TY - JOUR
T1 - Gram-scale solution-phase synthesis of selective sodium bicarbonate Co-transport Inhibitor S0859
T2 - in vitro efficacy studies in breast cancer cells
AU - Larsen, Ann Møller
AU - Krogsgaard-Larsen, Niels
AU - Lauritzen, Gitte
AU - Olesen, Christina W.
AU - Hansen, Steen Honore'
AU - Bødtkjer, Ebbe
AU - Pedersen, Stine Helene Falsig
AU - Bunch, Lennart
PY - 2012/10
Y1 - 2012/10
N2 - Na+-coupled HCO3- 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 50μM.
AB - Na+-coupled HCO3- 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 50μM.
U2 - 10.1002/cmdc.201200335
DO - 10.1002/cmdc.201200335
M3 - Journal article
SN - 1860-7179
VL - 7
SP - 1808
EP - 1814
JO - Farmaco, Edizione Pratica
JF - Farmaco, Edizione Pratica
IS - 10
ER -
