title: Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues.
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.
authors.affiliation: Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Haiyin
authors.initials: H
authors.lastname: He
authors.affiliation: Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Anokha S
authors.initials: AS
authors.lastname: Ratnayake
authors.affiliation: Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Janso
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: Novartis Institutes for BioMedical, Research, Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Pfizer Oncology , 401 N. Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.affiliation: Pfizer Oncology , 401 N. Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Boris
authors.initials: B
authors.lastname: Shor
authors.affiliation: Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Koehn
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019117:Burkholderia / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011714:Pyrans; D012333:RNA, Messenger; D013141:Spiro Compounds; C553684:spliceostatin A