3-{3,5-Bis[(2-but-oxy-eth-oxy)carbon-yl]-2,6-dimethyl-1,4-dihydro-pyridin-4-yl}-1-[(3,4,5-trimeth-oxy-benzo-yl)meth-yl]pyridinium bromide.

In the title salt, C37H51N2O10(+)·Br(-), the 1,4-dihydro-pyridine (1,4-DHP) ring adopts a slighly puckered boat conformation. The N and opposite C atoms deviate from the least-squares plane calculated through the four other ring atoms by 0.068 (5) and 0.224 (5) Å, respectively. The orientation of both C=O groups is similar (cis with respect to the double bonds of 1,4-DHP. The pyridinium ring has an axial orientation with respect to the1,4-DHP ring and is almost perpendicular to the least-squares plane of the 1,4-DHP ring, making a dihedral angle of 89.2 (3)°. The mol-ecule has a compact shape due to the parallel orientation of the long-chain substituents. One of the but-oxy groups was fond to be disordered (occupancy ratio 0.70:0.30). In the crystal, the bromide anion accepts a weak hydrogen bond from the N-H group of a neighboring 1,4-DHP ring.

3-Acetyl-2-methyl-4-(pyridin-3-yl)-1,4-di-hydro-indeno-[1,2-b]pyridin-5-one.

In the title compound, C20H16N2O2, the condensed tricyclic fragment is near to planar, with an r.m.s. deviation of 0.0531 Å. The 1,4-di-hydro-pyridine (1,4-DHP) ring adopts a slightly puckered boat-like conformation. The N and opposite C atoms deviate from the least-squares plane of the four other ring atoms by 0.039 (3) and 0.141 (3) Å, respectively. The C=O group located at the tricyclic fragment is fixed in an s-trans orientation, while the second C=O group adopts an s-cis orientation with respect to the double bonds of the 1,4-DHP ring. The pyridine ring has a pseudo-axial orientation with respect to the 1,4-DHP ring. The dihedral angle between the tricyclic system and the pyridine ring is 77.3 (3)°. In the crystal, the pyridine N atom accepts a hydrogen bond from the N-H group of the 1,4-DHP ring. The hydrogen bonds link the mol-ecules into infinite C(8) chains along the b-axis direction.

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

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 Ca2+ in SH-SY5Y cells. The intracellular free Ca2+ concentration was measured in confluent monolayers of SH-SY5Y cells and A7R5 cells with the Ca2+-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) Ca2+ (SERCA) stores were not affected. Ryanodine receptors (RyRs), another class of intracellular Ca2+ 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.

Crystal structure and metabolic activity of 4-(thien-2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxy-lic acid eth-oxy-carbonyl-phenyl-methyl-ester.

In the title compound, C25H25NO5S, which exhibits metabolism-regulating activity, the 1,4-di-hydro-pyridine ring adopts a flattened boat conformation while the cyclo-hexenone ring is in an envelope conformation. Mol-ecules in the crystal are assembled into C(6) chains along the a-axis direction via N-H⋯O hydrogen bonds. The thienyl fragment is disordered over two sets of sites in a 0.7220 (19):0.2780 (19) ratio.

Antioxidative 1,4-Dihydropyridine Derivatives Modulate Oxidative Stress and Growth of Human Osteoblast-Like Cells In Vitro.

Oxidative stress has been implicated in pathophysiology of different human stress- and age-associated disorders, including osteoporosis for which antioxidants could be considered as therapeutic remedies as was suggested recently. The 1,4-dihydropyridine (DHP) derivatives are known for their pleiotropic activity, with some also acting as antioxidants. To find compounds with potential antioxidative activity, a group of 27 structurally diverse DHPs, as well as one pyridine compound, were studied. A group of 11 DHPs with 10-fold higher antioxidative potential than of uric acid, were further tested in cell model of human osteoblast-like cells. Short-term combined effects of DHPs and 50 µM H2O2 (1-h each), revealed better antioxidative potential of DHPs if administered before a stressor. Indirect 24-h effect of DHPs was evaluated in cells further exposed to mild oxidative stress conditions induced either by H2O2 or tert-butyl hydroperoxide (both 50 µM). Cell growth (viability and proliferation), generation of ROS and intracellular glutathione concentration were evaluated. The promotion of cell growth was highly dependent on the concentrations of DHPs used, type of stressor applied and treatment set-up. Thiocarbatone III-1, E2-134-1 III-4, Carbatone II-1, AV-153 IV-1, and Diethone I could be considered as therapeutic agents for osteoporosis although further research is needed to elucidate their bioactivity mechanisms, in particular in respect to signaling pathways involving 4-hydroxynoneal and related second messengers of free radicals.

Dihydropyridine Derivatives as Cell Growth Modulators In Vitro.

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 on 3H-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.