Synthesis and antihypertensive activities of 1,4-dihydropyridine-5-phosphonate derivatives. I.

Morita, Iwao; Tada, Satoru; Kunimoto, Katsutoshi; Tsuda, Masami; Kise, Masahiro; Kimura, Kiyoshi

doi:10.1248/cpb.35.3898

Cited by 13 publications

(4 citation statements)

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“…2 outlines the synthesis of three such 4-phenyl-5-phosphonato-1,4-DHP derivatives, 5a-c: MRS 2154 (2,6-dimethyl), MRS 2155 (6-methyl-2-phenyl), and MRS 2156 (2-methyl-6-phenyl). All were synthesized through three-component (1-3) condensation reactions (Morita et al, 1987). The phosphonate methyl ester groups of the product, 4, were deprotected using trimethylsilyl bromide to give the free phosphonates, 5a-c. A phenyl group was necessary at the 4-position, since the product proved to be unstable during the deprotection reaction when the same synthetic route was applied to a 4-methyl analogue.…”

Section: Resultsmentioning

confidence: 99%

“…A solution of ethyl 3-aminocrotonate (1a, 63.2 μl, 0.5 mmol), benzaldehyde (2, 50.5 μl, 0.5 mmol) and dimethyl-(2-oxopropyl)phosphonate (3, 72.7 μl, 0.5 mmol) in 1 ml of EtOH was heated in a sealed tube at 90°C for 24 h (Morita et al, 1987). After evaporation, the residue was purified by preparative thin layer chromatography (CHCl 3 :MeOH=30:1) to afford 54 mg of 4a (30%).…”

Section: Dimethyl 26-dimethyl-3-(ethoxycarbonyl)-4-phenyl-14-(±)-dimentioning

confidence: 99%

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In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

Kim

King

2000

Journal of the Autonomic Nervous System

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Abstract1,4-Dihydropyridines are regarded as privileged structures for drug design, i.e. they tend to bind to a wide variety of receptor sites. We have shown that upon appropriate manipulation of the substituent groups on a 1,4-dihydropyridine template, high affinity and selectivity for the A 3 subtype of adenosine receptors ('P1 receptors') may be attained. In the present study we have begun to extend this approach to P2 receptors which are activated by ATP and other nucleotides. Nicardipine, a representative dihydropyridine, used otherwise as an L-type calcium channel blocker, was shown to be an antagonist at recombinant rat P2X 2 (IC 50 = 25 μM) and P2X 4 (IC 50 2 20 μM) receptors expressed in Xenopus oocytes. Thus, this class of compounds represents a suitable lead for enhancement of affinity through chemical synthesis. In an attempt to modify the 1,4-dihydropyridine structure with a predicted P2 receptor recognition moiety, we have replaced one of the ester groups with a negatively charged phosphonate group. Several 4-phenyl-5-phosphonato-1,4-dihydropyridine derivatives, MRS 2154 (2,6-dimethyl), MRS 2155 (6-methyl-2-phenyl), and MRS 2156 (2-methyl-6-phenyl), were synthesized through three component condensation reactions. These derivatives were not pure antagonists of the effects of ATP at P2X 2 receptors, rather were either inactive (MRS 2156) or potentiated the effects of ATP in a concentration-dependent manner (MRS 2154 in the 0.3-10 μM range and MRS 2155 at >1 μM). Antagonism of the effects of ATP at P2X 2 receptor superimposed on the potentiation was also observed at >10 μM (MRS 2154) or 0.3-1 μM (MRS 2155). Thus, while a conventional dihydropyridine, nicardipine, was found to antagonize rat P2X 2 receptors ninefold more potently than P2X 4 receptors, the effects of novel, anionic 5-phosphonate analogues at the receptor were more complex.

