title: Gram-scale solution-phase synthesis of selective sodium bicarbonate co-transport inhibitor S0859: in vitro efficacy studies in breast cancer cells.
abstract: Na(+)-coupled HCO(3)(-) transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast cancer, a malignant and widespread cancer with no targeted treatment options, and single-nucleotide polymorphisms in NBCn1 genetically link to breast cancer development and hypertension. The N-cyanosulfonamide S0859 has been shown to selectively inhibit NBCs, and its availability on the gram scale is therefore of significant interest to the scientific community. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials. The inhibitory effect of S0859 on recovery of intracellular pH after an acid load was verified in human and murine cancer cell lines in Ringer solutions. However, S0859 binds very strongly to components in plasma, and accordingly, measurements on isolated murine tissues showed no effect of S0859 at concentrations up to 50 μM.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Larsen
authors.forename: Niels
authors.initials: N
authors.lastname: Krogsgaard-Larsen
authors.forename: Gitte
authors.initials: G
authors.lastname: Lauritzen
authors.forename: Christina W
authors.initials: CW
authors.lastname: Olesen
authors.forename: Steen
authors.initials: S
authors.lastname: Honoré Hansen
authors.forename: Ebbe
authors.initials: E
authors.lastname: Boedtkjer
authors.forename: Stine F
authors.initials: SF
authors.lastname: Pedersen
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D027982:Sodium-Bicarbonate Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; C528718:S 0859 compound; D027982:Sodium-Bicarbonate Symporters; D013449:Sulfonamides