics have some relationship to spectinomycin (Figure 9), in which the aminoc y c l i t o l (actinamine) is f u l l y substituted and the amino groups are methylated. The final examples of diaminocyclitol antibiotics containing amino groups (substituted) in the 1- and 3-positions are the streptomycins (Figure 10), including bluensomycin, which contains a substituted monoaminocyclitol. These are characterized by guanidines, with carbamimidoyl groups attached to the amino groups in the aminocyclitol ring, as well as by a branched chain pentose, streptose or dihydrostreptose, and N-methyl-Lglucosamine. A recently discovered group of diaminocyclitols contains the fortimicins (14_) and the sporaricins (15J (Figure 11), compounds containing substituted 1,4-diaminocyclitols, again usually Nmethylated and sometimes substituted further by an acyl group. The fortimicins are presently undergoing c l i n i c a l t r i a l . Finally, a very few structurally dissimilar aminocyclitol antibiotics contain a monoaminocyclitol (Figure 12). The f i r s t of these reported was hygromycin A; other representatives are minosaminomycin and the validamycins, which contain a single amino group linked to two separate c y c l i t o l rings, each with a branching hydroxymethyl substituent. The present volume covers a number of aspects of aminoc y c l i t o l chemistry and biology and an attempt has been made in the ensuing pages to group papers according to their content. Thus, several papers deal with synthesis and modification of aminocyclitol antibiotics, some deal with structure-activity relationships, others with structural assignments. S t i l l others deal with biological aspects, such as mode of action, mode of inactivation, and biosynthesis of these important compounds. Acknowledgment. We appreciate greatly the permission received from the Journal of Antibiotics to use Figures 1-10 and 12, which have been adapted from those appearing in J . Antibiot., 319-353 (1976).
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
6
AMINOCYCLITOL ANTIBIOTICS
CH,NH OH
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HOÇHz
^ t>"
A
H.N
/NH
Journal of Antibiotics
η"
R
R'
R"
DESTOMYCIN A
Η
CH
3
Η
DESTOMYCIN
Β
Η
CH
S
CH
DESTOMYCIN C
Η
CH
3
CH
HYGROMYCIN Β
Η
Η
CH
SS-56
A
Η
Η
Η
SS-56
Β
Η
Η
SS-56
C
ΟΗ
Η
A-396-1 (SS-56D)
Η
Η
* R * DESTOMIC
(ORTHO E S T E R ) *
ACID
VM4-EPIDEST0MIC
OH
2
Figure 7. Apramycin, a monosubstituted deoxystreptamine antibiotic (1)
Y
\
2
NH
R
,V
R
V
ΟΗ
Η
3
Η
ΟΗ
t
3
ΟΗ
Η
*
3
ΟΗ
Η
*
Η
ΟΗ
Η
Η
ΟΗ
Η
Η
Η
ΟΗ
Η
*
Η
ΟΗ
Η
*
HOÇH
*
2
ACID (ORTHO E S T E R ) Journal of Antibiotics
Figure 8.
Destomycin group of monosubstituted deoxystreptamine antibiotics (l)
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
RINEHART AND SHIELD
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1.
7
Aminocyclitol Antibiotics: An Introduction
Journal of Antibiotics
Figure 9. Aminocyclitol antibiotics containing actinamine (1). Spectinomycin (hydrate form): X = Y = OH; dihydrospectinomycin: X = H, Y = OH
NHCNH,
STREPTOMYCIN N-DEMETHYLSTREPTOMYCIN HYDROXYSTREPTOMYCIN MANNOSIDOSTREPTOMYCIN MANNOSIDOHYDROXYSTREPTOMYCIN DIHYDROSTREPTOMYCIN BLUENSOMYCIN
R
R'
31
-NHC(«NH)NH -NHC(-NH)NH -NHC( -NH)NH -NHC( -NH)NH -NHC( -NH)NH -NHC( -NH)NH -0C0NH
CHO CHO CHO CHO CHO CH OH CH OH
H H OH H OH H H
2
2
2
2
2
2
2
2
2
_R!" _Ri
v
H H H » *
H H
CH H CH, CH CH CH CH S
3
3
3
3
CH OH 2
OH HO Journal of Antibiotics
Figure 10. Aminocyclitol antibiotics containing streptidine or bluensidine (1)
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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AMINOCYCLITOL ANTIBIOTICS
R C H
R"
R
OH
H
NH
OH
H
NH
R[
3
1
COCH NH 2
2
H
,V
2
3 CH
COCH NHCONH
OH
H
NH
2
H
COCHgNHg
OH
H
NH
2
C H
3
H
2
2
H
OH
H
CH
3
COCHgNHg
H
NH
CH
3
H
H
NH
2
2
2
NH H
2
H
CH NR' 3
Figure 11. Fortimicins and
?, 1,4-diaminocyclitol antibiotics
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
RINEHART AND SHIELD
Aminocyclitol Antibiotics: An Introduction
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1.
