Synthesis and biological activity of 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidine analogs as potent, highly selective, and orally bioavailable NHE-1 inhibitors

Atwal, Karnail S.; O’Neil, Steven V.; Ahmad, Saleem; Doweyko, Lidia M.; Kirby, Mark; Dorso, Charles R.; Chandrasena, Gamini; Chen, Bang‐Chi; Zhao, Rulin; Zahler, Robert

doi:10.1016/j.bmcl.2006.06.077

Cited by 42 publications

(25 citation statements)

References 11 publications

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“…A Na-K-Cl cotransporter-mediated cell volume increase may even precede activation of an abluminal ion efflux pathway, e.g., a swellingactivated Cl channel as has been reported to reside in CMEC (47). Similar phenomena have been described in a variety of Na-and Cl-transporting epithelia (2,11,40). With regard to maintaining coupling of Na-K-Cl cotransporter and Na/K pump during ischemia-induced Na and Cl secretion across the BBB, we have shown previously that Na/K pump activity and cell ATP levels do not fall for at least 4 h when CMEC are exposed to hypoxia (7.5% or 2% O 2 ) or combined hypoxia/ aglycemia and that even after 24 h of 2% O 2 (with or without aglycemia), the CMEC ATP content remains at ϳ60% of normoxic levels (12).…”

Section: Discussionmentioning

confidence: 55%

Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells

Brillault

Lam

Rutkowsky

et al. 2008

American Journal of Physiology-Cell Physiology

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Increased transport of Na across an intact blood-brain barrier (BBB) contributes to cerebral edema formation in ischemic stroke. Our previous studies have shown that ischemic factors stimulate activity of a luminal BBB Na-K-Cl cotransporter, and we have hypothesized that during ischemia, the cotransporter together with the abluminal Na/K pump mediates increased transport of Na from blood into the brain. However, it is possible that elevated Na-K-Cl cotransporter activity could also cause cell swelling if it outpaces ion efflux pathways. The present study was conducted to evaluate the effects of hypoxia on intracellular volume of BBB cells. Cerebral microvascular endothelial cell (CMEC) monolayers were exposed to varying levels of hypoxia for 1 to 5 h in an O(2)-controlled glove box, and cell volume was assessed using 3-O-methyl-D-[(3)H]glucose and [(14)C]sucrose as markers of total and extracellular water space, respectively. Cells exposed to either 7.5%, 3%, or 1% O(2) showed gradual increases in volume (compared with 19% O(2) normoxic controls) that became significant after 3 or more hours. By ion chromatography methods, we also found that a 30-min exposure to 7.5% O(2) caused an increase in bumetanide-sensitive net Na uptake by the cells without increasing cell Na content. CMEC Na content was significantly increased, however, following 3 or more hours of exposure to 7.5% O(2). These findings are consistent with the hypothesis that during cerebral ischemia, the BBB Na-K-Cl cotransporter is stimulated to mediate transendothelial uptake of Na into the brain and that increased cotransporter activity also contributes to gradual swelling of the cells.

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Section: Discussionmentioning

confidence: 55%

Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells

Brillault

Lam

Rutkowsky

et al. 2008

American Journal of Physiology-Cell Physiology

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“…Other compounds also have promising potential. Some are well absorbed by the gastrointestinal tract and can be given orally such as compound 9t (85,87).…”

Section: Nhe1 Inhibition As a Chemotherapy Strategy: The Challenge Ofmentioning

confidence: 99%

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

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“…More potent NHE1 inhibitor than CP is the so called "Compound 9t" (C9t). C9t is five hundred times more potent against NHE1 than cariporide apart from having a 1400-fold greater selectivity for NHE1 over NHE2 [181]. Similarly, Phx-3, is a non-toxic NHE1 inhibitor that induces tumor growth regression after leukemic cell transplantation, inducing selective apoptosis through intracellular acidification [28,185].…”

Section: ) Hydrogen Ion Dynamics In Multiple Drug Resistance (Mdr) Imentioning

confidence: 99%

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

Harguindey¹,

Alfarouk

Orozco³

et al. 2019

Preprint

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Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success story. The advances in surgery, chemotherapy and radiotherapy have not been sufficient. Indeed, the accumulated experience clearly indicates that new perspectives and non-main stream approaches are needed to better characterize the etiopathogenesis and treatment of this disease. This contibution deals with how the new pH-centric anticancer paradigm plays a fundamental role in reaching a more integral understanding of the etiology, etiopathogenesis and treatment of this multifactorial disease. For the first time the armamentarium available for the treatment of the different types and phases of BC is approached here from a Unitarian perspective based upon the hydrogen ion dynamics of cancer. The wide-ranged pH-related molecular, biochemical and metabolic model is able to embrace most the fields and subfields of breast cancer pathology. This single and integrated approach allows to advance a unidirectional program to treatment. Further efforts in this line are likely to first improve the therapeutics of each subtype of this tumor, then every phase of the disease and finally every individual patient.

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Synthesis and biological activity of 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidine analogs as potent, highly selective, and orally bioavailable NHE-1 inhibitors

Cited by 42 publications

References 11 publications

Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells

Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

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