Discoveries, target identifications, and biological applications of natural products that inhibit splicing factor 3B subunit 1

Pham, Dianne; Koide, Kazunori

doi:10.1039/c5np00110b

Cited by 27 publications

(40 citation statements)

References 81 publications

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“…A number of groups, including the Koide,[11] Webb,[12] Ghosh-Jurica,[13] Hoveyda,[14] Alvarez-Valcárcel,[15] and Nicolaou[17] groups, as well as Koehn and co-workers,[16] have explored the second and third families (Figure 4). In the first example, Webb used a Julia--Kocienski olefination strategy to complete the backbone of 4 ((Figure 4 a, blue), with the C(12)<C->C(13) epoxide being added in the last step.…”

Section: The Chemistry Of Splice Modulationmentioning

confidence: 99%

“…[12] Alternatively, the Koide group’s synthesis of 6 illustrated the use of olefin cross-metathesis to bring together both fragments ((Figure 4 b, blue). [11] The third approach was demonstrated by the Nicolaou group’s synthesis of 8 , which involved the use of a Suzuki coupling to unite the two olefins of the internal diene. [17]…”

Section: The Chemistry Of Splice Modulationmentioning

confidence: 99%

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A Challenging Pie to Splice: Drugging the Spliceosome

et al. 2017

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Since its discovery in 1977, the study of alternative RNA splicing has revealed a plethora of mechanisms that had never before been documented in nature. Understanding these transitions and their outcome at the level of the cell and organism has become one of the great frontiers of modern chemical biology. Until 2007, this field remained in the hands of RNA biologists. However, the recent identification of natural product and synthetic modulators of RNA splicing has opened new access to this field, allowing for the first time a chemical-based interrogation of RNA splicing processes. Simultaneously, we have begun to understand the vital importance of splicing in disease, which offers a new platform for molecular discovery and therapy. As with many natural systems, gaining clear mechanistic detail at the molecular level is key towards understanding the operation of any biological machine. This minireview presents recent lessons learned in this emerging field of RNA splicing chemistry and chemical biology.

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Section: The Chemistry Of Splice Modulationmentioning

confidence: 99%

Section: The Chemistry Of Splice Modulationmentioning

confidence: 99%

A Challenging Pie to Splice: Drugging the Spliceosome

et al. 2017

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“…Der Zugang zu Spleißmodulatoren (SPLMs) hat sich von den frühen Stadien der Naturstoffisolierung [3][4][5] bis zum heutigen Stand der medizinalchemischen Optimierung und zuverlässigen Totalsynthese [6][7][8][9][10][11][12][13][14][15][16][17] weiterentwickelt. Aktuell haben die am besten charakterisierten SPLMs den gleichen Wirkmechanismus ("mode of action", MOA);sie sind gegen die Multiproteinkomponente SF3b innerhalb des kleinen nukleären Ribonukleoproteins (snRNP) U2 im Spliceosom gerichtet.…”

Section: Die Chemie Der Spleißmodulationunclassified

“…Bei unseren Untersuchungen zu 3 (Abbildung 3c) [7] wur- Eine Reihe von Arbeitsgruppen, darunter die von Koide, [11] Webb, [12] Ghosh-Jurica, [13] Hoveyda, [14] Alvarez-Valcµrcel [15] und Nicolaou [17] ebenso wie Koehn et al [16] zweite und dritte Strukturfamilie untersucht (Abbildung 4). Im ersten Beispiel schlug Webb eine Julia-Kocienski-Olefinierungsstrategie ein, um das Gerüst von Fragment 4 zu vervollständigen (Abbildung 4a,b lau), an dem das C(12)-C-(13)-Epoxid im letzten Schritt eingeführt wurde.…”

Section: Herausforderungen Und Lçsungen Bei Der Syntheseunclassified

Das Spliceosom als Angriffspunkt für Pharmaka

et al. 2017

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Seit seiner Entdeckung im Jahr 1977 hat die Untersuchung des alternativen RNA‐Spleißens eine Vielzahl von Mechanismen zutage gefördert, die zuvor aus der Natur noch unbekannt waren. Die Erklärung dieser Umwandlungen und ihrer Resultate auf Ebene von Zellen und Organismen hat sich zu einer wichtigen Stoßrichtung der modernen chemischen Biologie entwickelt. Bis 2007 arbeiteten ausschließlich RNA‐Biologen an diesem Thema. Durch die vor kurzem erfolgte Identifizierung von Naturstoffen und synthetischen Modulatoren des RNA‐Spleißens sind aber auch chemische Untersuchungen des RNA‐Spleißens möglich geworden. Gleichzeitig wurde die Bedeutung des Spleißens bei Erkrankungen erkannt, was eine neue Therapieplattform erschließt. Wie bei vielen natürlichen Systemen ist die Kenntnis mechanistischer Details auf molekularer Ebene der Schlüssel für das Verständnis der Funktion einer biologischen Maschine. Dieser Kurzaufsatz stellt aktuelle Erkenntnisse und Schlussfolgerungen zur Chemie und Biochemie des RNA‐Spleißens vor.

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“…In the search of the mechanism by which Pladienolide B or E-7107 promote the formation of a defective spliceosome, it was found that E7 blocks ATP-dependent remodeling of U2 snRNP that exposes the branch point-binding region. Under this scenario, U2 snRNP fails to bind tightly to the pre-mRNA without disrupting the U2 particle or its association with SF3b [49, 103]. …”

Section: Mechanistic Insightsmentioning

confidence: 99%

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

Martínez-Montiel

Rosas-Murrieta

Martínez-Montiel

et al. 2016

BioMed Research International

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In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types of natural products that have been characterized as splicing inhibitors, the recent advances regarding molecular and cellular effects related to these molecules, and the applications reported so far in cancer therapeutics.

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Discoveries, target identifications, and biological applications of natural products that inhibit splicing factor 3B subunit 1

Cited by 27 publications

References 81 publications

A Challenging Pie to Splice: Drugging the Spliceosome

A Challenging Pie to Splice: Drugging the Spliceosome

Das Spliceosom als Angriffspunkt für Pharmaka

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

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