Structurally-related Compounds Research Articles

Correlation and estimation of solubilities of fatty acids in supercritical carbon dioxide using solution model approach

In this study, solid solubility data of five fatty acids in supercritical carbon dioxide (CO2) at different temperatures and pressures are correlated using a two-parameter solution model developed from the regular solution model coupled with the Flory⿿Huggins equation. The developed solution model with fewer parameters yields correlated results comparable to those from commonly used semi-empirical equations. In addition, both parameters in the solution model can be further generalized with the chain length of fatty acids and a new predictive solution model is proposed for solubility prediction. The predictive solution model proposed in this study provides better predicted results and yields average deviation in predicted solubilities of 22.1%. To further apply this solution model to other compounds, solid solubility data of three triglycerides in supercritical CO2 at 313K are also correlated. After model simplification and generalization, a new predictive solution model for triglycerides is also proposed, which yields average deviation in predicted solubilities of 29.8%. These results demonstrate that the solution model used in this study is applicable for correlation and prediction of solid solubilities of structure-related compounds in supercritical CO2.

Enantiomeric Selection Properties of β‐homoDNA: Enhanced Pairing for Heterochiral Complexes

The analysis of the physicochemical properties of sugarmodified nucleic acids is currently at the core of intense multidisciplinary investigations including chemistry, biology, biotechnology, and medicine. On one side, synthetic polymers acting as RNA/DNA mimics have extensively been devised for applications in therapy, diagnostics, and synthetic biology. On the other side, the construction of alternative pairing systems has been explored either to consider their use as orthogonal nucleic acid candidates or with the aim to potentially yield insights into the chemical evolution criteria ultimately leading to the current genetic system. In all cases, structural changes of natural (deoxy)ribose cores have been established to determine profound consequences in the pairing potential of the resulting artificial nucleic acids. In some noteworthy examples, oligonucleotide systems endowed with six-membered sugars in the backbone have been observed to hold the singular property (unique of its kind) of pairing with homochiral complements having opposite sense of chirality. Relevant to etiology-oriented investigations on nucleic acid structure, these findings could suggest the existence of a relationship between nature of the sugar backbone and chiral-selection properties of nucleic acids, thereby providing insights to enrich our understanding of the structural prerequisites for base pairing. From a comparative analysis of the pairing behavior of six-membered nucleic acids we perceived that, despite the large structural differences, oligonucleotide systems capable of isoand heterochiral hybridization (Figure 1) shared preorganized carbohydrate conformations with equatorially-oriented nucleobases. This observation took us to wonder if such an arrangement of the aglycon moiety, especially whereas inducing strong backbone-base inclination or even enabling formation of quasilinear oligomeric structures, could lead sugar chirality not to be crucial in hybridization processes. In view of systematic investigations aimed at addressing this question, we herein considered the chiral selection properties of the well-known pairing system composed of (6’!4’)-linked b-erythro-hexopyranosyl nucleotides (b-homoDNA; Figure 1). Based on above assumptions and early experimental data, we reasoned that the strongly inclined complexes provided by the “allequatorial” pyranose backbone of b-homoDNA could make the latter an interesting candidate displaying potential for heterochiral hybridization. An investigation into the enantioselectivity of the hybridization processes of b-homoDNA required access to oligomeric sequences in both enantiomeric forms (b-dand b-lhomoDNA). From a synthetic standpoint, while access to d-hexopyranosyl nucleosides was easily obtained by a carbohydrate-based route, the synthesis of the corresponding lenantiomers under the same reaction conditions was hampered by the limited commercial availability of almost all lhexoses. In an alternative path, our long studied de novo approach to l-monosaccharides and other structurallyrelated compounds was recently exploited for the preparation of the l-nucleosides 2a,b (T and A acting as model nucleobases) from the homologating agent 1 (Scheme 1). Figure 1. Sugar-modified nucleic acids displaying pairing aptitude for homochiral complements of opposite chirality.

Abstract 3329: The DNA-PK inhibitor, NU7441, sensitises cancer cells to microtubule-targeting agents and modulates vincristine efflux in multidrug resistant cells.

