Biochemical, histopathological and ultrastructural changes in rat liver induced by r-( + )-pulegone, a monoterpene ketone

Biochemical, histopathological and ultrastructural changes occurring at different time points after intraperitoneal administration of a single dose of pulegone (300 mg/kg) were studied. Significant decreases in the level of liver microsomal cytochrome P-450 (67%), heme (37%), aminopyrine N-demethylase (60%) and glucose-6-phosphatase (58%), were noticed 24 hr after pulegone treatment. Alanine amino transferase (ALT) levels increased in a time dependent manner, following exposure of rats to pulegone. Light microscopic studies of liver tissues showed dilation of central veins and distention of sinusoidal spaces 6 hr after pulegone treatment. Initial centrilobular necrosis was noticed at 12 hr. Centrilobular necrosis became severe at 18 hr and nuclear changes included karyorrhexis and karyolysis. Midzonal and periportal degenerative changes in addition to centrilobular necrosis was observed 24 hr after pulegone administration. Electron microscopic changes showed severe degeneration of endoplasmic reticulum, swelling of mitochondria and nuclear changes, 24 hr after administration of pulegone. The time course profile of the hepatocytes after treatment with pulegone indicates that endoplasmic reticulum is the organelle most affected, following which other degenerative changes occur ultimately leading to cell death.

Destruction Of Rat-Liver Microsomal Cytochrome-P-450 Invitro By A Monoterpene Ketone, Pulegone A Hepatotoxin

Significant destruction (68%) of liver microsomal cytochrome P-450 and homogeneous cytochrome P-450 purified from PB-treated rats is noticed upon incubation with 10 mM pulegone at 37-degrees-C for 30 min. There is also a concomitant loss of heme. The destructive phenomenon does not require metabolic activation of pulegone. The destruction of purified cytochrome P-450 is time-dependent and saturable. Structure-activity studies suggest that an alpha-isopropylidine ketone unit with a methyl positioned para to the isopropylidine group as in pulegone is necessary for the in vitro destruction of cytochrome P-450. SKF-525A at a concentration of 4-mM obliterates the destruction of cytochrome P-450 by pulegone. Experiments with C-14-pulegone suggest that pulegone or its rearranged product binds covalently to the prosthetic heme of cytochrome P-450.

b-Turn conformations in crystal structures of model peptides containing a,a-di-n-propylglycine (Dpg) and a,a-di-n-butyl-glycine (Dbg).

The crystal state conformations of three peptides containing the a,a-dialkylated residues, a,adi n-propylglycine (Dpg) and a,@-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Ala-OMe ( I ) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II @-turn conformations with Ala ( I ) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: 4 = 66.23 J/ = 19.3'; III: 4 = 66S0, J. = 21 .la)deviate appreciablyfrom ideal values for the i + 2 residue in a type II @-turn. In both peptides the observed(N. 0) distances between the Boc CO andAla(3) NHgroups are far too long (I:3.44 k; III: 3.63 k) for an intramolecular 4 + 1 hydrogen bond. Boc-Ala-Dpg-Ala-NHMe (II)crystallizes with two independent molecules in the asymmetric unit. Both molecules IIA and IIB adopt consecutive @-turn (type III-III in IIA and type III-I in IIB) or incipient 3,,,-helical structures, stabilized by two intramolecular 4 --t I hydrogen bonds. In all four molecules the bond angle N-C"-C' ( T ) at the Dxg residues are 2 1109 The observation of conformational angles in the helical region of 4,J/ space at these residues is consistent with theoretical predictions

One pot synthesis of polycyclic oxygen aromatics. Part IV reaction of THP ether of 2-bromomethyl phenols

Reaction of 2-bromomethyl-1-(2′-tetrahydropyranyloxy) benzene 3a with tetrachlorocatechol(TCC) in acetone in presence of anhydrous K2CO3 resulted in the formation of diastereomeric products to which cis- & trans- 6-chloro-8-hydroxy-8-(2-oxopropyl)spiro[9H-benzo[a]xanthen- 9,2′(1′H) benzofuran]-7(8H)-one (7a & 8a) structures were assigned, along with tetrachlorocatechol ethers (5a & 6a). Similar reaction of 3a with tetrabromocatechol(TBC) gave the expected monobromo compounds 7d & 8d along with the ethers 5d & 6d. When the reaction was repeated with substrates 3b–c with TCC/TBC in ketonic solvents(acetone/methyl ethyl ketone), the corresponding compounds 5b–c to 8b–c, 5e–f to 6e–f, 7e–g & 8e–h were obtained. A suitable explanation has been given for the formation of acetonyl compound 6 in this reaction.

