S0859

S0859, an N-cyanosulphonamide compound, reversibly inhibited NBC-mediated pH(i) recovery (K (i)=1.7 microM, full inhibition at approximately 30 microM). 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. Treatment with NBC inhibitor S0859 significantly increased caspase-3 activity and elevated the number of apoptotic EC. S0859 is potentially important for probing the transporter's functional role in heart and other tissues.

Inhibition of monocarboxylate transporter by N-cyanosulphonamide S0859.[Pubmed:26027796]

Eur J Pharmacol. 2015 Sep 5;762:344-9.

The synthetic compound N-cyanosulphonamide S0859 has been described as a selective inhibitor of sodium-bicarbonate cotransporters (NBC, SLC4) in mammalian heart (Ch'en et al., 2008). First, for comparison, the electrogenic human NBCe1 (SLC4A4) was heterologously expressed in Xenopus laevis oocytes, where its transport activity was inhibited by S0859 with an IC50 of 9microM. The activity of monocarboxylate transporter (MCT) isoforms 1, 2, and 4 (SLC16A1, SLC16A7, SLC16A3), which transport lactate, pyruvate and ketone bodies, were also heterologously expressed in Xenopus oocytes, and their transport activity was similarly and reversibly inhibited by S0859 with an IC50 of 4-10microM. Partial inhibition of lactate transport by S0859 (50microM) was also obtained in cultured astrocytes of mice. Thus, S0859 appears to be an inhibitor of anion transport with a broader spectrum than previously thought, and may also interfere with cellular metabolite uptake/release.

S0859, an N-cyanosulphonamide inhibitor of sodium-bicarbonate cotransport in the heart.[Pubmed:18204485]

Br J Pharmacol. 2008 Mar;153(5):972-82.

BACKGROUND AND PURPOSE: Intracellular pH (pH(i)) in heart is regulated by sarcolemmal H(+)-equivalent transporters such as Na(+)-H(+) exchange (NHE) and Na(+)-HCO(3) (-) cotransport (NBC). Inhibition of NBC influences pH(i) and can be cardioprotective in animal models of post-ischaemic reperfusion. Apart from a rabbit polyclonal NBC-antibody, a selective NBC inhibitor compound has not been studied. Compound S0859 (C(29)H(24)ClN(3)O(3)S) is a putative NBC inhibitor. Here, we provide the drug's chemical structure, test its potency and selectivity in ventricular cells and assess its suitability for experiments on cardiac contraction. EXPERIMENTAL APPROACH: pH(i) recovery from intracellular acidosis was monitored using pH-epifluorescence (SNARF-fluorophore) in guinea pig, rat and rabbit isolated ventricular myocytes. Electrically evoked cell shortening (contraction) was measured optically. With CO(2)/HCO(3) (-)-buffered superfusates containing 30 muM cariporide (to inhibit NHE), pH(i) recovery is mediated by NBC. KEY RESULTS: S0859, an N-cyanosulphonamide compound, reversibly inhibited NBC-mediated pH(i) recovery (K (i)=1.7 microM, full inhibition at approximately 30 microM). In HEPES-buffered superfusates, NHE-mediated pH(i) recovery was unaffected by 30 microM S0859. With CO(2)/HCO(3) (-) buffer, pH(i) recovery from intracellular alkalosis (mediated by Cl(-)/HCO(3) (-) and Cl(-)/OH(-) exchange) was also unaffected. Selective NBC-inhibition was not due to action on carbonic anhydrase (CA) enzymes, as 100 microM acetazolamide (a membrane-permeant CA-inhibitor) had no significant effect on NBC activity. pH(i) recovery from acidosis was associated with increased contractile-amplitude. The time course of recovery of pH(i) and contraction was slowed by S0859, confirming that NBC is a significant controller of contractility during acidosis. CONCLUSIONS AND IMPLICATIONS: Compound S0859 is a selective, high-affinity generic NBC inhibitor, potentially important for probing the transporter's functional role in heart and other tissues.

Gram-scale solution-phase synthesis of selective sodium bicarbonate co-transport inhibitor S0859: in vitro efficacy studies in breast cancer cells.[Pubmed:22927258]

ChemMedChem. 2012 Oct;7(10):1808-14.

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 muM.

S0859 is a selective, high-affinity generic NBC inhibitor. S0859 reversibly inhibits NBC-mediated intracellular pH (pHi) recovery (Ki=1.7 μM, full inhibition at approximately 30 μM).

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