James B. Morton

The megalomicins. Part 7. A structural revision by carbon-13 nuclear magnetic resonance and X-ray crystallography. Synthesis and conformational analysis of 3-dimethylamino- and 3-azido-D- and -L-hexopyranosides, and the crystal structure of 4″-O-(4-lodobenzoyl)megalomicin A

An X-ray crystallographic study on 4″-O-(4-iodobenzoyl)megalomicin A has led to the revision of the structures of the megalomicins and the XK-41 antibiotics. Crystals are orthorhombic, space group P212121 with a= 12.669(2), b= 19.501 (6), c= 25.741 (9)A, and Z= 4. The structure was solved by the heavy-atom technique, and 1 812 observed reflections led to a final R of 0.095. The novel amino-sugar previously thought to be D-rhodosamine has been shown to have the L-configuration and is therefore renamed L-megosamine. It has also been shown to be glycosidically attached to the tertiary 6-hydroxy group. The 13C n.m.r. and circular dichroism (c.d.) parameters of these macrolides are described. The syntheses of methyl α- and β-D-rhodosaminide, methyl α- and β-D-megosaminide, methyl α- and β-L-megosaminide, methyl α- and β-D-angolosaminide, and methyl 2,3,6-trideoxy-3(dimethylamino)-α-D-xylo-hexopyranoside are described and their conformations and 13C n.m.r. parameters are discussed. Methyl α-D- and -L-amicetoside, methyl α-D- and -L-cineruloside and other model 4-oxopyranosides and pyrans have been synthesized. Their c.d. properties have been determined and they have been shown to exhibit Anti-Octant behaviour.

Structures of the aminoglycoside antibiotics 66–40B and 66–40D produced by Micromonospora inyoensis

The novel amino-glycoside antibiotics 66–40B and 66–40D produced as minor components by fermentation of Micromonospora inyoensis have been shown to be O-2,6-diamino-2,3,4,6-tetradeoxy-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-3-methylamino-α-D-xylopyranosyl-(1→6)]-2-deoxy-D-streptamine and O-2,6-diamino-2,3,4,6-tetradeoxy-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-3-methylamino-β-L-arabinopyranosyl-(1→6)]-2-deoxy-D-streptamine, respectively. The novel 3-deoxy-3-methylamino-β-L-arabinopyranosyl sugar unit of 66–40D has not previously been found in any amino-glycoside antibiotic. Both 66–40B and D exhibit broad spectrum antibacterial activity.

Isolation of a novel morphinan 3-O-diglucuronide metabolite from dog urine.

Following oral administration of the narcotic antagonist nalmefene [17-(cyclopropyl-methyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol] labeled with 14C to the dog, approximately 50% of the dose was excreted in the urine as a highly polar water-soluble conjugate. Although this major metabolite could be hydrolyzed with β-glucuronidase to yield nalmefene, the intact conjugate was chromatographically more polar on reversed-phase high-performance liquid chromatography (HPLC) than authentic nalmefene 3-O-glucuronide. Milligram quantities of the metabolite were subsequently isolated and subjected to fast atom bombardment (FAB) mass spectral and nuclear magnetic resonance (NMR) analyses. The conjugate was identified as nalmefene 3-O-β-diglucuronide with a 1,2-β linkage between the two glucuronic acids. It is unlikely that this novel form of conjugate is unique to nalmefene and it is probably a metabolite of other morphinans and/or similar drugs in the dog. Nalmefene 3-O-diglucuronide is not a metabolite of nalmefene in man.

Semisynthetic aminoglycoside antibacterials. Part 10. Synthesis of novel 1-N-aminoalkoxycarbonyl and 1-N-aminoalkylcarboxamido derivatives of sisomicin, gentamicin B, gentamicin C1a, and kanamycin A

Suitably protected derivatives of sisomicin, 5-epi-sisomicin, gentamicin B, gentamicin C1a, and kanamycin A have been converted into a series of 1-N-alkoxycarbonyl, 1-N-alkoxycarbonyl, 1-N-carboxamido, 1-N-alkylcarboxamido, and 1-N-aminoalkylcarboxamido derivatives. Representative thio-analogues have also been prepared. 13C N.m.r. studies have revealed that these novel semisynthetic aminoglycosides have different solution conformations about the C-6–O glycosidic bond relative to the parent aminoglycosides from which they are derived.

Complete 1H and 13C NMR Assignments of the Oligosaccharide Antibiotic Sch 27899

The complete assignments of 1H and 13C data for Sch 27899 are described. The compound is an oligosaccharide antibiotic belonging to the class everninomicin. It has a molecular mass of 1629. The assignments are based on 2D HMQC, HMQC‐TOCSY and HMBC experiments.

Semisynthetic aminoglycoside antibacterials. Part 9. Synthesis of novel 1- and 3-substituted and 1- and 3-epi-substituted derivatives of sisomicin and gentamicin from the 1- and 3-oxo-derivatives

The conversion of selectively protected gentamicin and sisomicin derivatives into the 1- and 3-oxo-compounds by reaction with 3,5-di-t-butyl-1,2-benzoquinone is described. By application of suitable reductive techniques these oxo-aminoglycosides have been converted into novel 1- and 3-epi-, 1- and 3-deamino-1- and -3-hydroxy-, 1- and 3-deamino-1- and -3-epi-hydroxy-, and 1-deamino-derivatives. A study of the 13C n.m.r. parameters of the 1-epi- and 1-deamino-derivatives has led to the assignment of novel solution conformations for these new aminoglycosides.

Semisynthetic aminoglycoside antibacterials. Part 11. Solution conformations of semisynthetic and naturally occurring aminoglycoside antibiotics

A critical analysis of the 13C n.m.r. spectral data for a wide range of naturally occurring aminoglycoside antibiotics, as well as for a diverse assortment of semisynthetic aminoglycoside antibacterials, has revealed new insights into the solution conformation of these clinically important drugs. Correlation of the Δδc values for C-4 and C-6 determined in going from deoxystreptamine to the pseudo di-or tri-saccharides, as well as changes in the chemical shifts of C-1′ and C-1″, has revealed that these molecules adopt a wide range of well defined conformations in solution, that are dependent not only on the structure, but also the pH. The limitations of the ‘Nagabhushan–Daniels Rule,’ which has been reported to break down when applied to some classes of aminoglycosides, are discussed in the light of these new observations.

Structure of halomicin B

The antibiotic halomicin B has been shown by spectroscopic and chemical means to have the structure (1).

Structure of aminoglycoside 66-40 C, a novel unsaturated imine produced by Micromonospora inyoensis

The aminoglycoside 66-40 C, produced as a minor component in the fermentation of Micromonospora inyoensis, has been shown by spectroscopic and chemical degradative studies to have the novel dimeric structure (5), containing αβ-unsaturated imine groups not previously encountered in any aminoglycoside antibiotic.

Structure and absolute stereochemistry of everninose, a non-reducing sugar obtained on hydrolysis of everninomicin D

Everninose, a hydrolysis product of everninomicin B and D, has been shown to possess structure (I).