Synthesis and antibacterial activity of nocathiacin I analogues

Naidu, B. Narasimhulu; Sorenson, Margaret E.; Matiskella, John D.; Li, Wenying; Sausker, Justin B.; Zhang, Yunhui; Connolly, Timothy P.; Lam, Kentson; Bronson, Joanne J.; Pucci, Michael J.; Yang, Hao; Ueda, Yasutsugu

doi:10.1016/j.bmcl.2006.03.079

Cited by 44 publications

(26 citation statements)

References 17 publications

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“…Due to the promising antibacterial activity of nocathiacins and to the presence of several functional groups in their structure suitable for chemical manipulation, some research groups reported the semi-synthetic derivatives of these natural products in order to improve aqueous solubility while maintaining the intrinsic biological activity [93,94]. Representative N- hydroxyindole scaffold-based semi-synthetic products 49a-c in Table 2 were obtained by the addition of amines to the dehydroalanine side chain of nocathiacin I, in particular primary, secondary and cyclic amines with different functional groups were inserted to create analogues of nocathiacin I.…”

Section: N-hydroxy-substituted Fused Five-membered Ring Systemsmentioning

confidence: 99%

Bioactive heterocycles containing endocyclic N-hydroxy groups

Rani

Granchi

2015

European Journal of Medicinal Chemistry

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Drug-likeness rules consider N-O single bonds as “structural alerts” which should not be present in a perspective drug candidate. In most cases this concern is correct, since it is known that N-hydroxy metabolites of branded drugs produce reactive species that cause serious side effects. However, this dangerous reactivity of the N-OH species generally takes place when the nitrogen atom is not comprised in a cyclic moiety. In fact, the same type of metabolic behavior should not be expected when the nitrogen atom is included in the ring of an aromatic heterocyclic scaffold. Nevertheless, heterocycles bearing endocyclic N-hydroxy portions have so far been poorly studied as chemical classes that may provide new therapeutic agents. This review provides an overview of N-OH-containing heterocycles with reported bioactivities that may be considered as therapeutically relevant and, therefore, may extend the chemical space available for the future development of novel pharmaceuticals. A systematic treatment of the various chemical classes belonging to this particular family of molecules is described along with a discussion of the biological activities associated to the most important examples.

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Section: N-hydroxy-substituted Fused Five-membered Ring Systemsmentioning

confidence: 99%

Bioactive heterocycles containing endocyclic N-hydroxy groups

Rani

Granchi

2015

European Journal of Medicinal Chemistry

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“…[34] Alternatively, the Dha residue can be hydrogenated diastereoselectively to obtain the corresponding Ala side chain (10), which can be further modified: it can be converted enzymatically into acid 11 to introduce solubilizing groups, such as in 12, which should facilitate their formulation without losing potency ( Figure 5 b). [35] Degrada- [a] Activity and solubility values of the natural product appear in brackets next to that of the analogue. BLD: below limit of detection.…”

Section: Angewandte Reviewsmentioning

confidence: 99%

Thiopeptide Engineering: A Multidisciplinary Effort towards Future Drugs

2014

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The recent development of thiopeptide analogues of antibiotics has allowed some of the limitations inherent to these naturally occurring substances to be overcome. Chemical synthesis, semisynthetic derivatization, and engineering of the biosynthetic pathway have independently led to complementary modifications of various thiopeptides. Some of the new substances have displayed improved profiles, not only as antibiotics, but also as antiplasmodial and anticancer drugs. The design of novel molecules based on the thiopeptide scaffold appears to be the only strategy to exploit the high potential they have shown in vitro. Herein we present the most relevant achievements in the production of thiopeptide analogues and also discuss the way the different approaches might be combined in a multidisciplinary strategy to produce more sophisticated structures.

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“…[34] Alternativ dazu kann der Dha-Rest diastereoselektiv hydriert werden, um zu der Ala-Seitenkette (10) zu gelangen, die weiter modifiziert werden kann: Sie lässt sich enzymatisch in die Säure 11 umwandeln, um, wie in 12, die Lçslichkeit erhçhende Gruppen einzuführen, die ihre pharmazeutische Formulierung erleichtern sollten, ohne die Wirkung zu beeinträchtigen (Abbildung 5 b). [35] Der Abbau des Schwanzteils ist ebenfalls vielfach durchgeführt worden und gestattet je nach den gewählten Reaktionsbedingungen den Zugang zu zwei verschiedenen Produkten: dem Thiazol-4-carbonsäure-Derivat (Nocathiacinsäure) oder dem entsprechenden Amid (Nocathiacin IV). [36,37] Nocathiacinsäure muss nicht zur Steigerung der Lçslichkeit modifiziert werden, oder sie kann nachfolgend mit Aminen kondensiert werden.…”

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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Synthesis and antibacterial activity of nocathiacin I analogues

Cited by 44 publications

References 17 publications

Bioactive heterocycles containing endocyclic N-hydroxy groups

Bioactive heterocycles containing endocyclic N-hydroxy groups

Thiopeptide Engineering: A Multidisciplinary Effort towards Future Drugs

Engineering von Thiopeptiden: ein multidisziplinärer Weg zu neuen Wirkstoffen

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