Abstract Microtubules are involved in the formation of the mitotic spindle, and correct separation of the sister chromatids at mitosis is essential for maintaining genomic stability. Microtubule-targeting drugs arrest rapidly-dividing cells and are important chemotherapeutic agents, but the development of multidrug-resistance (MDR) is a serious clinical problem. Along with its role in DNA double-strand break repair, DNA-dependent protein kinase (DNA-PK) has also been shown to play an important role in stabilising spindle formation and preventing mitotic catastrophe (Shang et al, Cancer Res. 2010). In light of this novel finding, we hypothesised that inhibition of DNA-PK would sensitise cells to microtubule-targeting agents. Pilot studies showed that inhibition of DNA-PK by the selective inhibitor, NU7441, caused greater sensitisation to vincristine in multidrug-resistant cells compared to parental cells. Here, we further investigate the role of DNA-PK in response to microtubule-targeting drugs using a novel series of NU7441 analogues, and investigate whether these inhibitors interact with the efflux transporter, P-glycoprotein. In growth inhibition studies, CCRF-CEM leukaemia cells were sensitised 1.4-fold to vincristine by NU7441 (1μM) whereas their vincristine-resistant derivative CCRF-CEM VCR/R cells were sensitised 8-fold to vincristine. DNA-PK-deficient M059J glioblastoma cells were 2-fold more sensitive to docetaxel than DNA-PK-proficient cells, and NU7441 sensitised only DNA-PK-proficient M059J-Fus1 cells to docetaxel. CCRF-CEM VCR/R cells have a higher basal level of autophosphorylation of DNA-PKcs (Western blotting) than the CCRF-CEM cells and autophosphorylation in response to vincristine was abrogated by NU7441. To investigate the effects of NU7441 on drug transport, a doxorubicin fluorescence assay showed that in P-glycoprotein-overexpressing canine kidney MDCKII-MDR1 cells, 1μM NU7441 increased doxorubicin cellular fluorescence 16-fold by blocking drug efflux via P-glycoprotein. NU7441 and 3 structurally-related compounds (NU7742 (inactive NU7441 analogue), DRN1 (DNA-PK-inhibitory atropisomeric NU7441 derivative) or DRN2 (DNA-PK non-inhibitory atropisomeric NU7441 derivative)) all increased intracellular vincristine accumulation in the CCRF-CEM VCR/R cells to a level similar to verapamil, as measured by LC-MS. However, the non-inhibitory compound NU7742 was 5-fold less effective at sensitising CCRF-CEM VCR/R cells to vincristine than NU7441 (p=0.008). The novel finding that DNA-PK inhibition sensitises cells to microtubule-targeting agents suggests that along with its function in DNA repair, this enzyme plays a role in the mitotic spindle checkpoint. Additionally, in multidrug-resistant cells, NU7441 is able to block drug efflux via interaction with P-glycoprotein. Citation Format: Emily Mould, Philip Berry, David Jamieson, Christopher Hill, Niu Tan, Sarah Elliott, Barbara Durkacz, David Newell, Elaine Willmore. The DNA-PK inhibitor, NU7441, sensitises cancer cells to microtubule-targeting agents and modulates vincristine efflux in multidrug resistant cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3329. doi:10.1158/1538-7445.AM2013-3329

Extraction of Pb2+ with p-tert-butylcalix [4]-, [5]-, [6]Arene Carboxylic Acid Ligands and their Monomeric Counterpart: A Thermodynamic Approach

