Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene

Southgate, Emma H.; Holycross, Daniel R.; Šarlah, David

doi:10.1002/anie.201709712

Cited by 47 publications

(20 citation statements)

References 55 publications

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“…Until now, narciclasine has been isolated from the bulbs of narcissus. However, recent studies have successfully demonstrated organic routes for chemical synthesis of narciclasine and its analogs 26,27 . In this study, we show that compounds that are structurally related to narciclasine also display similar activity, albeit at higher doses.…”

Section: Discussionmentioning

confidence: 99%

Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma

Gopalakrishnan

Matta

Choi

et al. 2020

Sci Rep

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Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma associated with infection by Kaposi sarcoma-associated herpes virus (KSHV). PEL is an aggressive disease with extremely poor prognosis when treated with conventional chemotherapy. Narciclasine, a natural product present in Amaryllidaceae family of flowering plants including daffodils, belongs to a class of molecules termed 'isocarbostyril alkaloid'. We have found that narciclasine displays preferential cytotoxicity towards PEL at low nanomolar concentrations and is approximately 10 and 100-fold more potent than its structural analogs lycoricidine and lycorine, respectively. Narciclasine arrested cell-cycle progression at the G 1 phase and induced apoptosis in PEL, which is accompanied by activation of caspase-3/7, cleavage of PARP and increase in the surface expression of Annexin-V. Although narciclasine treatment resulted in a marked decrease in the expression of MYC and its direct target genes,time-course experiments revealed that MYC is not a direct target of narciclasine. Narciclasine treatment neither induces the expression of KSHV-RTA/ORF50 nor the production of infectious KSHV virions in PEL. Finally, narciclasine provides dramatic survival advantages to mice in two distinct mouse xenograft models of PEL. In conclusion, our results suggest that narciclasine could be a promising agent for the treatment of PEL. Primary effusion lymphoma (PEL) is an aggressive type of non-Hodgkin lymphoma with extremely poor prognosis when treated with conventional chemotherapy. The presence of KSHV in all tumor cells is the defining feature of PEL 1. Upon diagnosis with PEL, the median survival time of patients is only 3 to 6 months 2. Therefore, there is an immediate need to identify novel treatment options for PEL. Narciclasine (also known as lycoricidinol) is a natural product found in daffodils and other flowering plants belonging to the Amaryllidaceae (amaryllis) family. Narciclasine has been shown to possess potent anticancer activity against tumors of brain, skin and breast 3. Earlier studies have shown that translation elongation factor eEF1A is the direct target of narciclasine 4,5. Further, it has been found that narciclasine triggers actin stress fiber formation by activation of a small GTPase, RhoA 5,6. Recently, narciclasine was named 'Molecule of the Week' by American Chemical Society (ACS) for its potential as a cancer drug. MYC regulates numerous cellular activities, including signal transduction, cell cycle, proliferation, differentiation and apoptosis. MYC is deregulated in many cancers, and has been implicated in almost a third of all cancers 7. Even though, the Myc genomic locus is structurally intact in PEL, they modestly overexpress MYC and we have shown that compounds that down regulate MYC expression are effective and selective against PEL 8. In this study, we tested the effect of narciclasine and its structural analogs on a panel of cell lines comprising five hematological malignancies. We show that while all the cancer cell lines i...

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Section: Discussionmentioning

confidence: 99%

Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma

Gopalakrishnan

Matta

Choi

et al. 2020

Sci Rep

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“…Sarlah's research involves the discovery of new reactivities and guiding principles for organic synthesis and their application towards biologically active natural products and methods development. His group has described a total synthesis of lycoricidine and narciclasine and an arenophile‐mediated dearomative reduction in Communications in Angewandte Chemie .…”

Section: Awarded …mentioning

confidence: 99%

KNCV Gold Medal: Pascal Jonkheijm / Werner Prize: J. Luterbacher / Grammaticakis‐Neumann Award: D. Sarlah

2019

Angew Chem Int Ed

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“…Sarlah untersucht neue Reaktivitäten und Leitprinzipien in der organischen Synthese und wendet diese auf den Gebieten der biologisch aktiven Naturstoffe und der Methodenentwicklung an. Seine Gruppe beschrieb eine Totalsynthese von Lycoricidin und Narciclasin sowie eine Arenophil‐vermittelte Reduktion unter Desaromatisierung in Angewandte‐Chemie ‐Zuschriften.…”

Section: Ausgezeichnet …unclassified

KNCV‐Goldmedaille: Pascal / Jonkheijm Werner‐Preis: J. Luterbacher / Grammaticakis‐Neumann‐Preis: D. Sarlah

2019

Angewandte Chemie

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Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene

Cited by 47 publications

References 55 publications

Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma

Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma

KNCV Gold Medal: Pascal Jonkheijm / Werner Prize: J. Luterbacher / Grammaticakis‐Neumann Award: D. Sarlah

KNCV‐Goldmedaille: Pascal / Jonkheijm Werner‐Preis: J. Luterbacher / Grammaticakis‐Neumann‐Preis: D. Sarlah

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