Novel semi-synthetic nocathiacin antibiotics: synthesis and antibacterial activity of bis- and mono-O-alkylated derivatives

Regueiro‐Ren, Alicia; Naidu, B. Narasimhulu; Zheng, Xiaofan; Hudyma, Thomas W.; Connolly, Timothy P.; Matiskella, John D.; Zhang, Yunhui; Kim, Oak K.; Sorenson, Margaret E.; Pucci, Michael J.; Clark, Junius M.; Bronson, Joanne J.; Ueda, Yasutsugu

doi:10.1016/j.bmcl.2003.09.061

Cited by 35 publications

(21 citation statements)

References 13 publications

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“…Most of the chemical modifications were made on the hydroxyl groups that are present in the structure. 7,8 The structures of nocathiacin I and its analogs were characterized using a standard suite of 2D NMR experiments. One specific experiment, 1 H-15 N HMBC, was extremely valuable for establishment of connectivities, as the molecule contains 14 nitrogen atoms.…”

Section: Resultsmentioning

confidence: 99%

Observation of OH…N scalar coupling across a hydrogen bond in nocathiacin I

Huang

Liu

Constantine

et al. 2007

Magnetic Reson in Chemistry

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We report here the observation of O-H...N hydrogen-bond (1h)J(N,OH) scalar coupling in a biologically active natural product. The intramolecular hydrogen bond between the threonine hydroxyl (Thr-OH) group and the thiazolyl nitrogen at the second thiazole ring (Thz-2) in nocathiacin I was directly detected by a 1H-15N HMBC NMR experiment. The magnitude of the scalar coupling constant (1h)J(N,OH) was accurately measured to be 1.8 +/- 0.1 Hz by a J-resolved 1H-15N HMBC experiment. By adding the O-H...N distance restraint, the 3D solution structure of nocathiacin I was refined. The structure refinement indicated that the distance between the Thr-3 hydroxyl hydrogen and the Thz-2 nitrogen is or= 0.23 A. The presence of an intramolecular hydrogen bond in nocathiacin I is further supported by a number of NMR parameters and additional NMR experiments. This observation provides valuable information for characterizing molecular conformations, and for studying structure-activity relationships.

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Section: Resultsmentioning

confidence: 99%

Observation of OH…N scalar coupling across a hydrogen bond in nocathiacin I

Huang

Liu

Constantine

et al. 2007

Magnetic Reson in Chemistry

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“…Fractions of 40 mL were collected. Compounds of interest eluted in fractions [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. These fractions were pooled and concentrated to dryness to give 4.5 g of oily material.…”

Section: Methodsmentioning

confidence: 99%

Thiazomycins, Thiazolyl Peptide Antibiotics from Amycolatopsis fastidiosa

et al. 2009

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Thiazolyl peptides are a class of highly rigid trimacrocyclic compounds consisting of varying but large numbers of thiazole rings. The need for new antibacterial agents to treat infections caused by resistant bacteria prompted a reinvestigation of this class, leading to the previous isolation of thiazolyl peptides, namely, thiazomycin (5) and thiazomycin A (6), congeners of nocathiacins (1-4). Continued chemical screening led to the isolation of six new thiazolyl peptide congeners (8-13), of which three had truncated structures lacking an indole residue. From these, compound 8 showed activity similar to thiazomycin. Two compounds (9 and 10) showed intermediate activities, and the three truncated compounds (11-13) were essentially inactive. The discovery of the truncated compounds revealed the minimal structural requirements for activity and suggested probable biosynthetic pathways for more advanced compounds. The isolation, structure elucidation, antibacterial activity, and proposed biogenesis of thiazomycins are herein described.

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“…[41] Andere beschriebene Modifikationen von Nocathiacin I sind die selektive Substitution einer der beiden reaktiven Hydroxygruppen am Molekül, 2-Hydroxypyridyl-und NHydroxyindolyl-, was uns zu regioselektiven Alkylierungen und zur Bildung von Carbamaten und Phosphonaten führt. [42,43] Einfach (14) [50,51] die modifiziert oder sogar entfernt werden kann. Wird sie entfernt, entsteht an ihrer Stelle in derselben Weise ein Glycinrest, wie dies am Thiomuracin A durch Transformation mçglich ist (Abbildung 4 c,d).…”

Section: Einführungunclassified

“…[41] Andere beschriebene Modifikationen von Nocathiacin I sind die selektive Substitution einer der beiden reaktiven Hydroxygruppen am Molekül, 2-Hydroxypyridyl-und N-Hydroxyindolyl-, was uns zu regioselektiven Alkylierungen und zur Bildung von Carbamaten und Phosphonaten führt. [42,43] Einfach (14)…”

Section: Verschiedenartige Ansätze Zur Erzeugung Von Thiopeptidanalogaunclassified

Engineering von Thiopeptiden: ein multidisziplinärer Weg zu neuen Wirkstoffen

2014

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Durch jüngste Entwicklungen auf dem Gebiet der Thiopeptid‐Antibiotika‐Analoga konnten einige der Limitierungen dieser natürlich vorkommenden Substanzen überwunden werden. Chemische Synthesen, semisynthetische Derivatisierungen und die Umgestaltung von Biosynthesewegen haben unabhängig voneinander zu sich ergänzenden Modifikationen verschiedener Thiopeptide geführt. Einige der so gewonnenen neuen Substanzen zeigen verbesserte Wirkprofile, und das nicht nur als Antibiotika, sondern auch als Antimalaria‐ und Antikrebswirkstoffe. Der planerische Entwurf neuartiger Moleküle auf der Grundlage von Thiopeptidgerüsten stellt sich als die einzige Strategie für die volle Nutzung des großen Potenzials, das sie in vitro zeigen, dar. Hier stellen wir die wichtigsten Ergebnisse auf dem Gebiet der Herstellung von Thiopeptidanaloga vor und diskutieren, wie die unterschiedlichen Ansätze sich zu einer multidisziplinären Strategie zusammenführen lassen.

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Novel semi-synthetic nocathiacin antibiotics: synthesis and antibacterial activity of bis- and mono-O-alkylated derivatives

Cited by 35 publications

References 13 publications

Observation of OH…N scalar coupling across a hydrogen bond in nocathiacin I

Observation of OH…N scalar coupling across a hydrogen bond in nocathiacin I

Thiazomycins, Thiazolyl Peptide Antibiotics from Amycolatopsis fastidiosa

Engineering von Thiopeptiden: ein multidisziplinärer Weg zu neuen Wirkstoffen

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