Studies on extraction equilibrium constants at different temperatures and thermodynamic parameters of solvent extraction of Pb2+ ion with carboxylic acid derivatives of different ring size calixarenes and structure related monomeric compound have been carried out. The extraction equilibrium constants corresponding to calix[n]arene (n = 4, 5, 6) derivatives decrease in the order [5]arene > [6]arene > [4]arene. In all cases, the complexation process is primarily enthalpy driven. The favorable enthalpic contribution for extraction of Pb2+ is in the order hexamer ≈ monomer > tetramer > pentamer. However, the unfavorable entropic loss follows the order: monomer > hexamer > tetramer > pentamer. Overall stability of the host-guest complex is the function of entropy-enthalpy compensation and the free energy of complexation is minimum for the pentamer, followed by tetramer ≈ hexamer and monomer. Although the carboxylic acid derivative of calix[4]arene is more preorganized than the calix[5]arene derivative, extraction of Pb2+ ion with the tetramer passes through greater entropic loss than that with the pentamer and the degree of preorganization of calix[4]arene derivative is far from perfect for the complexation and extraction of Pb2+ ion. As compared to tetrameric and hexameric counterparts, the structural features of the carboxylic acid derivative of calix[5]arene prior to complexation contribute much to interact with the Pb2+ ion and form a thermodynamically stable complex. Supplementary materials are available for this article. Go to the publisher's online edition of Solvent Extraction and Ion Exchange to view the supplemental file.

Evaluation and comparison of various separation techniques for the analysis of closely-related compounds of pharmaceutical interest

The aim of the present work was to compare various separation techniques for the fast analysis of closely-related compounds, including structurally-related compounds, positional isomers, diastereoisomers, Z/E isomers. Three analytical techniques were evaluated, namely ultra high performance liquid chromatography (UHPLC), ultra high performance supercritical fluid chromatography (UHPSFC), both with sub-2μm particles, and capillary electrophoresis (CE) using non-aqueous solvents. To fairly compare the three analytical techniques, only two starting conditions for further method development were considered. All the selected mobile phases or background electrolyte were MS-compatible. As expected, CE often provided excellent results for the analysis of basic compounds but it was difficult to find out conditions that could be widely applied. On the other hand, UHPLC and UHPSFC were more generic and the performance was better than CE for the analysis of neutral and acidic compounds. In all cases, the analysis time was systematically lower than 3min. In conclusion, UHPLC was the most versatile strategy for the analysis of closely-related compounds and should be tested in a first instance. UHPSFC and CE approaches offered some drastic changes in selectivity and should be considered a second choice to reach alternative selectivity as they also allow high throughput separations.

Establishment of a search library about benzylisoquinoline alkaloids based on selective separation on the binaphthyl column and standard analysis on C18 column

A search library about benzylisoquinoline alkaloids was established based on preparation of alkaloid fractions from Rhizoma coptidis, Cortex phellodendri, and Rhizoma corydalis. In this work, two alkaloid fractions from each herbal medicine were first prepared based on selective separation on the "click" binaphthyl column. And then these alkaloid fractions were analyzed on C18 column by liquid chromatography coupled with tandem mass spectrometry. Many structure-related compounds were included in these alkaloids fractions, which led to easy separation and good MS response in further work. Therefore, a search library of 52 benzylisoquinoline alkaloids was established, which included eight aporphine, 19 tetrahydroprotoberberine, two protopine, two benzyltetrahydroisoquinoline, and 21 protoberberine alkaloids. The information of the search library contained compound names, structures, retention times, accurate masses, fragmentation pathways of benzylisoquionline alkaloids, and their sources from three herbal medicines. Using such a library, the alkaloids, especially those trace and unknown components in some herbal medicine could be accurately and quickly identified. In addition, the distribution of benzylisoquinoline alkaloids in the herbal medicines could be also summarized by searching the source samples in the library.

Synthesis and Field Evaluation of the Sex Pheromone Analogues to Soybean Pod Borer Leguminivora glycinivorella

