Data for the cytotoxicity, self-assembling properties and synthesis of 4-pyridinium-1,4-dihydropyridines.

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 In total, 5 unpublished compounds were obtained and characterised.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.

Data for the synthesis and characterisation of 2,6-di(bromomethyl)-3,5-bis(alkoxycarbonyl)-4-aryl-1,4-dihydropyridines as important intermediates for synthesis of amphiphilic 1,4-dihydropyridines.

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 In total, 6 unpublished compounds were obtained and characterised.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.

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

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.