Search

The reactivity and synthetic utility of dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates 1 (2,6-heptanediones) as new fluorinated reagents prepared from the reaction of 1,4-dihydropyridines with Selectfluor® for the synthesis of carbocycles and heterocyclic bridged systems is described. The contrasting behaviour of fluorinated 2,6-heptanediones 1 towards the reaction with amines or ammonia has been revealed. 2,6-Heptanediones 1 with alkylamines form alkylammonium 3-acetyl-5-(alkyloxycarbonyl)-3,5-difluoro-2,6-dioxo-4-phenylcyclohexan-1-ides 2; however, with the less basic aniline, they do not react under similar conditions. 2,6-Heptanediones with aqueous ammonia give alkyl 4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octane-7-carboxylates 4. The cytotoxicity of 2,6-heptanediones 1a,c, the salts of 3-acetyl-5-(alkoxycarbonyl)-3,5-difluoro-2,6-dioxo-4-phenylcyclohexan-1-ides 2a,c–f, and 2-oxa-6-azabicyclo[2.2.2]octanes 4a–c on different cancer cell lines and “normal” cells has been evaluated, thus providing a basis for further studies concerning the potential use of these new compounds.

This study was focused on the estimation of the targeted modification of 1,4-DHP core with (1) different alkyl chain lengths at 3,5-ester moieties of 1,4-DHP (C12, C14 and C16), (2) N-substituent at position 1 of 1,4-DHP (N-H or N-CH3), (3) substituents of pyridinium moieties at positions 2 and 6 of 1,4-DHP (H, 4-CN and 3-Ph), (4) substituent at position 4 of 1,4-DHP (phenyl and napthyl) on physicochemical properties of the entire molecules and on the characteristics of the obtained magnetoliposomes formed by them. It was shown that thermal behavior of the tested 1,4-DHP amphiphiles was related to the alkyl chains length, the elongation of which decreased their transition temperatures. The properties of 1,4-DHP amphiphile monolayers and their polar head areas were determined. The packing parameters of amphiphiles were in the 0.43–0.55 range. It was demonstrated that the structure of 1,4-DHPs affected the physicochemical properties of compounds. “Empty” liposomes and magnetoliposomes were prepared from selected 1,4-DHP amphiphiles. It was shown that the variation of alkyl chains length or the change of substituents at positions 4 of 1,4-DHP did not show a significant influence on properties of liposomes.

Three groups of synthetic lipids are chosen for studies: (1) 1,4-dihydropyridines (1,4-DHPs) containing two cationic moieties and their analogues; (2) 3,4-dihydro-2(1H)-pyridones containing a cationic moiety; and (3) acyclic, open-chain analogues, i.e., 2-amino-3-alkoxycarbonylalkylammonium derivatives. 1,4-DHPs possessing dodecyl alkyl chains in the ester groups in positions 3 and 5 and cationic nitrogen-containing groups in positions 2 and 6 have high cytotoxicity in cancer cells HT-1080 (human lung fibrosarcoma) and MH-22A (mouse hepatoma), but low cytotoxicity in the noncancerous NIH3T3 cells (mouse embryonic fibroblast). On the contrary, similar compounds having short (methyl, ethyl, or propoxyethyl) chains in the ester groups in positions 3 and 5 lack cytotoxicity in the cancer cells HT-1080 and MH-22A even at high doses. Inclusion of fluorine atoms in the alkyl chains in positions 3 and 5 of the DHP cycle decreases the cytotoxicity of the mentioned compounds. Structurally related dihydropyridones with a polar head group are substantially more toxic to normal and cancerous cells than the DHP analogues. Open-chain analogues of DHP lipids comprise the same conjugated aminovinylcarbonyl moiety and possess anticancer activity, but they also have high basal cytotoxicity. Electrochemical oxidation data demonstrate that oxidation potentials of selected compounds are in the range of 1.6–1.7 V for cationic 1,4-DHP, 2.0–2.4 V for cationic 3,4-dihydropyridones, and 1.2–1.5 V for 2-amino-3-alkoxycarbonylalkylammonium derivatives. Furthermore, the tested cationic 1,4-DHP amphiphiles possess antiradical activity. Molecular topological polar surface area values for the tested compounds were defined in accordance with the main fragments of compound structures. The determined log P values were highest for dodecyl ester groups in positions 3 and 5 of the 1,4-DHP and lowest for short alkyl chain-containing amphiphiles.

