Synthesis and Evaluation of Reducing Capacity and Calcium Channel Blocking Activity of Novel 3,5-Dipropargylcarbonyl-Substituted 1,4-Dihydropyridines*

Ruciņš, Mārtiņš; Gosteva, Marina; Домрачева, Илона; Kanepe, I.; Belyakov, Sergey; Plotniece, Māra; Pajuste, Kārlis; Čekavičus, Brigita; Jekabsone, Madara; Sobolev, Arkadij; Шестакова, И.; Plotniece, Aiva

doi:10.1007/s10593-014-1607-z

Cited by 6 publications

(8 citation statements)

References 33 publications

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“…The synthesis of selected 4-( N -alkylpyridinium)-1,4-dihydropyridine derivatives 1 – 11 differing in alkyl chain length and propargyl moiety/ties number and position was carried out by previously described methods [22,26]. Briefly, the 1,4-DHP derivatives were synthesised via typical synthetic routes, including the classical Hantzsch method [37], which involved the one-pot cyclocondensation of the corresponding esters of acetoacetic acid, and the corresponding aldehyde and ammonia or ammonium acetate as a nitrogen source in ethanol under reflux.…”

Section: Resultsmentioning

confidence: 99%

“…All of the 1,4-DHP derivatives (see Figure 2) provided for the studies have been synthesised in the Laboratory of Membrane active compounds of the Latvian Institute of Organic Synthesis. 4-( N -Alkylpyridinium)-1,4-DHP derivatives were obtained according to the already reported methods: 1,4-DHP derivatives 1 – 6 , 10, and 11 [22] and 1,4-DHP derivatives 7 – 9 [26].…”

Section: Methodsmentioning

confidence: 99%

“…Mass spectra were obtained on a Waters Acquity ultra performance liquid chromatography (UPLC) system (Waters, Milford, MA, USA) connected to a Waters SQ Detector-2 operating in the electrospray ionization (ESI) positive ion mode on a Waters Acquity UPLC ® BEH C18 column (1.7 µm, 2.1 × 50 mm) using a gradient elution with MeCN (0.01% CF 3 CO 2 H) in water (0.01% CF 3 CO 2 H) at a flow rate 0.5 mL/min and processed with the Waters MassLynx 4.1 chromatography data system [22,26].…”

Section: Methodsmentioning

confidence: 99%

“…We also found a direct correlation between the length of the alkyl moiety at N -quaternised 4-pyridyl-1,4-DHP and improvement of membranotropic effects such as incorporation in the liposomal membranes and bilayer fluidity [25]. Furthermore, studies of the calcium channel antagonist and agonist activities of the 3,5-dipropargylcarbonyl moieties containing 4-( N -alkylpyridinium)-1,4-DHPs confirmed that these compounds targeted only calcium channels in vascular smooth muscle cells, and did not affect the calcium channels in cardiac cells [26].…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines

