Total Synthesis of 6‑Deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 Cancer Cell Line

A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic...

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Veröffentlicht in:	Organic letters 2014-11, Vol.16 (21), p.5560-5563
Hauptverfasser:	Arai, Kenzo, Buonamici, Silvia, Chan, Betty, Corson, Laura, Endo, Atsushi, Gerard, Baudouin, Hao, Ming-Hong, Karr, Craig, Kira, Kazunobu, Lee, Linda, Liu, Xiang, Lowe, Jason T, Luo, Tuoping, Marcaurelle, Lisa A, Mizui, Yoshiharu, Nevalainen, Marta, O’Shea, Morgan Welzel, Park, Eun Sun, Perino, Samantha A, Prajapati, Sudeep, Shan, Mingde, Smith, Peter G, Tivitmahaisoon, Parcharee, Wang, John Yuan, Warmuth, Markus, Wu, Kuo-Ming, Yu, Lihua, Zhang, Huiming, Zheng, Guo-Zhu, Keaney, Gregg F
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Binding Sites Cell Line, Tumor - chemistry Cell Line, Tumor - drug effects Cell Proliferation - drug effects Epoxy Compounds - chemical synthesis Epoxy Compounds - chemistry Epoxy Compounds - metabolism Humans Macrolides - chemical synthesis Macrolides - chemistry Macrolides - metabolism Phosphoproteins - antagonists & inhibitors Phosphoproteins - chemistry Ribonucleoprotein, U2 Small Nuclear - antagonists & inhibitors Ribonucleoprotein, U2 Small Nuclear - chemistry RNA Splicing - drug effects RNA Splicing Factors
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Zusammenfassung:	A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
ISSN:	1523-7060 1523-7052
DOI:	10.1021/ol502556c