Belactosin A, a Novel Antitumor Antibiotic Acting on Cyclin/CDK Mediated Cell Cycle Regulation, Produced by Streptomyces sp.

Asai, Akira; Hasegawa, Asako; Ochiai, Keiko; Yamashita, Yoshihisa; Mizukami, Tamio

doi:10.7164/antibiotics.53.81

Cited by 122 publications

(100 citation statements)

References 4 publications

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“…UCK14, exhibits antitumor activity (17), which has been shown to be significantly increased upon acetylation of the free amino group and esterification of the carboxyl group, as well as replacement of the ornithine moiety with lysine to furnish bis-benzylprotected homobelactosin C (18). The latter shows IC 50 values against human pancreoma and colon cancer cells at the low nanomolar level (19).…”

Section: Resultsmentioning

confidence: 99%

Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

Groll

Larionov²,

Huber

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Section: Resultsmentioning

confidence: 99%

Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

Groll

Larionov²,

Huber

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Belactosin A is a tripeptide natural product produced by Streptomyces sp., that comprises L-alanine, 3-(trans-2-aminocyclopropyl)-L-alanine, and a chiral carboxy-β-lactone moiety, 12 and inhibits the proteasome ChT-L activity 13 by acylating the active-site Thr residue via its strained β-lactone opening, as confirmed by X-ray crystallographic analysis. [14][15][16] Due to its proteasome inhibitory activity, belactosin A prevents cell cycle progression at the G2/M stage in tumor cells and is therefore a novel lead for developing potent anticancer agents.…”

mentioning

confidence: 84%

“…[14][15][16] Due to its proteasome inhibitory activity, belactosin A prevents cell cycle progression at the G2/M stage in tumor cells and is therefore a novel lead for developing potent anticancer agents. 12,13 In recent years, we have performed systematic structure-activity relationship (SAR) studies of belactosin A [16][17][18][19] and identified a highly potent proteasome inhibitor 4 (IC 50 = 5.7 nM). However, synthetic accessibility of 4 is too low (total synthetic steps 26) due to its multi-chiral peptidic scaffold.…”

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confidence: 99%

Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A

et al. 2014

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Rational scaffold hopping of the natural product belactosin A derivative was successfully achieved based on the pharmacophore model constructed. The peptidic scaffold was replaced by significantly simplified non-peptidic scaffolds, by which weak belactosin A (IC 50 = 1440 nM) was converted into highly potent non-peptidic inhibitors (IC 50 = 26-393 nM).In the drug discovery process, not only desired biological effect on target biomolecule, but also other various properties such as metabolic stability, membrane permeability, solubility, toxicity profile, and synthetic accessibility of leads, have to be optimized.

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“…B. Belactosin A (12). [48] Dieses enthält eine cyclische b-Lactoneinheit, die als "chemical warhead" ("chemischer Gefechtskopf": für den molekularen Wirkmechanismus einer Verbindung verantwortliche/essenzielle funktionelle Gruppe) auch in einer weiteren, neuartigen Klasse von Proteasominhibitoren dient, die durch eine bicyclische g-Lactam-b-lactonKernstruktur charakerisiert ist.…”

Section: Das Proteasom -Ein Validiertes Target In Derunclassified

Salinosporamid‐Naturstoffe: potente Inhibitoren des 20S‐Proteasoms als vielversprechende Krebs‐Chemotherapeutika

Gulder

Moore

2010

Angewandte Chemie

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Proteasominhibitoren entwickeln sich rasch zu potenten Behandlungsoptionen in der Krebstherapie. Einer der vielversprechensten Wirkstoffkandidaten dieses Typs ist das Salinosporamid A aus dem Bakterium Salinispora tropica. Dieser marine Naturstoff hat einen komplexen, dicht funktionalisierten γ‐Lactam‐β‐lacton‐Pharmakophor, der für die irreversible Bindung zum Target, der β‐Untereinheit des 20S‐Proteasoms, verantwortlich ist. Klinische Studien der Phase I zur Behandlung von multiplem Myelom mit Salinosporamid A begannen nur drei Jahre nach dessen Entdeckung. Die starke biologische Aktivität und die faszinierende Struktur dieser Verbindung haben in den letzten Jahren intensive akademische und industrielle Forschungsarbeiten angetrieben, die zur Entwicklung von mehr als zehn Totalsynthesen, der Aufklärung des Biosyntheseweges und der Generierung vielversprechender Informationen zu Struktur‐Aktivitäts‐Beziehungen sowie onkologischer Daten geführt haben. Salinosporamid A ist daher ein faszinierendes Beispiel für das erfolgreiche Zusammenspiel von moderner Wirkstoffsuche und biomedizinischer Forschung, Medizinalchemie and Pharmakologie, Naturstoffanalyse und ‐synthese sowie Biosynthese und Bioengineering.

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Belactosin A, a Novel Antitumor Antibiotic Acting on Cyclin/CDK Mediated Cell Cycle Regulation, Produced by Streptomyces sp.

Cited by 122 publications

References 4 publications

Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A

Salinosporamid‐Naturstoffe: potente Inhibitoren des 20S‐Proteasoms als vielversprechende Krebs‐Chemotherapeutika

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