Potent Cardioprotective Effect of the 4-Anilinoquinazoline Derivative PD153035: Involvement of Mitochondrial K(ATP) Channel Activation

Background: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function. Methodology/Principal Findings: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation. Conclusions/Significance: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

Singlet molecular oxygen trapping by the fluorescent probe diethyl-3,3 '-(9,10-anthracenediyl)bisacrylate synthesized by the Heck reaction

Singlet molecular oxygen O(2)((1)Delta(g)) is a potent oxidant that can react with different biomolecules, including DNA, lipids and proteins. Many polycyclic aromatic hydrocarbons have been studied as O(2)((1)Delta(g)) chemical traps. Nevertheless, a suitable modification in the polycyclic aromatic ring must be made to increase the yield of O(2)((1)Delta(g)) chemical trapping. With this goal, an anthracene derivative, diethyl-3,3 '-(9,10-anthracenediyl)bisacrylate (DADB), was obtained from the reaction of 9,10-dibromoanthracene and ethyl acrylate through the Heck coupling reaction. The coupling of ethyl acrylate with the anthracene ring produced a new lipophilic, esterified, fluorescent probe reactive toward O(2)((1)Delta(g)). This compound reacts with O(2)((1)Delta(g)) at a rate of k(r) = 1.69 x 10(6) M(-1) s(-1) forming a stable endoperoxide (DADBO(2)), which was characterized by UV-Vis, fluorescence, HPLC/MS and (1)H and (13)C NMR techniques. The photophysical, photochemical and thermostability features of DADB were also evaluated. Furthermore, this compound has the potential for great application in biological systems because it is easily synthetized in large amount and generates specific endoperoxide (DADBO(2)), which can be easily detected by HPLC tandem mass spectrometry (HPLC/MS/MS).

3,3-Bis[(4-chlorophenyl)sulfanyl]-1-methylpiperidin-2-one

The piperidone ring in the title compound, C(18)H(17)Cl(2)NOS(2), has a distorted half-chair conformation. The S-bound benzene rings are approximately perpendicular to and splayed out of the mean plane through the piperidone ring [dihedral angles = 71.86 (13) and 46.94 (11)degrees]. In the crystal, C-H center dot center dot center dot O interactions link the molecules into [010] supramolecular chains with a helical topology. C-H center dot center dot center dot Cl and C-H center dot center dot center dot pi interactions are also present.

5-Methyl-2,4-bis(methylsulfanyl)tricyclo[6.2.1.0(2,7)]undeca-4,9-diene-3,6-dione

The structure analysis of the title compound, C(14)H(16)O(2)S(2), shows the SMe and H atoms of the bond linking the six-membered rings to be syn and also to be syn to the bridgehead -CH(2)- group. Each of the five-membered rings adopts an envelope conformation at the bridgehead -CH(2)- group. The dione-substituted ring adopts a folded conformation about the 1,4-C center dot center dot center dot C vector, with the ketone groups lying to one side. The cyclohexene ring adopts a boat conformation.

2-Cyclohexyl-4-methyltetrahydropyran-4-ol

In the title compound, C(12)H(22)O(2), the 4-methyltetrahydropyran-4-ol ring adopts a conformation close to that of a chair and with the two O atoms syn; the cyclohexyl group occupies an equatorial position and adopts a chair conformation. In the crystal packing, supramolecular chains along the b axis are sustained by O-H center dot center dot center dot O hydrogen bonds. These are connected into undulating layers in the ab plane by C-H center dot center dot center dot O interactions.

4-Methyl-3-(2-phenoxyacetyl)-5-phenyl-1,3,4-oxadiazinan-2-one

The 1,3,4-oxadiazinane ring in the title compound, C(18)H(18)N(2)O(4), is in a twisted boat conformation. The two carbonyl groups are orientated towards the same side of the molecule. The dihedral angle between the planes of the benzene rings is 76.6 (3)degrees. Molecules are sustained in the three-dimensional structure by a combination of C-H center dot center dot center dot O, C-H center dot center dot center dot pi and pi-pi [shortest centroid-centroid distance = 3.672 (6) angstrom] interactions.

Antimicrobial activity of Piper arboreum and Piper tuberculatum (Piperaceae) against opportunistic yeasts

In the scope of our ongoing research on bioactive agents from natural sources, 24 extracts and fractions obtained from Piper arboreum Aub. and Piper tuberculatum Jacq. ( Piperaceae) were screened for antifungal activity by using broth microdilution method. The current investigation reveals that P. arboreum extracts and fractions were more effective against Candida krusei and Candida parapsilosis than Cryptococcus neoformans. The growth of Candida albicans was weakly affected by all the tested extracts and fractions. The strongest effects were observed for hexane and ethyl acetate fractions from leaves of P. arboreum, with MIC values ( in mu g/ml) of 15.6 and 31.2 mu g/ml against C. krusei, respectively. Additionally, phytochemical investigation of the hexane fraction of P. arboreum leaves furnished 3 pyrrolidine amides; piperyline, 4,5-dihydropiperyline and tetrahydropiperyline, which could be responsible, at least in part for the observed antifungal activity. The most active compound, tetrahydropiperyline, displayed MIC values of 15.6 mu g/ml against C. krusei, C. parapsilosis and C. neoformans.