Studies on the metabolism of a monoterpene ketone, R-(+)-pulegone-a hepatotoxin in rat: isolation and characterization of new metabolites

1. The metabolic disposition of R-(+)-pulegone (1) was examined in rats following four daily oral doses (250 mg/kg). 2. Six metabolites, namely pulegol (II), 2-hydroxy-2-(1-hydroxy-1-methylethyl)-5-methylcyclohexanone (III), 3,6-dimethyl-7a-hydroxy-5,6,7,7a-tetrahydro-2(4H)-benzofuranone (IV), menthofuran (V), 5-methyl-2-(1-methyl-1-carboxyethylidene)cyclohexanone (VI), and 5-methyl-5-hydroxy-2-(1-hydroxy-1-carboxyethyl)cyclohexanone (VII) have previously been isolated from rat urine, and identified (Moorthy et al. (1989a). Eight new metabolites have now been isolated from rat urine, namely, 5-hydroxy-pulegone (VIII), piperitone (IX), piperitenone (X), 7-hydroxy-piperitone (XI), 8-hydroxy piperitone (XII), p-cresol (XIII), geranic acid (XIV) and neronic acid (XV). These were identified by n.m.r., i.r. and mass spectrometry. 3. Based on these results, metabolic pathways for the biotransformation of R-(+)-pulegone in rat have been proposed.

Constructions of 2D-Metallamacrocycles Using Half-Sandwich Ru-2(II) Precursors: Synthesis, Molecular Structures, and Self-Selection for a Single Linkage Isomer

Coordination-driven self-assembly of oxalato-bridged half-sandwich p-cymene ruthenium complex Ru-2(mu-eta(4)-C2O4)(MeOH)(2)(eta(6)-p-cymene)(2)] (O3SCF3)(2) (1a) with several ditopic donors (L-a-L-d) in methanol affords a series of bi- and tetranuclear metallamacrocycles (2a and 3-5). Similarly, the combination of 2,5-dihydroxy-1,4-benzoquinonato (dhbq)-bridged binuclear complex Ru-2(mu-eta(4)-C6H2O4)(MeOH)(2)(eta(6)-p-cymene)(2)](O3SCF3)(2) (1b) with a flexible bidentate amide linker (L-a) in 1:1 molar ratio gave the corresponding tetranuclear complex 2b. All the macrocycles were isolated as their triflate salts in high yields and were fully characterized by various spectroscopic techniques. Finally, the molecular structures of all the assemblies were determined unambiguously by single-crystal X-diffraction analysis. Interestingly, the combination of acceptor 1a or 1b with an unsymmetrical linear ditopic donor L-a results in a self-sorted linkage isomeric (head-to-tail) macrocycle (2a or 2b) despite the possibility of formation of two different isomeric macrocycles (head-to-head or head-to-tail) due to different connectivity of the donor. Molecular structures of the complexes 2a and 2b showed tetranuclear rectangular geometry with dimensions of 5.51 angstrom x 13.29 angstrom for 2a and 7.91 angstrom x 13.46 angstrom for 2b. In both cases, two binuclear Ru-2(II) building blocks are connected by a mu-N-(4-pyridyl)isonicotinamide donor in a head-to-tail fashion. Surprisingly, the macrocycle 2a loses one counteranion and cocrystallizes with monodeprotonated 1,3,5-trihydroxybenzene via strong intermolecular pi-pi stacking and hydrogen bonding. The tweezer complex 3 showed strong fluorescence in solution, and it showed fluorescence sensing toward nitroaromatic compounds. A fluorescence study demonstrated a marked quenching of the initial fluorescence intensity of the macrocycle 3 upon gradual addition of trinitrotoluene and exhibits significant fluorescence quenching response only for nitroaromatic compounds compared to various other aromatic compounds tested.