In order to develop efficient lures for soybean pod borer Leguminivora glycinivorella (Matsumura) in China, (E,E)-8,10-dodecadienyl acetate (EE-8,10-12:Ac), the main component of the pheromone of L. glycinivorella, and 12 structurally-related compounds were synthesised in good overall yields, regiospecificities, and stereo-selectivities via coupling reactions catalysed by Li2CuCl4. The effect of different synthetic compounds, alone or in combination with EE-8,10-12:Ac, on numbers of captured L. glycinivorella males was evaluated. EE-8,10-12:Ac, (E)-10-dodecenyl acetate(E-10-12:Ac), (E)-8-dodecenol (E-8-12:OH), tetradecyl acetate (14:Ac), and (Z)-9-tetradecenyl acetate (Z-9-14:Ac) alone displayed different attractiveness to L. glycinivorella males. 14:Ac, E-8-12:OH, E-10-12:Ac, (E,E)-8,10-dodecadienal (EE-8,10-12:Ald), (E)-8-dodecenal (E-8-12:Ald), (E)-10-dodecenal (E-10-12:Ald) and Z-9-14:Ac all showed a synergistic effect to EE-8,10-12:Ac at certain dosages. The binary mixtures of EE-8,10-12:Ac and E-10-12:Ald, Z-9-14:Ac,14:Ac, E-8-12:Ald, EE-8,10-12:Ald, E-8-12:OH, or E-10-12:Ac in suitable ratios give 17.00-, 10.98-, 10.67-, 6.73-, 5.54-, 4.30- and 4.50-fold increases in trap catch, respectively, over the standard pheromone lure, and as novel pheromone blends, demonstrated potential use in pheromone traps to monitor or control L. glycinivorella populations in China.

Performance of urinary and gene expression biomarkers in detecting the nephrotoxic effects of melamine and cyanuric acid following diverse scenarios of co-exposure

Although standard nephrotoxicity assessments primarily detect impaired renal function, KIM-1, clusterin, NGAL, osteopontin and TIMP-1 were recently identified biomarkers proposed to indicate earlier perturbations in renal integrity. The recent adulteration of infant and pet food with melamine (MEL) and structurally-related compounds revealed that co-ingestion of MEL and cyanuric acid (CYA) could form melamine–cyanurate crystals which obstruct renal tubules and induce acute renal failure. This study concurrently evaluated the ability of multiplexed urinary biomarker immunoassays and biomarker gene expression analysis to detect nephrotoxicity in F344 rats co-administered 60ppm each of MEL and CYA in feed or via gavage for 28days. The biomarkers were also evaluated for the ability to differentiate the effects of the compounds when co-administered using diverse dosing schedules (i.e., consecutive vs. staggered gavage) and dosing matrixes (i.e., feed vs. gavage). Our results illustrate the ability of both methods to detect and differentiate the severity of adverse effects in the staggered and consecutive gavage groups at much lower doses than previously observed in animals co-exposed to the compounds in feed. We also demonstrate that these urinary biomarkers outperform traditional diagnostic methods and represent a powerful, non-invasive indicator of chemical-induced nephrotoxicity prior to the onset of renal dysfunction.

P01.27. Assessment of polyphenols on PSA expression in a human co-culture model of reactive prostate stroma cells and LAPC4 prostate adenocarcinoma cells

Purpose The reactive stromal phenotype in the prostate is mechanistically important for understanding prostate cancer progression and may be a target for prevention. We mimicked the interaction of endocrine, paracrine, and immune factors on induced androgen metabolism in prostate stroma by coculturing human primary prostate stromal cells and LAPC-4 prostatic adenocarcinoma cells. The aim of the study was to use this model to investigate dose dependent effects of hop-derived polyphenols xanthohumol (Xan), isoxanthohumol (iXan), 8prenylnaringenin (8-PN) and structurally-related compounds quercetin (Que), naringenin (Nar), and 6dimethylallylnaringenin (6-DMAN) on PSA secretion.

Interkingdom signaling by structurally related cyanobacterial and algal secondary metabolites

Several groups of structurally-related compounds, comprised of either five or six-membered ring structures with attached lipophilic carbon chains and in some cases possessing halogen atoms, have been isolated from various marine algae and filamentous cyanobacteria. The related compounds considered in the present work include the coibacins, laurenciones, honaucins, malyngamides and the tumonoic acids. Members of all of these compound families were assayed and found to inhibit the production of nitric oxide in lipopolysaccharides-stimulated macrophages, indicating their anti-inflammatory potential. In addition, several of these same marine natural products were found to inhibit quorum sensing mediated phenotypes in Vibrio harveyi BB120 and/or Escherichia coli JB525. The mechanism and evolutionary significance for inhibition of these cellular processes in prokaryotic and eukaryotic systems are speculated on and discussed.

