Cytotoxic 2,3-secoaromadendrane-type sesquiterpenoids from the liverwort Plagiochila ovalifolia

The ether extract of the Japanese liverwort, Plagiochila ovalifolia Mitt. (Plagiochilaceae) yielded three 2,3-secoaromadendrane-type sesquiterpenoids, plagiochiline-A-15-yl octanoate, 14-hydroxyplagiochiline-A-15-yl 2E,4E-dodecadienoate and 14-hydroxyplagiochiline-A-15-yl 2E,4E,8Z-tetradecatrienoate. The two latter compounds were first isolated from the Plagiochila species. The structures of the new compounds were elucidated by spectroscopy. Plagiochiline-A-15-yl octanoate and 14-hydroxyplagiochiline-A-15-yl 2E,4E-dodecadienoate showed significant cytotoxicity against P-388 murine leukemia tumor cells, both compounds exhibiting an ID50 of 0.05 microgram/ml. Plagiochiline A also showed cytotoxic activity. The ID50 was 3.0 micrograms/ml.     

Enantioselectivity in capillary electrophoresis using the macrocyclic antibiotics

The macrocyclic antibiotics recently have been shown to exhibit powerful enantioselectivity towards numerous compounds. There are a number of ways that one can alter enantioselectivity in the macrocyclic antibiotic-based separation schemes. The macrocyclic antibiotics are enantioselective for positively-charged solutes using the ansamycins and enantioselective for anionic compounds using the glycopeptides. Within a given class of antibiotics such as the glycopeptides, enantioselectivity may also be altered by use of micelles, uncoated vs. coated capillaries, or manipulation of operating parameters such as pH or organic modifiers. In this work, we will examine the various ways to alter enantioselectivity in the macrocyclic-based separations.     

Animal Species in which N-nitroso compounds induce cancer

In reviews on the carcinogenicity of N-nitroso compounds (NC) the number of animal species in which these compounds induce cancer is understated. In recent years additional species have been used in experiments. Tumours have been induced by NC in 39 species which belong to 36 genera, 25 families, 17 orders and five class of animals. The names of these taxa are presented in Latin and the common names of species are given in English, French and German. The carcinogenic action of eight NC in various species is tabulated.     

Two new sesquiterpenoids from the seeds of Celastrus angulatus

An investigation of seeds of Celastrus angulatus led to the isolation of two new sesquiterpenoids (1 and 2) with a beta-dihydroagarofuran skeleton. Their structures were elucidated on the basis of spectroscopic methods.     

Amorphization of the CeFe2 Laves phase compound by hydrogen absorption

Structural changes of the CeFe₂ Laves phase compound during the hydrogen absorption and desorption process have been investigated by X-ray diffraction, transmission electron microscopy, thermal analysis and magnetic property measurements. The transition from the crystalline to the amorphous state has been confirmed to occur below about 500 K, where the formation of the elemental hydride, CeH₂, is virtually hindered. The whole crystalline phase does not change to the amorphous state in a uniform manner, but a part of the crystalline phase changes to the amorphous one which grows with further hydrogenation. The requirements for alloys to undergo hydrogen-induced amorphization were discussed. The proposed requirements are for alloys

• 1.(i) to have the Laves structure,
• 2.(ii) to contain hydride-forming elements
• 3.(iii) to have either a low melting point or a tendency to decompose into other intermetallic compounds.

     

A novel series of N-(1-aminoalkylidene)carboximidamides as potential hypoglycemic agents

Nitrogen heterocyclic carboximidamides, such as linogliride, 1a, have been shown to possess significant hypoglycemic activity and have shown clinical efficacy as potential antidiabetic agents. We evaluated the biological significance of the heterocyclic ring A of general structure 1, which has always been maintained in this class of compounds, by preparing acyclic compounds of general structure 2. Preliminary in vivo biological testing, i.e., the glucose tolerance test in rats, indicates that a number of the specific acyclic carboximidamides prepared, 6a-kk, possessed significant hypoglycemic activity often comparable to, and in some cases better than, the activity noted for our model compound, 1a. These results suggest that the heterocyclic ring A of 1 is not essential for hypoglycemic activity for this class of compounds.     