Photochemical intramolecular gamma-hydrogen abstraction in a ketone and an alkene and the role of tunneling of hydrogen

Intramolecular gamma-hydrogen abstraction reactions were examined in pentane-2-one and 2-methyl-1-pentene in their lowest triplet states using the AM1 semi-empirical molecular orbital method with the complete geometry optimization in the unrestricted Hartree-Fock frame. The results reveal that the oxygen atom of the carbonyl group and the end carbon atom of the olefinic bond acquire high free valence and spin density indices in their respective lowest triplet states, leading to abstraction of hydrogen from the gamma-position relative to the carbonyl and olefinic bonds. The theoretical energy profiles fit with a polynomial and the probability of tunneling of hydrogen was estimated by the WKB (Wentzel, Kramer and Brillouin) method. The results, after thermal averaging of the rate constants, reveal that tunneling of hydrogen is significant at room temperature.

The unusual formation of methyl alpha-(5,6-dimethoxycarbonyl-2,3-dimethoxyazepin-7-ylidene)-alpha-[5-methoxycarbonyl-2,3-dimethoxypyrid-6-yl)acetate during the pyrolysis of ''azido-meta-hemipinate'' - First example of a reaction involving a concomitant ring expansion and ring extrusion

he ortho methoxycarbonyl substituent constitutes a sole exception in the ring closure reactions of ortho substituted aryl azides, as it provides no rate acceleration to this reaction. Pyrolysis of ''azido-meta-hemipinate'', an aryl azide containing such a substituent, led us to the title compound, a new azepinylidenepyridylacetic ester, whose structure has been established unambiguously by a single crystal X-ray diffraction study. This is the first report of a reaction involving both a ring expansion to an azaheptafulvalene and a ring extrusion to a pyridyl ring residue.

ChemInform Abstract: Synthesis Based on Cyclohexadienes. Part 16. Synthesis of Methyl 2,7-Dimethyltricyclo (5.2.2.01,5)undec-5-ene-6-carboxylates

Synthesis of methyl 2, 7-dimethyltricyclo{5.2.2.0(1,5}undec-5-en-6-carboxylates, the tricyclic skeleton present in (+)-allo-cedrol (1) is described using the Diels-Alder strategy. Thus, Birch reduction of the aromatic acid 8 gives 5, the methyl ester of which is isomerised with DBU to a 1:1 mixture of the dienes 6 and 4. Cycloaddition of this mixture with 2-chloroacrylonitrile followed by hydrolysis yields the ketone 60 having the tricyclo{5.2.2.0(1.5)}undec-5-ene framework. Similar reaction with methyl vinyl ketone affords the regioisomeric adducts 61 and 62.

Dynamic Behavior of Poly(2-vinylpyridine) in Solution Studied by 13C Nuclear Magnetic Relaxation

Abstract: The dynamics of poly(2-vinylpyridine) in chloroform solution has been examined by C-13 spin-lattice relaxation time and NOE measurements as a function of temperature. The experiments were performed at 50.3 and 100.6 MHz. The backbone carbon relaxation data have been analyzed in terms of six motional models. Among these models, the models which consider conformational transitions and bond librations for the backbone were found to be more successful. Pyridyl ring motion has been modeled as a restricted rotation with the rotational amplitude varying with temperature. The activation energy parameters obtained from the relaxation data of the pyridyl ring carbon have been compared with the energy barrier for ring rotation estimated from conformational energy calculations using the AM1 semiempirical quantum chemical method. The results of the conformational energy calculations support the description of pyridyl ring motion as a restricted rotation.