The Promoter of Rv0560c Is Induced by Salicylate and Structurally-Related Compounds in Mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major global health threat. During infection, bacteria are believed to encounter adverse conditions such as iron depletion. Mycobacteria synthesize iron-sequestering mycobactins, which are essential for survival in the host, via the intermediate salicylate. Salicylate is a ubiquitous compound which is known to induce a mild antibiotic resistance phenotype. In M. tuberculosis salicylate highly induces the expression of Rv0560c, a putative methyltransferase. We identified and characterized the promoter and regulatory elements of Rv0560c. PRv0560c activity was highly inducible by salicylate in a dose-dependent manner. The induction kinetics of PRv0560c were slow, taking several days to reach maximal activity, which was sustained over several weeks. Promoter activity could also be induced by compounds structurally related to salicylate, such as aspirin or para-aminosalicylic acid, but not by benzoate, indicating that induction is specific to a structural motif. The −10 and −35 promoter elements were identified and residues involved in regulation of promoter activity were identified in close proximity to an inverted repeat spanning the −35 promoter element. We conclude that Rv0560c expression is controlled by a yet unknown repressor via a highly-inducible promoter.

Absolute Stereochemistry of Novel Isochromanone Derivatives fromLeptosphaeriasp. KTC 727

A novel isochromanone, (S)-8-hydroxy-6-methoxy-4,5-dimethyl-3-methylene-isochromen-1-one (1), known 2 and previously reported metabolites from Leptosphaeria sp. KTC 727 (JCM 13076 = MAFF 239586) were isolated from the same source by culturing for a relatively long period. The results of the present study disclose their structures involving the absolute stereochemistry. The planar structures of these molecules were established by ESIMS and NMR spectral analyses. The absolute configuration of 1 was established by comparing its electronic circular dichroism (ECD) spectrum with that of structurally-related known compound 3. The relative stereochemistry of 2 was revealed by a combination of nuclear Overhauser effect (NOE) experiments and thermodynamic discussions. Successful transformation of 1 to 2 led us to assign the configuration of 2 after comparing their ECD spectra. These compounds exhibited weak antifungal activities against Cochliobolus miyabeanus.

GABAA Receptor Subtype-Selective Modulators. II. α5-Selective Inverse Agonists for Cognition Enhancement

Benzodiazepine site agonists (such as diazepam) are well-known to impair cognition. Since benzodiazepines exert their effects via modulation of α1-, α2-, α3- and α5-containing GABA(A) receptors, the cognition-impairing effects of diazepam must be associated with one or several of these subtypes. Of these different subtypes, α5-containing GABA(A) receptors represent an attractive option as the "cognition" subtype based upon the preferential localization of these receptors within the hippocampus and the well-established role of the hippocampus in learning and memory. As a result, it is hypothesized that an inverse agonist selective for the α5 subtype should enhance cognition. For example, L-655708, a partial inverse agonist with 50-100-fold higher affinity for the α5 relative to the α1, α2 and α3 subtypes of GABA(A) receptors, enhanced cognitive performance in rats. Unfortunately, however, pharmacokinetic properties of this compound prevented it being developed further. In order to try achieve binding selectivity in a series structurally distinct from the imidazobenzodiazepines, the group at Merck, Sharp & Dohme commenced studies within the triazolopyridazine series. Although a degree of binding selectivity could be achieved (a maximum of 22-125-fold for α5 versus α1, α2 or α3) this approach was dropped in favour of a strategy to identify compounds with either a combination of selective affinity and selective efficacy or purely selective efficacy. With respect to the former, screening of the Merck chemical collection identified a novel, moderately α5-binding selective thiophene series and further optimization of this series produced MRK-536, which demonstrated a modest α5 binding selectivity (~10-fold) as well as α5-efficacy selectivity. However, the structure-activity relationship within this and the analogous tetralone series proved unpredictable and these series were not pursued further. The success of the selective efficacy approach on the α2/α3-selective agonist project led a similar paradigm being adopted for the α5 project. The starting point for this strategy was the triazolopyridazine 3 which, like MRK-536, possessed a degree of both α5 binding- and efficacy-selectivity. By changing the core from a triazolopyridazine to a triazolophthalazine structure, α5 binding selectivity was lost but with subsequent optimization, compounds with the desired profile (low or antagonist efficacy at the α1, α2 and α3 subtypes and marked inverse agonism at α5-containing receptors) could be achieved, allowing the clinical candidate α5IA as well as the structurally-related pharmacological tool compound α5IA-II to be identified. By appending features of the prototypic α2/α3-selective triazolopyridazine L-838417 (t-butyl and 1,2,4 triazole) along with the isoxazole of α5IA to a pyrazolotriazine core, an additional clinical candidate, MRK-016, was identified. Finally, a degree of α5 efficacy selectivity was achieved the pyridazine series but metabolic instability within this chemotype limited its further optimization. Overall, these studies demonstrate the feasibility of adopting a selective efficacy approach in the identification of α5 selective GABA(A) receptor inverse agonists.