In this data file the synthetic procedures for preparation of the original 4-pyridinium-1,4-dihydropyridines (4-Py-1,4-DHP) and their parent compounds – dialkyl 2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylates were described. In total, 5 unpublished compounds were obtained and characterised. All the structures of original compounds were confirmed by Nuclear Magnetic Resonance (NMR, including 1H NMR and 13C NMR) and low resolution mass spectra (MS) data. Additionally, the cytotoxic properties of four 4-Py-1,4-DHPs were evaluated on 3 cell lines – normal NIH3T3 (mouse embryonic fibroblast), cancerous HT-1080 (human lung fibrosarcoma) and MH-22A (mouse hepatoma) and self-assembling properties were studied and characterisation of formed nanoparticles were performed using dynamic light scattering technique. In this article provided data are directly related to the previously published research articles – “Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery” [1] where compound 5 was tested as gene delivery agent without full physico-chemical characterisation and “Synthesis and studies of calcium channel blocking and antioxidant activities of novel 4-pyridinium and/or N-propargyl substituted 1,4-dihydropyridine derivatives” [2] where synthesis and physico-chemical characterisation as well as calcium channel blocking and antioxidant activities were described for compound 6. Synthesis of other compounds – parent 1,4-DHPs 1 and 2, and 4-Py-1,4-DHPs 3–5, their characterisation, estimation of cytotoxicity and self-assembling properties for all 4-Py-1,4-DHPs 3–6 are reported herein for the first time. Information provided in this data file can be used in medicinal chemistry by other scientists to estimate structure-activity relationships for the analysis and construction of various cationic 1,4-dihydropyridine derivatives and related heterocycles.

New fluorinated 3,6-dihydropyridines were obtained by the electrophilic fluorination of 1,2-dihydropyridines with Selectfluor&reg, These 3-fluoro-3,6-dihydropyridines were easily converted to corresponding pyridines by the elimination of hydrogen fluoride under mild conditions. A new approach to the synthesis of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates by the fluorination of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines or 1,2-dihydropyridines with Selectfluor&reg, has been developed.

This data file describes the synthetic protocol for preparation of the original 2,6-di(bromomethyl)-3,5-bis(alkoxycarbonyl)-4-aryl-1,4-dihydropyridines. In total, 6 unpublished compounds were obtained and characterised. The 2,6-di(bromomethyl)-1,4-dihydropyridines are mainly used as intermediates for synthesis of various lipid-like compounds based on 1,4-dihydropyridine cycle. All the structures of 2,6-di(bromomethyl)-1,4-dihydropyridines were confirmed by Nuclear Magnetic Resonance (NMR, including 1H NMR and 13C NMR) data. The data provided herein are directly related to the previously published research article – “Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery” [1] where three derivatives (2,6-di(bromomethyl)-4-phenyl-1,4-dihydropyridines 2a-c) from six presented in this data file were used as starting materials in synthesis of amphiphilic 1,4-dihydropyridines without any purification and characterisation. Synthesis of other three 2,6-di(bromomethyl)-3,5-bis(alkoxycarbonyl)-4-aryl-1,4-dihydropyridines 2d-f and their characterisation are reported herein at the first time. Information provided in this data file can be used in organic synthesis by other chemists to develop synthetic strategies for the construction of various cationic 1,4-dihydropyridine derivatives and related heterocycles.

The contamination of water represents a major problem in many parts of the world. Endocrine disrupting compounds belong to the water contaminants and affect, besides other things, hormonal equilibrium in the living organisms. Such compounds are of different chemical structures and there is a demand for their fast determination in water samples. In our work, we focused on the development of a simple and fast method for separation and determination of five model hormone antagonists, exemestane, toremifene, letrozole, anastrozole, and mifepristone, by micellar electrokinetic chromatography. Within the best conditions, 50 mM sodium borate pH 9.5, 50 mM SDS, 15% 1-propanol, 20 kV, the separation of all the compounds lasted 8 min. The method was successfully validated with LODs of 1.2–7.7 µg mL−1, LOQs of 4.0–25.6 µg mL−1 and intraday repeatability of peak areas of 0.8–1.1%. Moreover, it was applied to the analysis of spiked water samples from a local waste-water treatment plant using SPE as a pretreatment step.

