New 1,4-Dihydropyridines Conjugated to Furoxanyl Moieties, Endowed with Both Nitric Oxide-like and Calcium Channel Antagonist Vasodilator Activities

Abstract:The article focuses attention on furoxan derivatives (1,2,5-oxadiazole 2-oxides) as NO donors. Possible mechanisms for NO release from these products in physiological solution and in segments of rabbit femoral artery are briefly considered. The in vitro antiaggregatory activities and the in vitro and in vivo vasodilating properties of a number of furoxans are examined with particular reference to involvement of NO in these actions. The use of the furoxan system to design new NO donor/drug hybrids is discussed in connection with the problem of the balance between NO-and drug-dependent activities of the resulting structures. Whether other biological activities (as yet, little studied) of furoxans, such as their antiparasite, antimicrobial, and antitumoral effects, are NO-dependent, is a matter still to be explored.

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“…2; Fig. 9) [21]. In fact, this product was found to dilate rat aorta strips precontracted with a solution of K + ions in a dose-dependent manner.…”

Section: Furoxan/drug Hybridsmentioning

confidence: 83%

NO donors: Focus on furoxan derivatives

Gasco

Fruttero

Sorba

et al. 2004

Pure and Applied Chemistry

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“…First 4-hydroxymethyl-2-oxyfurazan-3-carboxylic acid amide, the NOdonating agent, was prepared in three steps and then coupled to VGX-1027 (25). The new product was reduced to yield the desired compound GIT-27NO (Fig.…”

Section: Synthesis Of Git-27nomentioning

confidence: 99%

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić

Mijatović

Harhaji

et al. 2008

Molecular Cancer Therapeutics

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Preclinical studies have shown that nitric oxide (NO) -donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NOdeprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatinresistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.

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“…(I a-q ) in fair to satisfactory yields (Di Stilo et al, 1998). A series of acetoacetates were synthesized via Knoevenagel condensation of the corresponding benzaldehyde (1 a-q ) with methyl acetoacetate (2) in the presence of a catalytic amount of piperidine and acetic acid (Zoeller and Sumner, 1990).…”

mentioning

confidence: 99%

New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines as P-Glycoprotein Inhibitors

Zhou

Zhang²,

Tseng³

et al. 2004

Drug Metab Dispos

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ABSTRACT:Efflux of cytotoxic agents mediated by P-glycoprotein is believed to be an important mechanism of multidrug resistance, which remains a serious limitation to successful chemotherapy in cancers such as metastatic breast cancer. A series of 4-aryl-1,4-dihydropyridines and corresponding aromatized 4-arylpyridines have been synthesized based on structure modifications of niguldipine to enhance multidrug resistance reversal activity, while minimizing calcium channel binding. Thirty new compounds were characterized.

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New 1,4-Dihydropyridines Conjugated to Furoxanyl Moieties, Endowed with Both Nitric Oxide-like and Calcium Channel Antagonist Vasodilator Activities

Cited by 107 publications

References 19 publications

NO donors: Focus on furoxan derivatives

NO donors: Focus on furoxan derivatives

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines as P-Glycoprotein Inhibitors

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