title: Botryllamides: natural product inhibitors of ABCG2.
abstract: ABCG2 is a membrane-localized, human transporter protein that has been demonstrated to reduce the intracellular accumulation of substrates through ATP-dependent efflux. Highly expressed in placental syncytiotrophoblasts, brain microvasculature, and the gastrointestinal tract, ABCG2 has been shown to mediate normal tissue protection as well as limit oral bioavailability of substrate compounds. Development of ABCG2 inhibitors for clinical use may allow increased penetration of therapeutic agents into sanctuary sites and increased gastrointestinal absorption. Previously identified inhibitors have lacked potency or specificity or were toxic at concentrations needed to inhibit ABCG2; none are in clinical development. A previously developed high-throughput assay measuring inhibition of ABCG2-mediated pheophorbide a transport was applied to natural product extract libraries. Among the active samples were extracts from the marine ascidian Botryllus tyreus. Bioassay-guided fractionation resulted in purification of a series of botryllamides. Ten botryllamides were obtained, two of which (designated I and J) were novel. Activity against ABCG2 was confirmed by assessing the ability of the compounds to inhibit ABCG2-mediated BODIPY-prazosin transport in ABCG2-transfected HEK293 cells, compete with [(125)I]-iodoarylazidoprazosin (IAAP) labeling of ABCG2, stimulate ABCG2-associated ATPase activity, and reverse ABCG2-mediated resistance.
authors: Basic Research Program, SAIC-Frederick, Inc., MD, USA. henrichc@ncifcrf.gov
authors: Curtis J
authors: CJ
authors: Henrich
authors: Robert W
authors: RW
authors: Robey
authors: Kentaro
authors: K
authors: Takada
authors: Heidi R
authors: HR
authors: Bokesch
authors: Susan E
authors: SE
authors: Bates
authors: Suneet
authors: S
authors: Shukla
authors: Suresh V
authors: SV
authors: Ambudkar
authors: James B
authors: JB
authors: McMahon
authors: Kirk R
authors: KR
authors: Gustafson
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001688:Biological Products; D009363:Neoplasm Proteins; D000251:Adenosine Triphosphatases