(5R)-3-(2-Chloroacetyl)-4-methyl-5phenyl-1,3,4-oxadiazinan-2-one

The 1,3,4-oxadiazinan-2-one ring in the title compound, C(12)H(13)ClN(2)O(3), is in a distorted half-chair conformation. The phenyl and chloroacetyl groups occupy axial and equatorial positions, respectively, and lie to the opposite side of the molecule to the N-bound methyl substituent. Molecules are consolidated in the crystal structure by C-H center dot center dot center dot O interactions.

2-(4-Methoxyphenylsulfinyl)cyclohexan-1-one

The cyclohexanone ring in the title compound, C(13)H(16)O(3)S, is in a distorted chair conformation. The intramolecular S center dot center dot center dot O(carbonyl) distance is 2.814 (2) angstrom. Molecules are connected into a two-dimensional array via C-H center dot center dot center dot O contacts involving the carbonyl and sulfinyl O atoms.

1-Methyl-3-phenylsulfonyl-2-piperidone

The piperidone ring in the title compound, C12H15NO3S, has a slightly distorted half-chair conformation with the methyl, carbonyl and phenylsulfonyl ring substituents occupying equatorial, equatorial and axial positions, respectively. Molecules are connected into centrosymmetric dimers via C-H center dot center dot center dot O interactions and these associate into layers via C-H center dot center dot center dot O-S contacts. Further C-H center dot center dot center dot O interactions involving both the carbonyl and sulfonyl O atoms consolidate the crystal packing by providing connections between the layers.

Study of Salmonella typhimurium mutagenicity assay of (E)-piplartine by the Ames test

Phytochemical studies carried out with Piperaceae species have shown great diversity of secondary metabolites among which are several displayed considerable biological activities. The species Piper tuberculatum has been intensively investigated and a series of amides have been described. For instance, (E)-piplartine showed significant cytotoxic activity against tumor cell lines, especially human leukemia cell lines; antifungal activity against Cladosporium species; trypanocidal activity and others. Considering the popular use of P. tuberculatum and the lack of pharmacological studies regarding this plant species, the mutagenic and antimutagenic effect of (E)-piplartine was evaluated by the Ames test, using the strains TA97a, TA98, TA100 and TA102 of Salmonella typhimurium. No mutagenic activity was observed for this compound.

Morpholin-4-ium morpholine-4-carbodithioate

The title compound, C(4)H(10)NO(+)center dot C(5)H(8)NOS(2)(-), is built up of a morpholinium cation and a dithiocarbamate anion. In the crystal, two structurally independent formula units are linked via N-H center dot center dot center dot S hydrogen bonds, forming an inversion dimer, with graph-set motif R(4)(4)(12).

(4-Hydroxy-2,5-dimethylphenyl)phenylmethanone

The title compound, C(15)H(14)O(2), was obtained by Friedel-Crafts acylation between 2,5-dimethylphenol and benzoyl chloride in the presence of aluminium chloride as a catalyst. The dihedral angle between the benzene rings is 61.95 (4)degrees. In the crystal, O-H center dot center dot center dot O hydrogen bonding and C-H center dot center dot center dot O weak interactions lead to polymeric C(6), C(8) and C(11) chains along the a, b and c-axis directions, respectively.

Sodium piperidine-1-carbodithioate dihydrate

The asymmetric unit of the title compound, Na(+)center dot C(6)H(10)NS(2) center dot 2H(2)O, is composed of a sodium cation, a piperidinedithiocarbamate anion which exhibits positional disorder, and two lattice water molecules. The atoms of the piperidine ring are divided over two sites with occupancy factors of 0.554 (6) and 0.446 (6). In the crystal, the sodium cation (coordination number of 6) and the piperidinedithiocarbamate anion are linked, forming an infinite two-dimensional network extending parallel to (001). O-H center dot center dot center dot S hydrogen bonds, involving the lattice water molecules, also aid in stabilizing the crystal sructure.

Ammonium piperidine-1-carbodithioate

The title compound, NH(4) +center dot C(6)H(10)NS(2) -, is composed of an ammonium cation and a piperidine-1-carbodithioate anion which exhibits positional disorder. The atoms of the ring have a structural disorder and they are divided into two sites, with occupancy factors of 0.584 and 0.426.. In the crystal, the cation and anion are linked by N-H...S hydrogen bonds to form an infinite two-dimensional network.