Aminocyclitol Antibiotics: An Introduction

Transcription

1 1 Aminocyclitol Antibiotics: An Introduction KENNETH L. RINEHART, JR. and LOIS S. SHIELD Roger Adams Laboratory, University of Illinois, Urbana, IL Aminocyclitol antibiotics constitute an important class of clinically useful therapeutic agents, whose discovery dates from that of streptomycin in These compounds, which are less precisely, though widely, also referred to as aminoglycoside antibiotics, include some of the most successful commercial antibiotics and new members of the class are being added yearly. Numerous reviews of aminocyclitols are available (1-8), providing references to the individual antibiotics. Thus, the present introductory 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 deoxystreptamines include neomycins, paromomycins, lividomycins and 2230-C (Figure 1). These pseudotetra- and pseudopentasaccharides all contain one or more diaminohexoses. Another group of 4,5- disubstituted deoxystreptamine antibiotics consists of pseudotrisaccharides, including ribostamycin, xylostasin, the butirosins and the compounds now referred to (9) as 6'-deamino-6'-hydroxybutirosins (formerly BU-1709 E 1 and E 2 ), and LL BM408α (10) (Figure 2). These compounds are characterized by a di- or monoaminohexose and a ribose or xylose substituent and in some members of the class the 1-amino group of deoxystreptamine is substituted 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 compounds (Figure 5), and the dehydro analogs of the gentamicins X/80/ $05.00/ American Chemical Society

2 2 AMINOCYCLITOL ANTIBIOTICS NH Figure 1. Neomycin group of 4,5-disubstituted deoxystreptamine antibiotics (1) CH 2 R -Q woh R"NH 9 HOCHj>o R R' R" pl R,v RIBOSTAMYCIN NH 2 OH Η Η OH XYLOSTASIN NH 2 OH Η OH Η BUTIROSIN A NH 2 OH * OH Η BUTIROSIN Β NH 2 OH * Η OH 4-DE0XYBUTIR0SIN A NH 2 Η * OH Η 4-DE0XYBUTIR0SIN Β NH 2 Η * Η OH LL BM408a OH OH Η Η OH DAH-BUTIROSIN A OH OH * OH Η DAH-BUTIROSIN Β OH OH * Η OH *R"«-C0CH0HCH 2 CH 2 NH 2 Figure 2. Ribostamycin group of 4,5-disubstituted deoxystreptamine antibiotics w

3 RINEHART AND SHIELD Aminocyclitol Antibiotics: An Introduction CH 2 R R R' _?! _R^ KANAMYCIN A NH 2 OH OH Η KANAMYCIN Β NH 2 OH NH 2 Η KANAMYCIN C OH OH NH 2 Η TOBRAMYCIN NH 2 Η NH 2 Η NEBRAMYCIN FACTOR 4 NH 2 OH NH 2 CONH 2 NEBRAMYCIN FACTOR 5' NH 2 Η NH 2 CONH 2 Figure 3. Kanamycin group of 4,6-disubstituted deoxystreptamine antibiotics (1) CH,R JL Ji. SELDOMYCIN FACTOR I OH OH 2 NH 2 Η 3 NH 2 OH 5 NH 2 Η 'R"= NH 9 NH 9 Figure 4. Seldomycin group of 4,6-disubstituted deoxystreptamine antibiotics (1)

4 4 AMINOCYCLITOL ANTIBIOTICS RCHR* R R 1 R" R... R,v R v R VI R v " GENTAMICIN A H OH OH OH NH 2 H OH A, H OH OH OH NH 2 OH H A 2 H OH OH OH NH 2 H OH OH A, H NH 2 OH OH OH OH H NHCH S A 4 H OH OH OH NH 2 H OH N(CHO)CH 3 *2 H OH OH OH NH t Β H NH 2 OH OH OH Β, CH 3 NH 2 OH OH NH 2 c, CH 3 H H NH 2 c,. H NH 2 H H NH 2 c2 CH 3 NH 2 H H NH 2 C 20 * CH 3 NH 2 H H NH 2 C 2b * CCJ H H H NH 2 G-418 CH 3 OH OH OH NH 2 (GENTAMICIN X e ) H NH 2 OH OH NH 2 JI-20B CH 3 NH 2 OH OH NH 2 STEREOISOMER OF C 2 * SAG AM ICI Ν at C-6' Figure 5. Gentamicin group of 4,6-disubstituted deoxystreptamine antibiotics (1) RCHNHR' Figure 6. Sisomicin group of 4,6-disubstituted deoxystreptamine antibiotics (I)

5 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 aminocyclitol (actinamine) is fully 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 N- methylated and sometimes substituted further by an acyl group. The fortimicins are presently undergoing clinical trial. Finally, a very few structurally dissimilar aminocyclitol antibiotics contain a monoaminocyclitol (Figure 12). The first of these reported was hygromycin A; other representatives are minosaminomycin and the validamycins, which contain a single amino group linked to two separate cyclitol rings, each with a branching hydroxymethyl substituent. The present volume covers a number of aspects of aminocyclitol 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. Still 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 to use Figures 1-10 and 12, which have been adapted from those appearing in J. Antibiot., (1976).