HYGROMYCIN A Journal of Antibiotics
Figure 12.
Monoaminocyclitol antibiotics (I)
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
9
AMINOCYCLITOL ANTIBIOTICS
10
Literature Cited 1. Rinehart, K. L., Jr.; Stroshane, R. M.: "Biosynthesis of Aminocyclitol Antibiotics." J. Antibiot., 1976, 29, 319-353. 2. Rinehart, K. L., Jr.: "Mutasynthesis of New Antibiotics." Pure and Appl. Chem., 1977, 49, 1361-1384. 3. Rinehart, K. L., Jr.: "The Neomycins and Related Antibiotics." John Wiley and Sons, Inc., New York, 1964.
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4. Daniels, P. J. L.: "Aminoglycosides." Kirk-Othmer Encycl. Chem. Technol., 3rd Ed., 1978, 2, 819-852. 5. Umezawa, S.: "Structures and Syntheses of Aminoglycoside Antibiotics." Adv. Carbohydr. Chem. Biochem., 1974, 30, 111182. 6. Umezawa, S.: "The Chemistry and Conformation of Aminoglycoside Antibiotics." In Mitsuhashi, S., Ed., "Drug Action and Drug Resistance in Bacteria. Vol. 2, Aminoglycoside Antibiotics." University Park Press, Tokyo, 1975; pp. 3-43. 7. Price, Κ. E.; Godfrey, J. C.; Kawaguchi, H.: "Effect of Struc tural Modifications on the Biological Properties of Amino glycoside Antibiotics Containing 2-Deoxystreptamine." Adv. Appl. Microbiol., 1974, 18, 191-307. 8. Tanaka, N.: "Aminoglycoside Antibiotics." In Corcoran, J. W., and Hahn, F. E., Ed., "Antibiotics. III. Mechanism of Action of Antimicrobial and Antitumor Agents." Springer-Verlag, Berlin, 1975; pp. 340-364. 9. Takeda, K.; Aihara, K.; Furumai, T.; Ito, Y.: "Biosynthesis of Butirosins. I. Biosynthetic Pathways of Butirosins and Related Antibiotics." J. Antibiot., 1979, 32, 18-28. 10. Kirby, J. P.; Borders, D. B.; Korshalla, J. H.: "Antibiotic BM408α." U.S. Patent 3,928,317, Dec. 23, 1975; Chem. Abstr., 1976, 84, 149200g. 11. Egan, R. S.; Sinclair, A. C.; De Vault, R. L.; McAlpine, J. B.; Mueller, S. L.; Goodley, P. C.; Stanaszek, R. S.; Cirovic, M.; Mauritz, R. J.; Mitscher, L. Α.; Shirahata, K.; Sato, S.; Iida, T.: "A New Aminoglycoside Antibiotic Complex--The Seldo mycins. III. The Structures of Seldomycin Factors 1 and 2." J. Antibiot., 1977, 30, 31-38.
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
1.
RINEHART AND SHIELD
Aminocyclitol Antibiotics: An Introduction
11
12. McAlpine, J. B.; Sinclair, A. C.; Egan, R. S.; De Vault, R. L.; Stanaszek, R. S.; Cirovic, M.; Mueller, S. L.; Goodley, P. C.; Mauritz, R. J.; Wideburg, Ν. E.; Mitscher, L. Α.; Shirahata, K.; Matsushima, H.; Sato, S.; Iida, T . : "A New Aminoglycoside Antibiotic Complex--The Seldomycins. IV. The Structure of Seldomycin Factor 5." J. Antibiot., 1977, 30, 39-49.
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13. O'Connor, S.; Lam, L. K. T.; Jones, N. D.; Chaney, M. O.: "Apramycin, a Unique Aminocyclitol Antibiotic." J. Org. Chem., 1976, 41, 2087-2092. 14. Egan, R. S.; Stanaszek, R. S.; Cirovic, M.; Mueller, S. L.; Tadanier, J.; Martin, J. R.; Collum, P.; Goldstein, A. W.; De Vault, R. L.; Sinclair, A. C.; Fager, Ε. E.; Mitscher, L. Α.: "Fortimicins A and B, New Aminoglycoside Antibiotics. III. Structural Identification." J. Antibiot., 1977, 30, 552-563. 15. Deushi, T.; Nakayama, M.; Watanabe, I.; Mori, T.; Naganawa, H.; Umezawa, H.: "A New Broad-Spectrum Aminoglycoside Anti biotic Complex, Sporaricin. III. The Structures of Sporari cins A and B." J. Antibiot., 1979, 32, 187-192. RECEIVED November 30, 1979.
In Aminocyclitol Antibiotics; Rinehart, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
