Estael Ochoa Rodríguez

Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine–dihydropyridine hybrid molecule

Abstract Objectives: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. Methods: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. Results: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure’s onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. Conclusions: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.

The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms

Several 1,4-dihydropyridine derivatives overcome the multidrug resistance in tumors, but their intrinsic cytotoxic mechanisms remain unclear. Here we addressed if mitochondria are involved in the cytotoxicity of the novel 1,4-dihydropyridine derivative VE-3N [ethyl 6-chloro-5-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In HepG2 cells, VE-3N induced mitochondrial membrane potential dissipation, ATP depletion, annexin V/propidium iodide double labeling, and Hoechst staining; events indicating apoptosis induction. In isolated rat liver mitochondria, VE-3N promoted mitochondrial uncoupling by exerting protonophoric actions and by increasing membrane fluidity. Mitochondrial uncoupling was evidenced by an increase in resting respiration, dissipation of mitochondrial membrane potential, inhibition of Ca2+ uptake, stimulation of Ca2+ release, decrease in ATP synthesis, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. Furthermore, uncoupling concentrations of VE-3N in the presence of Ca2+ plus ruthenium red induced the mitochondrial permeability transition process. These results indicate that mitochondrial uncoupling is potentially involved in the VE-3N cytotoxic actions towards HepG2 cells. Considering that hepatocellular carcinoma is the most common form of liver cancer, our findings may open a new avenue for the development of VE-3N-based cancer therapies, and help to unravel the cytotoxic mechanisms of 1,4-dihydropyridines towards cancer cells.

Ethyl methyl 1,4-dihydro-4-(3-nitrophenyl)-2, 6-bis(1-piperidylmethyl)pyridine-3,5-dicarboxylate.

In the title compound, C(28)H(38)N(4)O(6), the 4-aryl substituent occupies a pseudo-axial position approximately orthogonal to the plane of the dihydropyridine ring [88.1 (3) degrees ]. The dihydropyridine ring adopts a flattened boat conformation. The H atom on the pyridine N atom is involved in a bifurcated intramolecular hydrogen bond, the acceptors being the N atoms of the two piperidylmethyl groups [N.N 2.629 (4) and 2.695 (4) A].

3,3,6,6-Tetramethyl-9-(3-nitrophenyl)-3,4,5,6,9,10-hexahydroacridine-1,8(2H,7H)-dione

In the title compound, C 23 H 26 N 2 O 4 , the central ring adopts a distorted boat conformation, while the two outer rings are almost in ideal envelope conformations. The molecular packing is stabilized by van der Waals interactions and hydrogen bonds.

3‐(2‐Hydroxyphenylamino)‐5,5‐dimethylcyclohex‐2‐enone

In the title compound, C 14 H 17 NO 2 , the molecules are linked through two hydrogen bonds to form a two-dimensional network in the (100) plane. The carbonyl-O atom is involved in two intermolecular hydrogen bonds, one with the amino group and the other with the hydroxy group. The cyclohexenone ring is disordered into two distorted half-chair conformations. The phenyl and cyclohexenone moieties are not coplanar.

5-Methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydro-2(1H)-pyridone

Crystals of the title compound, C 14 H 15 NO 3 are stabilized by intermolecular hydrogen bonds between the NH group and one O atom of the carbonyl group. The six-membered ring adopts a twist conformation and the lactone ring a planar conformation.