6 6 AMINOCYCLITOL ANTIBIOTICS CH,NH OH HOÇHz ^ t>" Figure 7. Apramycin, a monosubstituted deoxystreptamine antibiotic (1) H.N A /NH 2 \ NH 2 OH R R' R" η" R,V R V DESTOMYCIN A Η CH 3 Η ΟΗ Η * DESTOMYCIN Β Η CH S CH 3 Η ΟΗ t DESTOMYCIN C Η CH 3 CH 3 ΟΗ Η * HYGROMYCIN Β Η Η CH 3 ΟΗ Η * SS-56 A Η Η Η Η ΟΗ Η SS-56 Β Η Η Η ΟΗ Η Η SS-56 C ΟΗ Η Η ΟΗ Η * A (SS-56D) Η Η Η ΟΗ Η * *R Y * DESTOMIC ACID (ORTHO ESTER) * HOÇH 2 VM4-EPIDEST0MIC ACID (ORTHO ESTER) Figure 8. Destomycin group of monosubstituted deoxystreptamine antibiotics (l)

7 1. RINEHART AND SHIELD Aminocyclitol Antibiotics: An Introduction 7 NHCNH, Figure 9. Aminocyclitol antibiotics containing actinamine (1). Spectinomycin (hydrate form): X = Y = OH; dihydrospectinomycin: X = H, Y = OH R R' 31 _R!" _Ri v STREPTOMYCIN -NHC(«NH)NH 2 CHO H H CH S N-DEMETHYLSTREPTOMYCIN -NHC(-NH)NH 2 CHO H H H HYDROXYSTREPTOMYCIN -NHC(-NH)NH 2 CHO OH H CH, MANNOSIDOSTREPTOMYCIN -NHC(-NH)NH 2 CHO H» CH 3 MANNOSIDOHYDROXYSTREPTOMYCIN -NHC(-NH)NH 2 CHO OH * CH 3 DIHYDROSTREPTOMYCIN -NHC(-NH)NH 2 CH 2 OH H H CH 3 BLUENSOMYCIN -0C0NH 2 CH 2 OH H H CH 3 CH 2 OH OH HO Figure 10. Aminocyclitol antibiotics containing streptidine or bluensidine (1)

8 8 AMINOCYCLITOL ANTIBIOTICS CH 3NR' Figure 11. Fortimicins and R R[ R 1 " R,V C H 3 COCH 2 NH 2 OH H NH 2 3 H OH H NH 2 C H CH 3 COCH 2 NHCONH 2 OH H NH 2 H COCHgNHg OH H NH 2 H H OH H NH 2 CH 3 COCHgNHg H NH 2 H CH 3 H H NH 2 H?, 1,4-diaminocyclitol antibiotics

9 1. RINEHART AND SHIELD Aminocyclitol Antibiotics: An Introduction 9 HYGROMYCIN A Figure 12. Monoaminocyclitol antibiotics (I)

10 10 AMINOCYCLITOL ANTIBIOTICS Literature Cited 1. Rinehart, K. L., Jr.; Stroshane, R. M.: "Biosynthesis of Aminocyclitol Antibiotics." J. Antibiot., 1976, 29, Rinehart, K. L., Jr.: "Mutasynthesis of New Antibiotics." Pure and Appl. Chem., 1977, 49, Rinehart, K. L., Jr.: "The Neomycins and Related Antibiotics." John Wiley and Sons, Inc., New York, Daniels, P. J. L.: "Aminoglycosides." Kirk-Othmer Encycl. Chem. Technol., 3rd Ed., 1978, 2, Umezawa, S.: "Structures and Syntheses of Aminoglycoside Antibiotics." Adv. Carbohydr. Chem. Biochem., 1974, 30, 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 Price, Κ. E.; Godfrey, J. C.; Kawaguchi, H.: "Effect of Structural Modifications on the Biological Properties of Aminoglycoside Antibiotics Containing 2-Deoxystreptamine." Adv. Appl. Microbiol., 1974, 18, 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 Takeda, K.; Aihara, K.; Furumai, T.; Ito, Y.: "Biosynthesis of Butirosins. I. Biosynthetic Pathways of Butirosins and Related Antibiotics." J. Antibiot., 1979, 32, Kirby, J. P.; Borders, D. B.; Korshalla, J. H.: "Antibiotic BM408α." U.S. Patent 3,928,317, Dec. 23, 1975; Chem. Abstr., 1976, 84, g. 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 Seldomycins. III. The Structures of Seldomycin Factors 1 and 2." J. Antibiot., 1977, 30,

11 1. RINEHART AND SHIELD Aminocyclitol Antibiotics: An Introduction 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, O'Connor, S.; Lam, L. K. T.; Jones, N. D.; Chaney, M. O.: "Apramycin, a Unique Aminocyclitol Antibiotic." J. Org. Chem., 1976, 41, 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, Deushi, T.; Nakayama, M.; Watanabe, I.; Mori, T.; Naganawa, H.; Umezawa, H.: "A New Broad-Spectrum Aminoglycoside Antibiotic Complex, Sporaricin. III. The Structures of Sporaricins A and B." J. Antibiot., 1979, 32, RECEIVED November 30, 1979.