A Novel Anti-Ischemic ATP-Sensitive Potassium Channel (KATP) Opener without Vasorelaxation:  N-(6-Aminobenzopyranyl)-N‘-benzyl-N‘ ‘-cyanoguanidine Analogue

Yoo, Sung‐Eun; Yi, Kyu Yang; Lee, Jimin; Suh, Jeehee; Kim, Nakjeong; Lee, Byung Ho; Seo, Ho Won; Kim, Sun-Ok; Lee, Dong-Ha; Lim, Hong; Shin, Hwa Sup

doi:10.1021/jm010183f

Cited by 40 publications

(14 citation statements)

References 30 publications

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“…In the previous report, KR-31378 reduced the myocardial infarct zone to an area at risk in the ischemic myocardium rat model [8]. 5-Hydroxydecaoate (5-HD), a blocker of MitoK ATP channel, abolished the cardioprotective effect by KR-31378, suggesting that KR31378 acted through MitoK ATP channel [8]. This study further examined whether KR-31378 modulated ROS generation and demonstrated that CH-induced ROS formation was prevented by KR-31378 in H9c2 cells.…”

Section: Discussionmentioning

confidence: 84%

“…And ROS plays an important role both upstream and downstream of the MitoK ATP channel during ischemia [27]. In the previous report, KR-31378 reduced the myocardial infarct zone to an area at risk in the ischemic myocardium rat model [8]. 5-Hydroxydecaoate (5-HD), a blocker of MitoK ATP channel, abolished the cardioprotective effect by KR-31378, suggesting that KR31378 acted through MitoK ATP channel [8].…”

Section: Discussionmentioning

confidence: 98%

“…1), was synthesized by the Korea Research Institute of Chemical Technology (Daejeon, Korea) as a chemical preconditioning agent [8]. KR-31378 is an antioxidant K ATP channel opener that has been shown to protect rat cortex neurons against iron-induced oxidative injury, and it significantly reduces infarct size in a model of rat transient cerebral ischemia [9][10][11].…”

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confidence: 99%

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KR-31378 Protects Cardiac H9c2 Cells from Chemical Hypoxia-Induced Cell Death via Inhibition of JNK/p38 MAPK Activation

Jung

Lee²,

Lim³

et al. 2004

JJP

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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KR-31378 Protects Cardiac H9c2 Cells from Chemical Hypoxia-Induced Cell Death via Inhibition of JNK/p38 MAPK Activation

Jung

Lee²,

Lim³

et al. 2004

JJP

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“…The suggested mechanism of this antitumor effect is the activation of ATP-sensitive potassium channels leading to the inhibition of the intracellular Ca 2+ signaling mechanism (1). Although a series of 4,6-disubstituted 2,2-dimethylchromans structurally related to cromakalim have been synthesized and reported to possess several pharmacological effects including potassium channel activating, antihypertensive and anti-ischemic properties (2)(3)(4)(5), no attempt has been made to evaluate the cytotoxicity of cromakalim analogues, and the exact pathways involved in their cytotoxic effect are not completely elucidated in the case of human cervical carcinoma HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

A novel cromakalim analogue induces cell cycle arrest and apoptosis in human cervical carcinoma HeLa cells through the caspase- and mitochondria-dependent pathway

Zhang

Zhao²,

Kang³

et al. 2011

Int J Oncol

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Abstract. In the present study, a series of seven synthetic cromakalim analogues were prepared and evaluated for cytotoxic effect on human cervical carcinoma HeLa cells using WST-8 assay. A preliminary screening of these cromakalim analogues showed that 1-[(3S,4R)-4-(2-ethoxy-4-methyl-1H-pyrrol-1-yl)-3-hydroxy-2,2-dimethylchroman-6-yl-3-phenylurea (compound 6) had the highest cytotoxic effect (IC 50 of 138 µM) and significantly inhibited HeLa cell proliferation after 36 h. In an effort to understand the cytotoxic mechanism of compound 6, we examined its effect on apoptosis and cell cycle distribution. Our results showed that compound 6 induced marked changes in apoptotic morphology and significantly increased early apoptosis of HeLa cells after 48 h by using Annexin V-FITC/PI dual staining assay. This apoptotic induction was associated with an increase in Bax expression, a decrease in Bcl-2 expression, release of cytochrome c and subsequent activation of caspase-9 and -3, which indicated that compound 6 induced apoptosis via caspaseand mitochondria-dependent pathway. By DNA content analysis and [ 3 H]thymidine incorporation assay, compound 6 was found to induce an increase in the number of cells in G1 phase, accompanied by a decrease in the S phase to prevent DNA synthesis after 24 h of treatment. In addition, compound 6 caused significant DNA damage, as detected by the alkaline comet assay. Taken together, the data demonstrate that compound 6 induces apoptosis in HeLa cells through caspase-and mitochondriadependent pathway and this apoptotic effect is associated with cell cycle arrest and DNA damage. These findings provide further understanding of the molecular mechanisms of compound 6 in cervical cancer. IntroductionCromakalim, a potassium channel opener, presents antitumor potential against human neuroblastoma and human astrocytoma cell lines. The suggested mechanism of this antitumor effect is the activation of ATP-sensitive potassium channels leading to the inhibition of the intracellular Ca 2+ signaling mechanism (1). Although a series of 4,6-disubstituted 2,2-dimethylchromans structurally related to cromakalim have been synthesized and reported to possess several pharmacological effects including potassium channel activating, antihypertensive and anti-ischemic properties (2-5), no attempt has been made to evaluate the cytotoxicity of cromakalim analogues, and the exact pathways involved in their cytotoxic effect are not completely elucidated in the case of human cervical carcinoma HeLa cells.Many reports demonstrated that DNA damage was induced in cancer cells by exposure to chemotherapy drugs (6,7), and that DNA-strand breakage may be one reason for DNA lesions, which can be sensitively detected by the single-cell gel electrophoresis (comet) assay in anticancer studies (8). Detection of genomic lesions activates the DNA damage response, which determines cell fate according to the extent of damage. If the damage is manageable, the DNA damage response arrests the cell cycle progression and induces DNA repa...

