A Lack of Studies on the Metabolism and Disposition of Hot Compound Class: Triphenylphosphonium-Conjugated Compounds.

Short-chain aliphatic epoxides and ketones are two classes of toxic organic compounds formed biogenically and anthropogenically. In spite of their toxicity, these compounds are utilized as primary carbon and energy sources or are generated as intermediate metabolites in the metabolism of other compounds (e.g., alkenes, alkanes, and secondary alcohols) by a number of diverse bacteria. One bacterium capable of using both classes of compounds is the gram-negative aerobe Xanthobacter strain Py2. Studies of epoxide and ketone (acetone) metabolism by Xanthobacter strain Py2 have revealed a central role for CO2 in these processes. Both classes of compounds are metabolized by carboxylation reactions that produce beta-keto acids as products. The epoxide- and ketone-converting enzymes are distinct carboxylases with molecular properties and cofactor requirements unprecedented for other carboxylases. Epoxide carboxylase is a four-component multienzyme complex that requires NADPH and NAD+ as cofactors. In the course of epoxide carboxylation, a transhydrogenation reaction occurs wherein NADPH undergoes oxidation and NAD+ undergoes reduction. Acetone carboxylase is a multimeric (three-subunit) ATP-dependent enzyme that forms AMP and inorganic phosphate as ATP hydrolysis products in the course of acetone carboxylation. Recent studies have demonstrated that acetone metabolism in diverse anaerobic bacteria (sulfate reducers, denitrifiers, phototrophs, and fermenters) also proceeds by carboxylation reactions. ATP-dependent acetone carboxylase activity has been demonstrated in cell-free extracts of the anaerobic acetone-utilizers Rhodobacter capsulatus, Rhodomicrobium vannielii, and Thiosphaera pantotropha. These studies have identified new roles for CO2 as a cosubstrate in the metabolism of two classes of important xenobiotic compounds. In addition, two new classes of carboxylases have been identified, the investigation of which promises to reveal new insights into biological strategies for the fixation of CO2 to organic substrates.

Computational chemistry calculations were performed to investigate the interactions of ionic liquids with different classes of volatile organic compounds (VOCs), including alcohols, aldehydes, ketones, alkanes, alkenes, alkynes and aromatic compounds. At least one VOC was studied to represent each class. Initially, 1-butyl-3-methylimindazolium chloride (abbreviated as C(4)mimCl) was used as the test ionic liquid compound. Calculated interaction lengths between atoms in the ionic liquid and the VOC tested as well as thermodynamic data suggest that C(4)mimCl preferentially interacts with alcohols as compared to other classes of volatile organic compounds. The interactions of methanol with different kinds of ionic liquids, specifically 1-butyl-3-methylimidazolium bromine (C(4)mimBr) and 1-butyl-3-methylimidazolium tetrafluoroborate (C(4)mimBF(4)) were also studied. In comparing C(4)mimCl, C(4)mimBr, and C(4)mimBF(4), the computational results suggest that C(4)mimCl is more likely to interact with methanol. Laboratory experiments were performed to provide further evidence for the interaction between C(4)mimCl and different classes of VOCs. Fourier transform infrared spectroscopy was used to probe the ionic liquid surface before and after exposure to the VOCs that were tested. New spectral features were detected after exposure of C(4)mimCl to various alcohols. The new features are characteristic of the alcohols tested. No new IR features were detected after exposure of the C(4)mimCl to the aldehyde, ketone, alkane, alkene, alkyne or aromatic compounds studied. In addition, after exposing the C(4)mimCl to a multi-component mixture of various classes of compounds (including an alcohol), the only new peaks that were detected were characteristic of the alcohol that was tested. These experimental results demonstrated that C(4)mimCl is selective to alcohols, even in complex mixtures. The findings in this work provide information for future gas-phase alcohol sensor design.