Katarzyna Niemirowicz-Laskowska,1 Katarzyna Głuszek,1 Ewelina Piktel,1 Karlis Pajuste,2 Bonita Durnaś,3 Grzegorz Król,3 Agnieszka Z Wilczewska,4 Paul A Janmey,5 Aiva Plotniece,2 Robert Bucki1 1Department of Microbiological and Nanobiomedical Engineering, Medical University of Bialystok, Bialystok, Poland; 2Laboratory of Membrane Active Compounds and β-Diketones, Latvian Institute of Organic Synthesis, Riga, Latvia; 3Department of Microbiology and Immunology, The Faculty of Health Sciences of the Jan Kochanowski University in Kielce, Kielce, 4Institute of Chemistry, University of Bialystok, Białystok, Poland; 5Department of Physiology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA Background: 1,4-Dihydropyridine (1,4-DHP) and its derivatives are well-known calcium channel blockers with antiarrhythmic and antihypertensive activities. These compounds exhibit pleiotropic effects including antimicrobial activities that rely on their positive charge and amphipathic nature. Use of magnetic nanoparticles (MNPs) as carriers of 1,4-DHP modulates their properties and enables improved formulations with higher efficacy and less toxicity. Methods: In this study, the antimicrobial and immunomodulatory activities of novel 1,4-DHP derivatives in free form and immobilized on MNPs were determined by evaluating pathogen outgrowth and proinflammatory cytokine release in experimental settings that involve incubation of various 1,4-DHPs with clinical isolates of bacteria or fungi as well as mammalian cell culture models. Results: Conventional immobilization of 1,4-DHP on aminosilane-coated MNPs markedly enhances their antimicrobial activity compared to nonimmobilized molecules, in part because of the higher affinity of these nanosystems for bacterial cell wall components in the presence of human body fluids. Conclusion: Optimized nanosystems are characterized by improved biocompatibility and higher anti-inflammatory properties that provide new opportunities for the therapy of infectious diseases. Keywords: magnetic nanoparticles, 1,4-dihydropyridine, antibacterial, antifungal, immunomodulatory properties

Electrophilic fluorination of Hantzsch-type 1,4-dihydropyridines with Selectfluor® led to the formation of new fluorinated 2,6-heptanediones - dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates. Novel 2,6-heptanedione derivatives in reaction with hydrazine hydrate easily form 6-amino-4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octanes instead of the corresponding diazepine derivatives. The obtained 2-оxa-6-azabicyclo[2,2,2]octanes are thermally stable at the temperatures below 50°С. At higher temperatures rearrangement of 2-oxa-6-azabicyclo[2,2,2]octanes offers new fluorine-containing pyrazolinone derivatives - alkyl esters of 2-fluoro-2-((4-fluoro-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)-3-oxobutanoates.

The synthesis of multisubstituted 4-nitrobuta-1,3-dien-1-amines (nitrodienamines) from 3-aminocrotonates and nitroacetaldehyde potassium salt, has been performed in 45–89% yields. This one-step protocol works efficiently with a broad range of N-H and N-substituted 3-aminocrotonates and delivers both primary and secondary nitrodienamines. In addition, the possible variations of the substituents at the positions 2 and 3 of 4-nitrobuta-1,3-dien-1-amine have been shown. Generally, the yields of secondary 4-nitrobuta-1,3-dien-1-amines were lower than those of primary ones. The synthetic usefulness of obtained 4-nitrobuta-1,3-dien-1-amines has also been demonstrated by achieving the synthesis of multisubstituted 5-nitro-1,6-dihydropyridines in two-component cyclocondensation reactions of 4-nitrobuta-1,3-dien-1-amines with aromatic or aliphatic aldehydes. Lastly, diverse N-H and N-substituted 5-nitro-1,6-dihydropyridines have been obtained in 35–87% yields.

The use of 1,4-dihydropyridine (DHP) vesicles as drug delivery agents can improve the diffusion of nucleoside and nucleotide prodrugs through the cellular membrane without degradation. Different NMR studies: spin–lattice relaxation in the rotating frame (T1ρ), saturation transfer double difference (STDD), 1H NMR chemical shift titration, as well as isothermal titration calorimetry (ITC) experiments, showed that mononucleotides bind to 1,4-DHP vesicles. The influence of the structure of the mononucleotides as well as that of the derivatives of 1,4-DHP on the complexation parameters was studied.

