Synthesis and biological evaluation of aroylguanidines related to amiloride as inhibitors of the human platelet Na+/H+ exchanger

Laeckmann, Didier; Rogister, F.; Dejardin, J. V.; Prosperi-Meys, Christelle; Géczy, Joseph; Delarge, J.; Masereel, Bernard

doi:10.1016/s0968-0896(02)00022-6

Cited by 31 publications

(5 citation statements)

References 37 publications

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“…Somewhat later two sets of alterations gave rise to a new series of inhibitors where the pyrazine moiety of amiloride was substituted with a phenyl ring or a heterocycle pyridine to produce benzoylguanidines ( see Table 1, part B). For example, the replacement of the pyrazine ring of amiloride by a pyridine or a phenyl ring improved the NHE inhibitory potency (36-and 54-times more active than amiloride on human platelet NHE1, respectively) [105]. The simultaneous substitution of the 6-chloro by a sulfomethyl with the deleation of the 2-amino or its replacement by a methyl group gave rise to the benzoylguanidine group of inhibitors such as HOE-694 [106], cariporide (HOE-642; R2: -H and R5: -CH(CH3)2 [107], eniporide (EMD85131; R2: -CH3 and R5: -N ring; [108]) and BIIB-513 [109].…”

Section: Nhe1 Pharmacologymentioning

confidence: 99%

Na+-H+ Exchanger, pH Regulation and Cancer

Reshkin

Cardone²,

Harguindey³

2012

PRA

130

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Cancer cells and tissues, regardless of their origin and genetic background, have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the intracellular to extracellular pH gradient (pHi to pHe) in cancer cells and tissue as compared to normal tissue. This perturbation in pH dynamics rises very early in carcinogenesis and is one of the most common patho-physiological hallmarks of tumors. Recently, there has been a very large increase in our knowledge of the importance and roles of pHi and pHe in developing and driving a series of tumor hallmarks. This reversed proton gradient is driven by a series of proton export mechanisms that underlie the initiation and progression of the neoplastic process. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na + /H + exchanger isoform 1 (NHE1). The NHE1 is an integral membrane transport protein involved in regulating pH and in tumor cells is a major contributor to the production and maintenance of their reversed proton gradient. It is activated during oncogene-dependent transformation resulting in cytosolic alkalinization which then drives subsequent hallmark behaviors including growth factor-and substrate-independent growth, and glycolytic metabolism. It is further activated by various growth factors, hormone, the metabolic microenvironment (low serum, acidic pHe and hypoxia) or by ECM receptor activation. This review will present the recent progress in understanding the role the NHE1 in determining tumor progression and invadopodia-guided invasion/metastasis and recent patents for NHE1 inhibitors and novel therapeutic protocols for anti-NHE1 pharmacological approaches. These may represent a real possibility to open up new avenues for widespread and efficient treatments against cancer.

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Section: Nhe1 Pharmacologymentioning

confidence: 99%

Na+-H+ Exchanger, pH Regulation and Cancer

Reshkin

Cardone²,

Harguindey³

2012

PRA

130

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“…Key words: cardiovascular activity, ligustrazine, stilbene derivatives, synthesis Substituted pyrazine derivatives with a broad spectrum of biological activities play a very important role in pharmaceutical applications [1,2], especially in the therapeutic effects on cardiovascular diseases, such as antihypertensive, vasodilating effects, and anti-cerebrocardiac ischemia. Currently, structurally based pyrazine drugs, such as Ligustrazine, amiloride, pyrazinoylguanidine, and their derivatives, have been widely used in the clinical for treatment of cardiovascular diseases [3][4][5][6][7][8].…”

mentioning

confidence: 99%

Ligustrazine Derivatives. Part 4: Design, Synthesis, and Biological Evaluation of Novel Ligustrazine‐based Stilbene Derivatives as Potential Cardiovascular Agents

Deng¹,

Guo²,

Zhai³

et al. 2012

Chem Biol Drug Des

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A series of novel stilbene derivatives containing ligustrazinyl moiety was designed, synthesized, and assayed for their protective effects on damaged endothelial cells. The results showed that most ligustrazinyl stilbene derivatives exhibited high protective effects on the human umbilical vascular endothelial cells (HUVECs) damaged by hydrogen peroxide in comparison with Ligustrazine. The stilbene derivatives A6, A9, A11, A21, A24, A25, and A27 exhibited high potency with low EC 50 values ranged from 0.0249 lM to 0.0898 mM. Compound A27 displayed EC 50 0.0249 lM, which is 30 000 times higher than that of Ligustrazine, presenting a most promising lead for further investigation. Structure-activity relationships were briefly discussed.

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“…Compounds A12-14 and B14-16 were prepared by condensation of the intermediate 1 with intermediate 4-halo-4'-hydroxy- diphenyl or 4-amino-4'-halodiphenyl, respectively [28][29][30] . Substituted benzoyl guanidines (C1-4) and substituted phenyl guanidines (D1-D4) were synthesized according to the literature [31,32] . 4-Guanidinobenzoic acid and 4-guanidinophenylacetic acid were synthesized by the reaction of aminoiminomethanesulfonic acid with 4-aminobenzoic acid and 4-aminophenylacetic acid, respectively [33] , followed by condensation with 4-phenylphenol using dicyclohexylcarbodiimide (DCC) to give 4-phenylphenyl 4-guanidinobenzoate (E1) and 4-phenylphenyl 4-guanidinophenylacetate (E2) [23] .…”

Section: Methodsmentioning

confidence: 99%

Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents: synthesis and bioactivity

Yang

Xie³

et al. 2008

Acta Pharmacologica Sinica

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Aim: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide. Methods: A total of 44 derivatives of aryl-4-guanidinomethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method. Results: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 µg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin. Conclusion: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.

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Synthesis and biological evaluation of aroylguanidines related to amiloride as inhibitors of the human platelet Na+/H+ exchanger

Cited by 31 publications

References 37 publications

Na+-H+ Exchanger, pH Regulation and Cancer

Na+-H+ Exchanger, pH Regulation and Cancer

Ligustrazine Derivatives. Part 4: Design, Synthesis, and Biological Evaluation of Novel Ligustrazine‐based Stilbene Derivatives as Potential Cardiovascular Agents

Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents: synthesis and bioactivity

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