The actin cytoskeleton is an ideal chemotherapeutic target due to its role in numerous biological processes essential for tumor cell growth and survival. Targeting actin however has been problematic due to unacceptable levels of toxicity associated with impacting actin containing structures essential for normal cell function. We have developed a novel class of compounds which target tropomyosin, the second core component of an actin microfilament. By targeting the cancer associated tropomyosin, Tm5NM1 we are able to discriminate between the actin filament populations in normal and transformed cells. We have demonstrated that our first in class anti-Tm compound, TR100, impacts actin filament integrity leading to tumor cell death in vitro and in vivo in neuroblastoma and melanoma models. In this study we investigate the molecular mechanisms by which disruption of the actin cytoskeleton with the next generation anti-Tm compounds leads to tumor cell death. Preliminary studies have indicated that these compounds initiate cell death via the intrinsic mitochondrial apoptotic pathway. SH-EP neuroblastoma cells treated with TR200 showed a dose dependent increase in both caspase activation and annexin V staining as measured by Western Blotting and FACS analysis respectively. Significant changes in mitochondrial membrane integrity were also observed using TMRE staining in SH-EP cells treated with 5 µM TR200 for 24h. Interestingly, mitochondrial permeabilization was independent of the presence of proapoptotic factors Bax and Bak as Bax/Bak null MEFs still displayed sensitivity to TR200. To delineate the signaling pathways leading to apoptosis, a kinexus phospho-antibody array was conducted using SH-EP cells treated with 10 µM DTR200 for 8 and 24h. DTR200 treatment for 8h reduced the phospho-activity of key intermediates of the MEK/ERK pathway, in particular a significant decrease in the phosphorylation of the RSK1/2 family of kinases. Preliminary data would suggest that the compounds at 24h are mediating their effect through the downregulation of the MEK/ERK and p38/JNK cell survival pathways. We are now validating these findings to elucidate which signaling pathways mediate the apoptotic response to the anti-Tm compounds. Understanding the molecular mechanisms involved in anti-Tm mediated cell death will allow us to determine how these compounds can be used in combination with existing therapies to lower the apoptotic threshold of a tumor cell and ultimately improve the outcome of patients with neuroblastoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C208. Citation Format: Melissa Desouza, Margaret Nguyen, Peter W. Gunning, Justine R. Stehn. Targeting the actin cytoskeleton of neuroblastoma: Elucidating the mechanism by which a novel class of anti-cancer compounds induces tumor cell death. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C208.

Quinones and organochalcogens are classes of compounds with great biological applicability, such as antioxidant, anticancer, anti-Alzheimer, and antidepressant activities, among others. Thus, the combination of these two classes of compounds is important to obtain new hits with biological activities that are additive or synergistic. Several methodologies for the preparation of this class of hybrid compound have been widely described. Many of the prepared hybrid molecules have shown increased biological activities and, in some cases, to act as two distinct pharmacophores. In this review, methods for the preparation of selenium-quinones, tellurium-quinones and their biological applications are highlighted.

Phenolic constituents and anticancer properties of Morus alba (white mulberry) leaves

Based on a comparison of the known constituents in high-level nuclear waste stored at the Savannah River Site (SRS) and explosive compounds reported in the literature, only two classes of explosive compounds (metal NO{sub x} compounds and organic compounds) were identified as requiring further work to determine if they exist in the waste, and if so, in what quantities. Of the fourteen classes of explosive compounds identified as conceivably being present in tank farm operations, nine classes (metal fulminates, metal azides, halogen compounds, metal-amine complexes, nitrate/oxalate mixtures, metal oxalates, metal oxohalogenates, metal cyanides/cyanates, and peroxides) are not a hazard because these classes of compounds cannot be formed or accumulated in sufficient quantity, or they are not reactive at the conditions which exist in the tank farm facilities. Three of the classes (flammable gases, metal nitrides, and ammonia compounds and derivatives) are known to have the potential to build up to concentrations at which an observable reaction might occur. Controls have been in place for some time to limit the formation or control the concentration of these classes of compounds. A comprehensive list of conceivable explosive compounds is provided in Appendix 3.