The effects of eleven 1,4-dihydropyridine derivatives (DHPs) used alone or together with prooxidant anticancer drug doxorubicin were examined on two cancer (HOS, HeLa) and two nonmalignant cell lines (HMEC, L929). Their effects on the cell growth (3H-thymidine incorporation) were compared with their antiradical activities (DPPH assay), using well-known DHP antioxidant diludine as a reference. Thus, tested DHPs belong to three groups:(1)antioxidant diludine;(2)derivatives with pyridinium moieties at position 4 of the 1,4-DHP ring;(3)DHPs containing cationic methylene onium (pyridinium, trialkylammonium) moieties at positions 2 and 6 of the 1,4-DHP ring. Diludine and DHPs of group 3 exerted antiradical activities, unlike compounds of group 2. However, novel DHPs had cell type and concentration dependent effects on3H-thymidine incorporation, while diludine did not. Hence, IB-32 (group 2) suppressed the growth of HOS and HeLa, enhancing growth of L929 cells, while K-2-11 (group 3) enhanced growth of every cell line tested, even in the presence of doxorubicin. Therefore, growth regulating and antiradical activity principles of novel DHPs should be further studied to find if DHPs of group 2 could selectively suppress cancer growth and if those of group 3 promote wound healing.

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 &micro, M (compound 11) to 43.3 &micro, M (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)&mdash, 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&ndash, 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.

The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.

A series of variously substituted 5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives were synthesized and their oxidation potentials determined by cyclic voltammetry. The resulting 2-pyridone structure and a tricyclic heterocycle which was formed during an attempted synthesis of 4-(2-hydroxyphenyl) substituted 3,4-dihydro-2(1H)-pyridone were confirmed by single crystal X-ray crystallography.

The purpose of this review is to highlight recent developments in the synthesis of chiral 1,4-dihydropyridines and their fused analogues. 1,4-Dihydropyridines are among the most active calcium antagonists that are used for the treatment of hypertension. Enantiomers of unsymmetrical 1,4-dihydropyridines often show different biological activities and may have even an opposite action profile. Hantzsch synthesis usually produces racemic mixtures of unsymmetrical 1,4-dihydropyridines. Therefore, the development of stereoselective synthesis of 1,4-dihydropyridines is one of the priorities of medicinal chemistry. Over the years, numerous methodologies have been developed for the production of enantiopure 1,4-dihydropyridines, such as stereoselective synthesis using chiral auxiliaries and chiral cyclocondensation partners, chromatographical methods, resolution of diastereomeric 1,4-dihydropyridine salts, enzyme catalysed kinetic resolution, or asymmetrisation of ester groups of 1,4-dihydropyridines. These approaches have been studied in detail and are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. Substantial progress has been made toward the development of enantioselective organocatalytic methods for the construction of the chiral dihydropyridines. However, most of them do not provide a convenient way to pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates. Organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes also has great promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates.

Complex, focused anticancer therapy approach has been developed in the Latvian Institute of Organic Synthesis by making use of privileged partially hydrogenated nitrogen-containing heterocycles, namely dihydropyridines, dihydropyrimidines, their oxidized heteroaromatic derivatives. Topics of research include: 1. Conventional approach by chemotherapy and synergism of anticancer drugs [1]; 2. Inhibition of multidrug resistance by inhibition of drug efflux pumps [2]; 3. Mitigation of cancer risk factors – e.g., hepatitis B virus chemotherapy for prevention of chronic liver diseases, because chronic hepatitis, in up to 40% of cases, progresses to cyrrhosis and further to hepatocellular carcinoma [3]; 4. Improvement of efficacy of cancer radiotherapy by use of radioprotectors to prevent damage of normal tissues. So, radioprotector diethone (dietone) for skin protection was discovered, elaborated, and developed as ointment. Compounds for protection of eyes, mucous tissues, salivary glands etc have been synthesized. Toxicity of dietone and novel radioprotectors is very low; 5.Amphiphilic compounds have been synthesized, nanoparticles for anticancer drug and gene delivery have been created, pleiotropic properties have been checked, inclusion of magnetic particles for targeted transport performed [4]. Acknowledgements The research was partially supported by the Latvian State Program Biomedicine. References 1.Bisenieks E., Duburs G. et al., Pharmaceutical combination of 5-fluorouracil and derivatives of 1,4-dihydropyridine. US 8492413B2, 2013. 2.Krauze A., Grinberga S. et al., Thieno[2,3-b]pyridines – a new class of multidrug resistance (MDR) modulators. Bioorg.Med.Chem. 2014, 22 (21), 5860-5870. 3.Sipola A., Dubova U., et al., Synthesis and evaluation of 1,4-dihydropyrimidine derivatives – hepatitis B virus capsid self-assembly inhibitors. EFMC International Symposium on Medicinal Chemistry. Ljubljana, Slovenia, 2018, P176. 4.Pajuste K. et al., Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J.Chem. 2013, 37 (10), 3062-3075.

