Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues

J Nat Prod. 2014 Aug 22;77(8):1864-70. doi: 10.1021/np500342m.

Haiyin He ¹, Anokha S Ratnayake ¹, Jeffrey E Janso ¹, Min He ², Hui Y Yang ³, Frank Loganzo ⁴, Boris Shor ⁴, Christopher J O'Donnell ¹, Frank E Koehn ¹

Affiliations

1 Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
2 Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health , 9609 Medical Center Drive, Bethesda, Maryland 20892, United States.
3 Novartis Institutes for BioMedical, Research, Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
4 Pfizer Oncology , 401 N. Middletown Road, Pearl River, New York 10965, United States.

PMID: 25098528 DOI: 10.1021/np500342m

Abstract

The spliceostatin class of Natural Products was reported to be potent cytotoxic agents via inhibition of the spliceosome, a key protein complex in the biosynthesis of mature mRNA. As part of an effort to discover novel leads for Cancer chemotherapy, we re-examined this class of compounds from several angles, including fermentation of the producing strains, isolation and structure determination of new analogues, and semisynthetic modification. Accordingly, a group of spliceostatins were isolated from a culture broth of Burkholderia sp. FERM BP-3421, and their structures identified by analysis of spectroscopic data. Semisynthesis was performed on the major components 4 and 5 to generate ester and amide derivatives with improved in vitro potency. With their potent activity against tumor cells and unique mode of action, spliceostatins can be considered potential leads for development of Cancer drugs.

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