Novel classes of heterocyclic compounds as adenosine antagonists were developed based on a template approach. Structure-affinity relationships revealed insights for extended knowledge of the receptor-ligand interaction. We replaced the bicyclic heterocyclic ring system of earlier described isoquinoline and quinazoline adenosine A(3) receptor ligands by several monocyclic rings and investigated the influence thereof on adenosine receptor affinity. The thiazole or thiadiazole derivatives seemed most promising, so we continued our investigations with these two classes of compounds. The large difference between a pyridine and isoquinoline ring in binding adenosine A(1) and A(3) receptors showed the importance of the second ring of the isoquinoline ligands. We prepared several N-[4-(2-pyridyl)thiazol-2-yl]benzamides, and these compounds showed adenosine affinities in the micromolar range. Most surprising in the series of the N-[4-(2-pyridyl)thiazol-2-yl]amides were the retained adenosine affinities by introduction of a cylopentanamide instead of the benzamide. A second series of compounds, the thiadiazolobenzamide series of compounds, revealed potent and selective adenosine receptor antagonists, especially N-(3-phenyl-1,2,4-thiadiazol-5-yl)-4-hydroxybenzamide (LUF5437, 8h) showing a K(i) value of 7 nM at the adenosine A(1) receptor and N-(3-phenyl-1,2,4-thiadiazol-5-yl)-4-methoxybenzamide (LUF5417, 8e) with a K(i) value of 82 nM at the adenosine A(3) receptor. 4-Hydroxybenzamide 8h is the most potent adenosine A(1) receptor antagonist of this new class of compounds. Structure--affinity relationships showed the existence of a steric restriction at the para-position of the benzamide ring for binding adenosine A(1) and A(3) receptors. The electronic nature of the 4-substituents played an important role in binding the adenosine A(3) receptor. Cis- and trans-4-substituted cyclohexyl derivatives were made next to the 4-substituted benzamide analogues. We used them to study the proposed specific interaction between the adenosine A(1) receptor and the 4-hydroxy group of this class of thiadiazolo compounds, as well as a suggested special role for the 4-methoxy group in binding the A(3) receptor. Both the adenosine A(1) and A(3) receptor slightly preferred the trans-analogues over the cis-analogues, while all compounds showed low affinities at the adenosine A(2A) receptor. Our investigations provided the potent and highly selective adenosine A(1) antagonist N-(3-phenyl-1,2,4-thiadiazol-5-yl)-trans-4-hydroxycyclohexanamide (VUF5472, 8m) showing a K(i) value of 20 nM. A third series of compounds was formed by urea analogues, N-substituted with thiazolo and thiadiazolo heterocycles. The SAR of this class of compounds was not commensurate with the SAR of the previously described quinazoline urea. On the basis of these findings we suggest the existence of a special interaction between adenosine receptors and a region of high electron density positioned between the thia(dia)zole ring and phenyl(pyridyl) ring. Molecular electrostatic potential contour plots showed that for this reason the ligands need either a thiadiazole ring instead of a thiazole or a 2-pyridyl group instead of a phenyl. The derived novel classes of antagonists will be useful for a better understanding of the molecular recognition at the adenosine receptors.

Six classes (flavones, flavonols, C-glycosylflavones, 6-hydroxyflavones, 6-hydroxyflavonols, and 6-methoxyflavones) of foliar flavonoid compounds are the major constituents for 45 species in 11 sections of North American Coreopsis. Sections Calliopsis, Palmatae, and Pseudoagarista are uniform in that all or most species display the same classes of compounds, whereas sections Coreopsis, Eublepharis, Euleptosyne, and Pugiopappus exhibit pronounced interspecific variation. There are general correlations between presence of particular flavonoid classes and three groups of sections in North American Coreopsis. These three groups are viewed as two phyletic lines and a basal primitive group. There is also one monotypic section (Silphidium) of uncertain affinities. One phyletic line centered in the southeastern United States has four sections (Calliopsis, Coreopsis, Eublepharis, Palmatae), which contain a 6-hydroxyflavonol and 6-methoxyflavones; these flavonoid classes are not detected in other sections of North American Coreopsis. The second phyletic line includes sections Tuckermannia, Pugiopappus, and Euleptosyne, which occur primarily in California and contain C-glycosylflavones and 6-hydroxyflavones. The former class of compounds is unknown in the southeastern United States sections, and the latter occurs rarely. Section Silphidium of the southeastern United States has only flavones. Sections Electra, Anathysana, and Pseudoagarista, representing the presumed primitive elements, consist of woody plants occurring in Mexico, and they are more similar chemically to the three sections from California than to plants from the southeastern United States Leaf flavonoid chemistry offers few clues to the origin of the two phyletic lines from the putatively more primitive plants of Mexico.