This work demonstrates studies of ferromagnetic nanoparticle functionalization by a lipid-like compound, cationic pyridine amphiphile derived from 1,4-dihydropyridine, 1,1'-{[3,5-bis(dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]dimethanediyl}dipyridinium dibromide, and determination of optimal conditions for the production of magnetoliposomes. The following methodologies, such as sonication, spontaneous swelling, and reverse-phase evaporation, were used for the preparation of liposomes. Ferrofluid containing γ-Fe2O3 nanoparticles with a positively charged surface was used for the preparation of magnetoliposomes. The obtained soft matter objects were studied by optical microscopy, transmission electron microscopy, and dynamic light scattering techniques. The optimal conditions for the production of magnetoliposomes were found by spontaneous swelling and reverse-phase evaporation methods using ferrofluid with positively charged γ-Fe2O3 nanoparticles and cationic 1,4-dihydropyridine derivative.

This microreview is devoted to the specific recent synthetic approaches toward 1,4-dihydropyridines which represent significant group of N-containing heterocycles due to the wide applications of their pharmacological activities. Mainly 1,4-dihydropyridines are synthesized in Hantzsch reaction and its modifications. Nowadays a number of strategies and various catalysts or catalytic systems have been developed to improve the yields of 1,4-dihydropyridines and to reduce chemical impact on environment. Here the contemporary synthetic aspects from last five years such as use of ionic liquids, metal oxide nanoparticles and some reports about enzymatic approaches are discussed.

Methylene bridged polycyclic diazocines 2a and 2b were obtained in reactions of 1,3-indanedione, or benzo[b]thiophen-3(2H)one-1,1-dioxide, or 2,2′-methylene derivatives 3a,b with paraformaldehyde and ammonia or hexamethylenetetramine in acidic medium. A structural revision of methylene bridged benzothieno-diazocine 2b based on results of X-ray diffraction analysis is presented. Internal rearrangement of methylene bridged polycyclic diazocines into spiroheterocycles 4a,b is also described.

A reaction of diethyl 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylate with 1, 2, and more equivalents of N-bromosuccinimide (NBS) in methanol was investigated by NMR spectroscopy at a temperature interval ranging from 25 to 40°C. The reaction was found to proceed through several steps. The structures of the intermediates diethyl 3-bromo-2,4,6-trimethyl-3,4-dihydropyridine-3,5-dicarboxylate, diethyl 3-bromo-2-methoxy-2,4,6-trimethyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate, and diethyl 3,5-dibromo-2-methoxy-2,4,6-trimethyl-2,3,4,5-tetrahydropyridine-3,5-dicarboxylate were identified by multinuclear (1H, 13C, and 15N) NMR spectral data. The optimal structures of all species participating in the reaction as well as changes in their relative energies along with the proposed pathway of the reaction were analyzed by quantum-chemical calculations. The mechanism of bromination of diethyl 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylate with NBS in methanol was found to favor the bromination in the 2,6-methyl side chains as the only products in full agreement with experimental observations.

Structural characteristics of 1,4-dihydropyridines influencing the nonequivalence of the diastereotopic methylene protons in substituents at positions 2 and 6 were studied. The combined effect of magnetically anisotropic groups and intramolecular hydrogen bonds leads to a considerable difference in the chemical shifts of the methylene protons of the AB system. The unusual reversible temperature evolution of these proton signals in monocyclic 1,4-dihydropyridines is associated with two simultaneous conformational processes. It was estimated that the energetically most favorable conformations are stabilized by an intramolecular СН⋯О hydrogen bond.