On the Rotational Analysis of the Ground Vibrational State of CH3D Molecule

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been developed using comparative molecular field analysis (CoMFA) on a large data set (118 compounds) of diverse cyclic urea derivatives as protease inhibitors against the human immunodeficiency virus type 1 (HIV-1). X-ray crystal structures of HIV-1 protease bound with this class of inhibitors were used to derive the most probable bioactive conformations of the inhibitors. The enzyme active site was used as a constraint to limit the number of possible conformations that are sterically accessible. The test sets have been created keeping in mind structural diversity as well as the uniform simple statistical criteria (mean, standard deviation, high and low values) of the protease inhibitory activities of the molecules compared to the training sets. Multiple predictive models have been developed with the training sets (93 compounds in each set) and validated with the corresponding test sets (25 compounds in each set). All the models yielded high predictive correlation coefficients (q2 from 0.699 to 0.727), substantially high fitted correlation coefficients (r2 from 0.965 to 0.973), and reasonably low standard errors of estimates (S from 0. 239 to 0.265). The steric and electrostatic effects have approximately equal contributions, 45% and 55% (approximately), respectively, toward explaining protease inhibitory activities. This analysis yielded models with significant information on steric and electrostatic interactions clearly discerned by the respective coefficient contour plots when overlapped on the X-ray structure of the HIV-1 protease. The HINT CoMFA study revealed significant contribution of hydrophobicity toward protease inhibitory activity. The 3D visualization technique utilizing these contour plots as well as the receptor site geometry may significantly improve our understanding of the inhibitor-protease (HIV-1) interactions and help in designing compounds with improved activity.     

Combined synthetic/CD strategy for the preparation and configurational assignments of model acyclic 1,3-polyols with a 1,2-diol terminal

Acyclic 1,3-polyols or skipped polyols are widely distributed in nature. Particularly skipped 1,3-polyols with a terminal 1,2-diol group are present in numerous antifungal polyene macrolides in various masked forms. Although over 200 polyene macrolides are known, the planar structures of only about 40 have been determined, while those for which the full stereochemistry has been elucidated is less than ten. No simple method exists for configurational assignments of the 1,3-polyols moieties; moreover, this class of compounds are difficult to crystallize. In order to develop a general chiroptical method for structure determination of acyclic 1,3-polyols, we have combined a divergent synthetic approach with CD to prepare all possible stereoisomers of 1,2,4-triols, 1,2,4,6-tetrols and 1,2,4,6,8-pentols. The current set of reference polyols should be useful for setting up reference CD libraries and for model studies leading to a general method for configurational assignment of acyclic polyols. This strategy can be used to synthesize further extended members of acyclic 1,3-polyols and mixed 1,2/1,3-polyols which can be used for structural investigations of polyene macrolides and related compounds.     

ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.     

Analysis of causes of the parotid pleomorphic adenoma recurrence

1. Human stroke is a complex and heterogeneous phenomenon that may defy attempts to develop a unitary animal model with which to address all of the relevant issues. 2. Focal models are regarded by many to be the approach of choice, but both global and focal models of cerebral ischemia can be sources of useful and complementary insight. 3. Of the global models, four-vessel occlusion requires a preparatory operative procedure that may increase the risk of extraneous factors confounding the response to the ischemic insult itself. The procedures are only partly reversible, with the vertebral arteries remaining permanently occluded. 4. The two-vessel occlusion model is easier to perform in a single procedure, and the less-intrusive surgical intervention allows greater scope for recovery experiments. The occlusion is fully reversible. 5. Many classes of compounds with therapeutic potential have been identified in the laboratory, often on the basis of success in one class of animal model, but translating these successes into a clinical context has proved singularly difficult. If, in future, compounds of interest are tested across a range of the available models, the likelihood of subsequent clinical success may be enhanced.     

Synthesis and activity of bivalent FKBP12 ligands for the regulated dimerization of proteins

The total synthesis and in vitro activities of a series of chemical inducers of dimerization (CIDs) is described. The use of small-molecule CIDs to control the dimerization of engineered FKBP12-containing fusion proteins has been demonstrated to have broad utility in biological research as well as potential medical applications in gene and cell therapies. The facility and flexibility of preparation make this new class of wholly synthetic compounds exceptionally versatile tools for the study of intracellular signaling events mediated by protein-protein interactions or protein localization. While some congeners possess potency comparable to or better than the first generation natural product-derived CID, FK1012, structure-activity relationships are complex and underscore the need for application-specific compound optimizations.     

Non-peptide cholecystokinin-B/gastrin receptor antagonists based on bicyclic, heteroaromatic skeletons

A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.     