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Section: Resultsmentioning

confidence: 99%

Section: Dimethyl 26-dimethyl-3-(ethoxycarbonyl)-4-phenyl-14-(±)-dimentioning

confidence: 99%

In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

Kim

King

2000

Journal of the Autonomic Nervous System

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“…A few 1,2,3-triazol-5-yl-phosphonates (2) were identified as promising cytotoxic and antibacterial agents [10]. Similarly, to the 1,4-dihydropyridine-3,5-dicarboxylates, several 1,4-dihydropyridine-5-phosphonates (3) showed significant antihypertensive activity [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3,4-Dihydropyrimidin-2(1H)-one-phosphonates by the Microwave-Assisted Biginelli Reaction

et al. 2020

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The synthesis of novel 3,4-dihydropyrimidin-2(1H)-one-phosphonates was elaborated by the microwave (MW)-assisted three-component Biginelli reaction of β-ketophosphonates, aromatic or aliphatic aldehydes and urea derivatives. The condensation was optimized on a selected model reaction in respect of the reaction parameters, such as the heating method, the type of the catalyst and solvent, the temperature, the reaction time and the molar ratio of the starting materials. The fast and solvent-free MW-assisted procedure was then extended for the preparation of further new 3,4-dihydropyrimidin-2(1H)-one-phosphonate derivatives starting from different aromatic aldehydes, β-ketophosphonates and urea derivatives to prove the wide scope of the process. As a novel by-product of the Biginelli-type synthesis of 3,4-dihydropyrimidin-2(1H)-one-phosphonates, the 5-diethoxyphosphoryl-4-phenyl-6-styryl-3,4-dihydropyrimidin-2(1H)-one was also isolated and characterized. Our MW-assisted method made also possible the condensation of aliphatic aldehydes, diethyl (2-oxopropyl)phosphonate and urea, which reaction was previously reported to be impossible in the literature.

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“…On the other hand, phosphorus containing heterocyclic compounds is known to be used as a catalytic antibody as well as an anti-cancer agent [4] . These derivatives are also known to be anti-hypertensive agents [5] . It is widely accepted that the distribution, metabolism, and efficacy of many drugs can be altered based on their affinity to serum albumin [6] .…”

Section: Introductionmentioning

confidence: 99%

Binding interaction of phosphorus heterocycles with bovine serum albumin: A biochemical study

Roy

Nandi

Ganai

et al. 2017

Journal of Pharmaceutical Analysis

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Interaction between bovine serum albumin (BSA) and phosphorus heterocycles (PHs) was studied using multi-spectroscopic techniques. The results indicated the high binding affinity of PHs to BSA as it quenches the intrinsic fluorescence of BSA. The experimental data suggested the fluorescence quenching mechanism between PHs and BSA as a dynamic quenching. From the UV–vis studies, the apparent association constant (Kapp) was found to be 9.25×102, 1.27×104 and 9.01×102 L/mol for the interaction of BSA with PH-1, PH-2 and PH-3 respectively. According to the Förster's non-radiation energy transfer (FRET) theory, the binding distances between BSA and PHs were calculated. The binding distances (r) of PH-1, PH-2 and PH-3 were found to be 2.86, 3.03, and 5.12 nm, respectively, indicating energy transfer occurs between BSA and PHs. The binding constants of the PHs obtained from the fluorescence quenching data were found to be decreased with increase of temperature. The negative values of the thermodynamic parameters ΔH, ΔS and ΔG at different temperatures revealed that the binding process is spontaneous; hydrogen bonds and van der Waals interaction were the main force to stabilize the complex. The microenvironment of the protein-binding site was studied by synchronous fluorescence and circular dichroism (CD) techniques and data indicated that the conformation of BSA changed in the presence of PHs. Finally, we studied the BSA-PHs docking using Autodock and results suggest that PHs is located in the cleft between the domains of BSA.

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Synthesis and antihypertensive activities of 1,4-dihydropyridine-5-phosphonate derivatives. I.

Cited by 13 publications

References 1 publication

In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

Synthesis of 3,4-Dihydropyrimidin-2(1H)-one-phosphonates by the Microwave-Assisted Biginelli Reaction

Binding interaction of phosphorus heterocycles with bovine serum albumin: A biochemical study

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