SummaryAdsorptive interactions of organic molecules with soil minerals often impair their bioavailability. However, little is known about the adsorption behaviour of phenolic and nitrogenous compounds on different minerals and their mutual interaction with respect to competition and surface conditioning (i.e. surface modification induced by preceding adsorption of the other class of compounds). Therefore, batch adsorption experiments were done to study the interaction between phenolic acids (PAs; salicylic acid, Sal; syringic acid, Syr; ferulic acid, Fer; vanillic acid, Van) and amino acids (AAs; lysine, Lys; glutamic acid, Glu; leucine, Leu; phenylalanine, Phe) during adsorption on goethite and Ca2+‐montmorillonite at pH 6 by applying adsorbate concentrations of 0.01, 0.05 and 0.1 mm. Larger adsorption of PAs was observed on goethite than montmorillonite, whereas the phyllosilicate was a better adsorbent for AAs than the oxide. Among all tested PAs, Sal was preferentially adsorbed on both minerals. For the AAs, Glu was preferentially adsorbed on goethite and Lys on montmorillonite. The AAs were more competitive than PAs and partially suppressed the adsorption of PAs on both minerals. The adsorption of PAs or AAs on both minerals was enhanced by surface conditioning with the other group, with larger effects for goethite than montmorillonite. For goethite, surface conditioning by PAs enhanced the adsorption of AAs more (by 97–161%) than did AAs for PAs (9–48%). The results support the hypothesis that pre‐adsorption of one class of organic compound can enhance the retention of another class. This suggests that adsorbed organic matter on soil mineral phases might be subject to a self‐strengthening effect.Highlights Phenolic acids (PAs) were preferentially retained on goethite. Amino acids (AAs) were preferentially retained on montmorillonite. AAs were more competitive than PAs for adsorption sites on both minerals. Pre‐adsorption of one class of compound can enhance the retention of another class.

Thiocoumarins and dithiocoumarins are two important classes of sulphurcontaining heterocyclic compounds, which are bioisosteres of coumarins. Herein, various synthetic strategies for these two classes of heterocyclic compounds reported in the literature have been discussed. Different solvents, catalysts, reagents and reaction conditions, which were employed successfully for synthesizing thiocoumarins and dithiocoumarins have also been described concisely in this review. Mechanistic overview has been given wherever it was necessary. In addition, a comparative view of various solvents, catalysts and reagents focusing on their efficiency for synthesizing thiocoumarins and dithiocoumarins, has been discussed as well. Furthermore, pharmacological activities of these two classes of compounds have also been discussed.

The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics). Figure 1 Summary of the typical classes of organometallic compounds used in medicinal chemistry. In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

Results of some QSAR studies in which the training set contained aromatic compounds with toxic effect onTetrahymena pyriformisare presented. The QSAR studies reveal the existence of two classes of compounds – with and without hydrogen bonds – for which the calculation of some QSAR separated equations are recommended. QSAR equations obtained for the two classes of aromatic compounds have good predictive powers:N=87,p=6,r2=0.7962,s=0.3178, andN=113,p=5,r2=0.8950,s=0.2637, respectively. For the compounds with hydrogen bonds, “moment of inertiaB” and “QSPR of percentage of mass fragments” are molecular characteristics with a powerful influence on toxicity values, and logKowhas a moderate influence. For compounds without hydrogen bonds “bonds number weighted total energy” and “LUMO‐HOMO gap weighted molecular volume” are the molecular characteristics with a powerful effect on toxicity values, and topological descriptor AAA has a moderate effect.

Caffeine and more specific antagonists of the adenosine A(2A) receptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A(2A) antagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP(+), we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP(+) and of MPP(+), suggesting that CSC blocks the conversion of MPTP to MPDP(+) in vivo. In assessing the direct effects of CSC and A(2A) receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with a K(i) value of 100 nm, whereas caffeine and another relatively specific A(2A) antagonist produced little or no inhibition. The A(2A) receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A(2A) receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A(2A) receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A(2A) receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.

Structure-activity relationships in aquatic toxicology

The complete graph conjecture that encodes the inner-core electrons of atoms with principal quantum number n >or= 2 with complete graphs, and especially with odd complete graphs, is discussed. This conjecture is used to derive new values for the molecular connectivity and pseudoconnectivity basis indices of hydrogen-suppressed chemical pseudographs. For atoms with n = 2 the new values derived with this conjecture are coincident with the old ones. The modeling ability of the new homogeneous basis indices, and of the higher-order terms, is tested and compared with previous modeling studies, which are centered on basis indices that are either based on quantum concepts or partially based on this new conjecture for the inner-core electrons. Two similar algorithms have been proposed with this conjecture, and they parallel the two "quantum" algorithms put forward by molecular connectivity for atoms with n > 2. Nine properties of five classes of compounds have been tested: the molecular polarizabilities of a class of organic compounds, the dipole moment, molar refraction, boiling points, ionization energies, and parachor of a series of halomethanes, the lattice enthalpy of metal halides, the rates of hydrogen abstraction of chlorofluorocarbons, and the pED(50) of phenylalkylamines. The two tested algorithms based on the odd complete graph conjecture give rise to a highly interesting model of the nine properties, and three of them can even be modeled by the same set of basis indices. Interesting is the role of some basis indices all along the model.