et al. 2019

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The design of nanoparticle delivery materials possessing biological activities is an attractive strategy for the development of various therapies. In this study, 11 cationic amphiphilic 4-(N-alkylpyridinium)-1,4-dihydropyridine (1,4-DHP) derivatives differing in alkyl chain length and propargyl moiety/ties number and position were selected for the study of their self-assembling properties, evaluation of their cytotoxicity in vitro and toxicity on microorganisms, and the characterisation of their interaction with phospholipids. These lipid-like 1,4-DHPs have been earlier proposed as promising nanocarriers for DNA delivery. We have revealed that the mean diameter of freshly prepared nanoparticles varied from 58 to 513 nm, depending upon the 4-(N-alkylpyridinium)-1,4-DHP structure. Additionally, we have confirmed that only nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3 and 6, and by 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 were stable after two weeks of storage. The nanoparticles of these compounds were found to be homogenous in size distribution, ranging from 124 to 221 nm. The polydispersity index (PDI) values of 1,4-DHPs samples 3, 6, 10, and 11 were in the range of 0.10 to 0.37. We also demonstrated that the nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3, 6, and 9, and 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 had zeta-potentials from +26.07 mV (compound 6) to +62.80 mV (compound 11), indicating a strongly positive surface charge and confirming the relative electrostatic stability of these nanoparticle solutions. Transmission electron microscopy (TEM) images of nanoaggregates formed by 1,4-DHPs 3 and 11 confirmed liposome-like structures with diameters around 70 to 170 nm. The critical aggregation concentration (CAC) value interval for 4-(N-alkylpyridinium)-1,4-DHP was from 7.6 µM (compound 11) to 43.3 µM (compound 6). The tested 4-(N-alkylpyridinium)-1,4-DHP derivatives were able to quench the fluorescence of the binary 1,6-diphenyl-1,3,5-hexatriene (DPH)—1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) system, demonstrating hydrophobic interactions of 1,4-DHPs with phospholipids. Thus, 4-(N-dodecylpyridinium)-1,4-DHP derivative 3 quenched the fluorescence of the DPH–DPPC system more efficiently than the other 4-(N-alkylpyridinium)-1,4-DHP derivatives. Likewise the compound 3, also 4-(N-dodecylpyridinium)-1,4-DHP derivative 9 interacted with the phospholipids. Moreover, we have established that increasing the length of the alkyl chain at the quaternised nitrogen of the 4-(N-alkylpyridinium)-1,4-DHP molecule or the introduction of propargyl moieties in the 1,4-DHP molecule significantly influences the cytotoxicity on HT-1080 (human fibrosarcoma) and MH-22A (mouse hepatocarcinoma) cell lines, as well as the estimated basal cytotoxicity. Additionally, it was demonstrated that the toxicity of the 4-(N-alkylpyridinium)-1,4-DHP derivatives on the Gram-positive and Gram-negative bacteria species and eukaryotic microorganism depended on the presence of the alkyl chain length at the N-alkyl pyridinium moiety, as well as the number of propargyl groups. These lipid-like compounds may be proposed for the further development of drug formulations to be used in cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines

et al. 2019

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“…To the best of our knowledge, this is a novel observation. It has been mentioned that some 3,5-dipropargyloxycarbonyl-4-N-alkylpyridinio-1,4-DHPs possess calcium antagonist activity, and also, calcium agonist activity was detected (but not measured) on H9C2 and A7R5 cells [41].…”

Section: Discussionmentioning

confidence: 99%

4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action

Домрачева

Kanepe

Vilšķe̅rsts

et al. 2020

Oxidative Medicine and Cellular Longevity

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A set of six new 4-pyridinio-1,4-dihydropyridine (1,4-DHP) compounds has been synthesized. The calcium channel modulating activity of these compounds was evaluated in an aorta vascular smooth muscle cell line (A7R5), in an isolated rat aortic ring model, and in human neuroblastoma cell lines (SH-SY5Y). The antagonistic effect of these 1,4-DHP was tested by modulating the impact of carbachol-dependent mobilization of intracellular Ca 2+ in SH-SY5Y cells. The intracellular free Ca 2+ concentration was measured in confluent monolayers of SH-SY5Y cells and A7R5 cells with the Ca 2+ -sensitive fluorescent indicator Fluo-4 NW. Only four compounds showed calcium channel blocking activity in SH-SY5Y and A7R5 cells as well as in the aortic ring model. Among them, compound 3 was the most active calcium channel antagonist, which had 3 times higher activity on carbachol-activated SH-SY5Y cells than amlodipine. Two of the compounds were inactive. Compound 4 had 9 times higher calcium agonist activity than the classic DHP calcium agonist Bay K8644. The intracellular mechanism for the action of compound 4 using inhibitor analysis was elucidated. Nicotinic as well as muscarinic receptors were not involved. Sarcoplasmic reticulum (ER) Ca 2+ (SERCA) stores were not affected. Ryanodine receptors (RyRs), another class of intracellular Ca 2+ releasing channels, participated in the agonist response evoked by compound 4. The electrooxidation data suggest that the studied compounds could serve as antioxidants in OS.

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8-Ethynylxanthines as promising antiproliferative agents, angiogenesis inhibitors, and calcium channel activity modulators

Arsenyan

Vasiljeva

Домрачева

et al. 2020

Chem Heterocycl Comp

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Synthesis and Evaluation of Reducing Capacity and Calcium Channel Blocking Activity of Novel 3,5-Dipropargylcarbonyl-Substituted 1,4-Dihydropyridines*

Cited by 6 publications

References 33 publications

Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines

Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines

4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action

8-Ethynylxanthines as promising antiproliferative agents, angiogenesis inhibitors, and calcium channel activity modulators

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