A convenient enantiospecific methodology for (-)-(1R,5S)-1,5-dimethylbicyclo[3.3.0]octa-2,7-dione: A formal total synthesis of (-)-ceratopicanol

An enantiospecific formal total synthesis of (-)-ceratopicanol starting from the readily and abundantly available monoterpene (R)-limonene is described. A combination of Claisen rearrangement-intramolecular diazo-ketone cyclopropanation-regiospecific reductive cyclopropane cleavage reactions are employed for the stereo- and regiospecific generation of the two vicinal ring junction quaternary carbon atoms.

Complexes of rare-earth perchlorates with ditbutyl amides of di, tri and tetraglycolic acids

New complexes of lanthanide perchlorates with di-t-butyl amides of di, tri and tetraglycolic acids have been synthesised. The complexes have the general formula Ln(DiGA)3(ClO4)3; Ln(TriGA)2 (ClO4)3 and Ln(TetGA)2 (C1O4)3, where Ln = La-Yb and Y and DiGA = N,N′, di-t-butyl diglycolamide, TriGA N,N′, di-t-butyl triglycolamide and TetGA = N,N′ di-t-butyl tetraglycolamide, respectively. The complexes have been characterized by analysis, electrolytic conductance, infrared,1H and13C nuclear magnetic resonance and electronic spectral data.Infrared spectra indicate the coordination of all the available ether oxygens and the amide carbonyls in each of the ligands, to the metal ions. IR and conductance data show that the perchlorate groups in all the complexes are ionic.1H and13C NMR data support the IR data regarding the mode of coordination of ligands to the metal ions. Electronic spectral shapes have been interpreted in terms of nine, eight and ten coordination in DiGA, TriGA and TetGA complexes respectively.

Coordination-driven self-assembly of 2D-metallamacrocycles using a shape-selective Pt(2)(II)-organometallic 90 degrees acceptor: design, synthesis and sensing study

Synthesis of a series of two-dimensional metallamacrocycles via coordination-driven self-assembly of a shape-selective Pt(2)(II)-molecular building unit incorporating carbazole-ethynyl functionality is described. An equimolar (1 : 1) combination of a Pt(2)(II)-organometallic 90 degrees acceptor, 1, with rigid linear ditopic donors (L(a) and L(b)) afforded [4 + 4] self-assembled octanuclear molecular squares, 2 and 3, in quantitative yields, respectively [L(a) = 4,4'-bipyridine; L(b) = trans-1,2-bis(4-pyridyl)ethylene]. Conversely, a similar treatment of 1 with an amide-based unsymmetrical flexible ditopic donor, L(c), resulted in the formation of a [2 + 2] self-sorted molecular rhomboid (4a) as a single product [L(c) = N-(4-pyridyl)isonicotinamide]. Despite the possibility of several linkage isomeric macrocycles (rhomboid, triangle and square) due to the different connectivity of L(c), the formation of a single and symmetrical molecular rhomboid (4a) as the only product is an interesting observation. All the self-assembled macrocycles (2, 3 and 4a) were fully characterized by multinuclear NMR ((1)H and (31)P) and ESI-MS analysis. Further structural insights about the size and shape of the macrocycles were obtained through energy minimization using density functional theory (DFT) calculations. Decoration of the starting carbazole building unit with Pt-ethynyl functionality enriches the assemblies to be more p-electron rich and luminescent in nature. Macrocycles 2 and 3 could sense the presence of electron deficient nitroaromatics in solution by quenching of the initial intensity upon gradual addition of picric acid (PA). They exhibited the largest quenching response with high selectivity for nitroaromatics compared to several other electron deficient aromatics tested.

Synthesis of 5-p-hydroxybenzyl-5,6-dihydro-2-naphthol, (+/-)-sequirin-d

A high-yield six-step synthesis of sequirin D (1a), a naturally occurring norlignan, is described. Michael addition of deoxyanisoin (2) to acrylonitrile gives a ketonitrile (3), which on Wolff–Kishner reduction is reduced and hyrolysed in situ to 4,5-bis-p-methoxyphenylpentanoic acid (4). Cyclodehydration of (4) with polyphosphoric acid, followed by borohydride reduction and dehydration furnishes di-O-methylsequirin D (1b) which affords on demethylation sequirin D (1a) in an overall yield from (2) of 60%. The key synthon (4) has also been prepared by three other routes.