The novel 1,4-dihydropyridine derivatives containing the cationic pyridine moiety at the position 4, and the N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle were designed, synthesised, and assessed in biological tests. Among all the novel compounds, the 4-(N-dodecyl) pyridinium group-containing compounds 11 (without the N-propargyl group) and 12 (with the N-propargyl group) demonstrated the highest calcium antagonistic properties against neuroblastoma SH-SY5Y (IC50 about 5–14 mM) and the vascular smooth muscle A7r5 cell (IC50 – 0.6–0.7 mM) lines, indicating that they predominantly target the L-type calcium channels. These compounds showed a slight total antioxidant activity. At concentrations close to those of L-type calcium channel blocking ones, compound 12 did not affect mitochondrial functioning; also, no toxicity was obtained in vivo. The N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle did not essentially influence the compounds’ activity. The 4-(N-dodecyl) pyridinium moiety-containing compounds can be considered as prototype molecules for further chemical modifications and studies as cardioprotective/neuroprotective agents. This study was supported by ESF project No. 2009/ 0217/1DP/1.1.1.2.0/09/APIA/VIAA/031; the EuroNanoMed project ‘‘CheTherDel’’; Portuguese Research Council (FCT), Faculty of Medicine, Centre for Neuroscience and Cell Biology (CNC) and Marine and Environmental Research Centre (IMAR–CMA) of the University of Coimbra, Portugal.

In this work we describe the studies of preparation and stability of liposomes formed by 1,1'-[(3,5-didodeciloxycarbonyl-4-phenyl-1,4-dihydropyridine-2,6-diil) dimethylebispyridinium dibromide, novel lipid-like compound. The influence of the amount of amphiphilic compound, solvent and sonication time was studied. Liposomes were prepared by dispersing of compound in the corresponding media at a selected concentration by sonication using a probe type sonicator and characterised by atomic force microscopy (AFM) and dynamic light scattering (DLS) methods.

Polycyclic 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides and 4,5-dihydro-1H-indeno[1,2-b]pyridines having ester or cyano group at the position 3 of dihydropyridine ring have been synthesised. Reactivity of N-bromosuccinimide (NBS) towards polycyclic 1,4-dihydropyridine derivatives has been investigated. It has been found that 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides are easily oxidised with NBS in methanol at rt in high yields, whereas 4,5-dihydro-1H-indeno[1,2-b]pyridines in reaction with NBS in methanol are brominated at 4a position affording stable 4a-bromo-4a,5-dihydroindeno[1,2-b]pyridine-3-carboxylates or unstable 3-carbonitriles, which rapidly undergo dehydrobromination reaction leading to the corresponding 5H-indeno[1,2-b]pyridine-3-carbonitriles.

Based on x-ray diffraction analysis, we have proved that the recently published results for ethyl 6-amino-5-cyano-4-aryl-1,4-dihydropyridine-3-carboxylate synthesis is in fact an environmentally friendly synthesis of 6-amino-5-cyano-4-aryl-4H-pyran derivatives using a multicomponent room-temperature grinding procedure of ethyl acetoacetate, [(2-aryl)methylene]malononitriles, and ammonium acetate.

The synthesis of a series of new π-conjugated amphiphilic derivatives of carbazole of the "stilbene" type, substituted with N-alkylpyridinium groups at positions 2 and 7, is described. Due to the presence of polar cationic groups and nonpolar alkyl substituents, the obtained compounds are potentially capable of acting as agents for the transportation of genetic material inside a cell, and the extended and effective conjugation chain leads to the appearance of intense photoluminescence both in solutions and in biological media, making it possible to use them as cell probes. The absorption maxima of the compounds are in the region of 422-450 nm, while the luminescence maxima are in the yellow-green region at 575-617 nm.

Cyclisation of γ-halo-β-ketoesters with aromatic amines and aldehydes in methanol gave novel polysubstituted 3-pyrroline derivatives. A plausible mechanism for the reaction has been proposed. The structures of 1,2,3,4-tetrasubstituted 3-pyrrolines were confirmed by NMR spectroscopy and X-ray crystallography.

The diastereotopy of the methylene protons at positions 2 and 6 in 1,4-dihydropiridine derivatives with various substituents has been investigated. NMR spectroscopy and quantum chemistry calculations show that the CH···O intramolecular hydrogen bond is one of the factors amplifying the chemical shift differences in the 1H-NMR spectra.

The effect of the solvent nature and temperature on the quaternization of 3,5-diethoxycarbonyl-2,6-di- methyl-4-(3-pyridyl)-1,4-dihydropyridine by lipophilic alkyl bromides has been investigated. By comparison of the solvent effect (acetone, acetonitrile, and 2-butanone) on the alkylation of the pyridine fragment of 3,5-diethoxycarbonyl-2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine it was established that conducting the reaction in acetonitrile at 81 °C is the most optimal.