Analogues of 8-[[6-(diethylamino) hexyl]amino]-6-methoxy-4-methylquinoline as candidate antileishmanial agents

8-[[6-(Diethylamino)hexyl]amino]-6-methoxy-4-methylquinoline (I) has been shown to be highly effective against Leishmania donovani in hamsters, being approximately 475 times as active as the standard meglumine antimoniate. Several nuclear and side-chain analogues of I have been prepared in an attempt to further enhance the antileishmanial activity of this class of compounds. The compounds were tested against L. donovani in the golden hamster. Although several analogues had meglumine antimoniate indexes in excess of 300, none was superior to the model compound.     

The catalytic mechanism of beta-lactamases: NMR titration of an active-site lysine residue of the TEM-1 enzyme

Beta-Lactamases are widespread in the bacterial world, where they are responsible for resistance to penicillins, cephalosporins, and related compounds, currently the most widely used antibacterial agents. Detailed structural and mechanistic understanding of these enzymes can be expected to guide the design of new antibacterial compounds resistant to their action. A number of high-resolution structures are available for class A beta-lactamases, whose catalytic mechanism involves the acylation of a serine residue at the active site. The identity of the general base which participates in the activation of this serine residue during catalysis has been the subject of controversy, both a lysine residue and a glutamic acid residue having been proposed as candidates for this role. We have used the pH dependence of chemical modification of epsilon-amino groups by 2,4,6,-trinitrobenzenesulfonate and the pH dependence of the epsilon-methylene 1H and 13C chemical shifts (in enzyme selectively labeled with [epsilon-13C]lysine) to estimate the pKa of the relevant lysine residue, lysine-73, of TEM-1 beta-lactamase. Both methods show that the pKa of this residue is > 10, making it very unlikely that this residue could act as a proton acceptor in catalysis. An alternative mechanism in which this role is performed by glutamate-166 through an intervening water molecule is described.     

Alpha-smooth muscle actin distribution in the pulmonary vasculature comparing hypoplastic and normal fetal lungs

The present paper highlights and reviews current research in the field of hemoprotein models. Hemoproteins have been extensively studied in order to understand structure-function relationships, and to design new molecules with desired functions. A wide number of synthetic analogues have been developed, using quite different approaches. They differ in molecular structures, ranging from simple meso-substituted tetraaryl-metalloporphyrins and peptide-porphyrin conjugates. In this paper we summarize the state of the art on peptide based hemoprotein models. We also report here the approach used by us to develop a new class of molecules, named mimochromes. They can be regarded as miniaturized hemoproteins, because mimochromes are low molecular weight compounds with some structural and functional properties common to those of the parent high molecular weight protein. The basic structure of mimochromes is a deuteroporphyrin ring covalently linked to two helical peptide chains. Two molecules of this series have been fully characterized. All the information derived from their structural analysis has been applied to the design of new analogues with additional functions.     

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.     

Physicochemical properties of aluminum hydroxychlorides of various basicity

Physicochemical properties of aluminum hydroxychlorides (AHOCs) of various basicity (1/3, 2/3, 5/6) have been considered. Dependences of their density and viscosity on the concentration and temperature of solutions have been plotted. Data on the pH and crystallization temperatures of AHOC solutions of various basicity are given depending on the Al₂O₃ concentration and Al: Cl ratio in the solution. The quality of AHOC has been established to depend on the presence of different forms of aluminum compounds, i.e., monomers, oligomers, and polymers. The degree of polymerization of various hydroxycomplexes present in the AHOC solution has been estimated. The effect of the polymeric component on the density, viscosity, and crystallization temperature of AHOC solutions of various basicity has been revealed.     

Induction of micronuclei and aneuploidy by the quinone-forming agents benzene and o-phenylphenol

A number of carcinogens appear to exert their tumorigenic effects through the formation of quinone metabolites. These quinone-forming carcinogens are generally inactive or weakly active in standard gene mutation assays. Accumulating evidence indicates that this class of compounds may exert their genotoxic and carcinogenic effects through the induction of large-scale gene alterations. This article presents an overview of work that has been performed using recently developed molecular cytogenic techniques to investigate the aneuploidy-inducing and clastogenic properties of the major quinone-forming metabolites of benzene, a widely used industrial chemical, and o-phenylphenol, a fungicide and disinfectant. These metabolites of benzene (hydroquinone, catechol, and benzenetriol) and o-phenylphenol (phenylhydroquinone) have each been shown to be capable of interfering with chromosome segregation and inducing chromosomal breakage. These results indicate that both numerical and structural chromosomal aberrations induced by the quinone metabolites of benzene and o-phenylphenol may play a role in the carcinogenic effects of these two agents.