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“…Benzopyran is one of the most frequently used back-bones of synthetic drugs, including anti-oxidants, anti-hypertensive and therapeutic agents for ischemia-related diseases. A variety of amines were introduced at the 4-position of benzopyran for the identification of ATP sensitive potassium channel (K ATP ) openers targeting ischemic diseases, such as myocardial infarction and stroke (6). Previously, we reported that KR-31831 plays a role as a novel anti-angiogenic agent in bovine aortic endothelial cells (BAECs) (7).…”

Section: Introductionmentioning

confidence: 99%

KR-31831, benzopyran derivative, inhibits VEGF-induced angiogenesis of HUVECs through suppressing KDR expression

Park

Seo²,

Song³

et al. 2008

Int J Oncol

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Abstract. Angiogenesis is important in the development and progression of cancer, therefore the therapeutic approach based on anti-angiogenesis may represent a promising therapeutic option. KR-31831 is a novel anti-ischemic agent. Previously, we reported the anti-angiogenic activity of KR-31831. In the present study we investigated the molecular mechanisms underlying anti-angiogenic activity of KR-31831. We show that KR-31831 inhibits vascular endothelial growth factor (VEGF)-induced proliferation and tube formation via release of intracellular Ca 2+ and phosphorylation of extra-cellular regulated kinase 1/2 (Erk1/2) in human umbilical vein endothelial cells (HUVECs). Moreover, the expression of VEGF receptor 2 (VEGFR2, known as Flk-1 or KDR) was reduced by the treatment of KR-31831. These results suggest that KR-31831 may have inhibitory effects on tumor angiogenesis through down-regulation of KDR expression. IntroductionAngiogenesis is the formation of new blood vessels from pre-existing vessels that occurs in many physiological and pathological conditions such as embryonic development, chronic inflammation, wound healing, and tumor progression and metastasis. Angiogenesis is tightly controlled by a wide variety of regulators which include growth factors, cytokines, lipid metabolites and cryptic fragments of hemostatic proteins (1). VEGF is a potent angiogenic stimulator produced by various types of tumor cells, which plays an important role in the growth and metastasis of tumors by promoting neovascularization (2-5).Angiogenic activity of VEGF is thought to be mediated by the high-affinity receptor tyrosine kinases, VEGFR1 (fms-like tyrosine kinase, Flt-1) and VEGFR2 (kinase insert-domain containing receptor, KDR, in human and its murine homologue, fetal liver kinase-1, Flk-1). Although both receptors are co-expressed on most endothelial cells, VEGFR-2 is thought to dominate the angiogenic response. Binding of VEGF to its receptors causes dimerization of the receptor and activation of the intrinsic tyrosine kinase domain, followed by autophosphorylation of the receptor and subsequent signal transduction.KR-31831 (2R,3R,4S)-6-amino-4-[n-(4-chlorophenyl)-N-(1H-imidazol-2ylmethyl)amino]-3-hydroxyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran, is a novel synthetic anti-ischemic agent. Benzopyran is one of the most frequently used back-bones of synthetic drugs, including anti-oxidants, anti-hypertensive and therapeutic agents for ischemia-related diseases. A variety of amines were introduced at the 4-position of benzopyran for the identification of ATP sensitive potassium channel (K ATP ) openers targeting ischemic diseases, such as myocardial infarction and stroke (6). Previously, we reported that KR-31831 plays a role as a novel anti-angiogenic agent in bovine aortic endothelial cells (BAECs) (7). KR-31831 suppressed endothelial cell proliferation, tube formation, invasion and migration in vitro. Also, this agent inhibited vessel formation in the mouse Matrigel plug assay in vivo.In the present study w...

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A Novel Anti-Ischemic ATP-Sensitive Potassium Channel (K_ATP) Opener without Vasorelaxation: N-(6-Aminobenzopyranyl)-N‘-benzyl-N‘ ‘-cyanoguanidine Analogue

Cited by 40 publications

References 30 publications

KR-31378 Protects Cardiac H9c2 Cells from Chemical Hypoxia-Induced Cell Death via Inhibition of JNK/p38 MAPK Activation

KR-31378 Protects Cardiac H9c2 Cells from Chemical Hypoxia-Induced Cell Death via Inhibition of JNK/p38 MAPK Activation

A novel cromakalim analogue induces cell cycle arrest and apoptosis in human cervical carcinoma HeLa cells through the caspase- and mitochondria-dependent pathway

KR-31831, benzopyran derivative, inhibits VEGF-induced angiogenesis of HUVECs through suppressing KDR expression

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