A new aminoglycoside antibiotic complex - The seldomycins. IV. The structure of seldomycin factor 5.

Abstract

Seldomycin factor 5 is shown to be 4-0-[2,6-diamino-2,4,6-trideoxy-a-D-xylo-hexo. pyranosyl]-6-O-[2, 3-diamino-2, 3-dideoxy-4-O-methyl-a-D-xylo-pyranosyl]-2-deoxystreptamine.Seldomycin factor 5 is the most active antibiotic isolated from the fermentation broth of Streptomyces hofunensis. The taxonomy and fermentation of this organism have been described.) The isolation procedure and the physical properties'' of seldomycin factor 5 characterize this antibiotic as a watersoluble basic compound of the aminoglycoside class. The antibacterial spectrum of seldomycin factor 5 indicates that this compound is probably a close relative of the kanamycin-gentamicin group. Moreover, the activity or lack of activity of seldomycin factor 5 against a number of isolates having known mechanisms of resistance, involving in each case the modification of a functional group, was strongly suggestive of the absence or presence of these groups in the structure of seldomycin factor 5.2) Spectrometric analysis of seldomycin factor 5 and a number of degradation products has allowed for the definition of the structure and stereochemistry of this antibiotic. Results and DiscussionThe mass spectrum of the free base of seldomycin factor 5 (Table 1) shows an M+ I peak at 451 amu in agreement with the molecular formula C18H38N6O72) The degradation pattern is indicative of a diglycoside of 2-deoxystreptamine in which each of the three basic carbohydrate units has the same molecular formula, namely C6H,4N203. The per-N-acetyl-per-O-trimethylsilyl derivatives) of seldomycin factor 5 was prepared and the mass spectrum obtained from this derivative (Table 2, Fig. 1) indicates the presence of six primary or secondary amino groups in the parent molecule, two in each of the subunits. Also, each of two adjacent subunits of the parent bears an hydroxyl group.++ Also known as XK-88-5 * Present address:

A comprehensive review of glycosylated bacterial natural products

“…In addition to a few sugars highlighted in the previous paragraph found appended at C-6 of aminoglycoside core aglycons ( 2 , 4 , 8 , 10 , 12 ), 54,62,63 additional sugar diversity has been found at C-6 including: α-D-glucose ( 18 ); 64 3′-amino-3′-deoxy-α-D-xylose 21 (gentamicins and sisomicins) 37,65 and its C-4′-methyl branched 19 (prevalent in a range of aminoglycosides); 51,66,67 C-4′-methyl branched 3′-amino-3′-deoxy-α-D-galactose 20 (combimicins); 56 3′-amino-3′-deoxy-β-L-arabinose ( 22 , gentamicins and related compounds); 37,65 2′-amino-2′-deoxy-α-D-xylose 24 and its corresponding 2′,3′-diamino-2′,3′-dideoxy analog 23 (seldomycins); 58,68 as well as 3′-amino-3′-deoxy-β-D-mannose ( 42 ) and the diasaccharide I [comprised of the uniquely C-6′ oxidized mannose 43 and 2′-amino-2′-deoxy-α-D-xylose ( 24 ) in boholmycin]. 50 Other C-6′-appended sugars include L-streptose ( 28 ), 5′-hydroxy-L-streptose ( 30 ) and the corresponding reduced forms 29 and 31 have been found among streptomycins 69–71 wherein further C-2′ glycosylation of the streptose moiety with 2′-amino-2′-deoxy-α-L-glucose ( 32 ) has been observed.…”

“…12). 79,[178][179][180][181] Naturally-occurring jadomycins are C-8-O-glycosides of a-L-digitoxose (68) and an engineered variant that led to a replacement of this sugar with 6 0 -deoxy-a-L-altrose (62) has been reported. 180 The naturally-occurring B ring Streptomyces metabolite phenanthroviridin and is alternatively conjugated at C-1 to a-D-ristosamine (69).…”

Coevolution: Mankind and Microbes

“…The reader will recall that chelocardin is a product of a micromonospora, and dactylocycline is produced by a Dactylosporangium sp., as relevant examples. Among the fruits of the Abbott-Kyowa effort were the discovery of some additional megalomicins (12, in which R and R 1 are selected from hydrogen, acetyl, and propionyl ester groups) from a Micromonospora, 50,51 seldomycins (13 is factor 5) [52][53][54][55] and the fortimicins (14a is fortimicin A and 14b is fortimicin B), which are usedclinicallyinJapanforthetreatmentofGram-negativeinfections, [56][57][58][59] also from a Micromonospora. [60][61][62][63][64] Chemical ionization mass spectrometry, novel at the time, was very helpful in elucidating the magalomicin's structures, and circular dichroism spectra of molecular complexes formed with copper(II) ion in cupra a solutions contributed strongly to the structure determination and absolute stereochemistry of the seldomycins and the fortimicins.…”

“…The reader will recall that chelocardin is a product of a micromonospora, and dactylocycline is produced by a Dactylosporangium sp., as relevant examples. Among the fruits of the Abbott-Kyowa effort were the discovery of some additional megalomicins ( 12 , in which R and R 1 are selected from hydrogen, acetyl, and propionyl ester groups) from a Micromonospora, , seldomycins ( 13 is factor 5) – and the fortimicins ( 14a is fortimicin A and 14b is fortimicin B), which are used clinically in Japan for the treatment of Gram-negative infections, – also from a Micromonospora. – …”

Synthesis of 3'-deoxyseldomycin 5.

“…Hexa-N-ethoxycarbonyl-3'-O-t osyl sel d omyci n 5 (2), prepared as reported in a previous paper4), was treated with sodium borohydride in DMSO5), affording after usual work-up and chromatography (silica gel) pure hexa-N-ethoxycarbonyl-3'-deoxyseldomycin 5 (3) Removal of the ethoxycarbonyl groups of compound 3 with aq. potassium hydroxidemethanol followed by usual work-up and chromatography(Amberlite CG-50, ammonium cycle) gave 3'-deoxyseldomycin 5 free base (4) The clear evidence that deoxygenation occurred at 3'-position and other functional groups in the molecule remained intact was obtained by comparison of the CMR spectrum of 4 with that of seldomycin 5 and the reported data of gentamicin C,a (5)6) ( Table 1).…”