A new look at old compounds

A new look at old compounds

Abstract 607: Restoration of p53 pathway signaling and apoptotic induction by prodigiosin and its structurally-related compound (NSC247562) in p53-deficient human colon carcinoma cells

Abstract p53 deficiency occurs commonly in human tumors, and contributes to radio- and chemo-resistance as well as an aggressive phenotype. It is believed that specific restoration of p53 will be beneficial in the treatment of aggressive or resistant tumors. Using a p53 mutant cell line (SW480) stably integrated p53-responsive reporter, we sought to identify small molecules with p53 rescue activity by screening of the NCI drug library. We found prodigiosin and its structurally related compound (NSC247562) can activate p53-dependent transcriptional activity in SW480, DLD1 as well as HCT116 p53−/− colon tumor cells. The induction of p53-dependent transcriptional activity by prodigiosin and its related compound (NSC247562) is stronger than that induced by CP31398 or ellipticine, which were previously reported as p53 function-restoring drugs. Furthermore, prodigiosin and its related compound (NSC247562) are found to induce the expression of p53 target genes (p21, Puma, DR5 and DR4) in mutant-p53 containing or p53-null human colon cancer cells. The restoration of p53 transcriptional activity by prodigiosin and its related compound (NSC247562) is accompanied by apoptotic induction as indicated by an increase of sub-G1 population and PARP cleavage. More importantly, prodigiosin and its related compound (NSC247562) induced tumor cell death, but have little or no detectable cytotoxicity towards normal human fibroblasts. Thus prodigiosin and its related compound may serve as promising compounds for the development of anticancer drugs which rescue p53 activity and induce cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 607. doi:10.1158/1538-7445.AM2011-607

Abstract 5441: A rapid homogeneous immunoassay for the therapeutic drug management of imatinib in plasma using a novel selective monoclonal antibody

Abstract Objective: Imatinib is a potent and selective inhibitor of the Bcr-Abl and KIT protein tyrosine kinases. It is widely used for treatment of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) and KIT-positive gastrointestinal stromal tumor (GIST). Studies have shown a significant inter-patient variability in imatinib trough concentrations up to 16 fold and a correlation between systemic exposure of the drug and clinical outcome. The current physical methods for measuring imatinib require specially trained personnel, larger sample sizes, are expensive, time consuming and not amenable for widespread use. The objective of this study is to develop an automated immunoassay that provides a rapid, simple and inexpensive method to routinely measure exposure of imatinib in patients undergoing chemotherapy. Methods: A library containing five novel and highly selective antibodies to imatinib were covalently linked to carboxyl-modified nanoparticles to develop a prototype automated homogenous assay for use on the Beckman Coulter AU®400 clinical analyzer which uses a two reagent system and 2 uL of plasma to quantitate imatinib. The degree of aggregation of nanoparticles, inversely proportional to the concentration of imatinib in a sample, was monitored at 600 nm. Total imprecision and linearity of the assay were evaluated by testing normal human plasma (NHP) pools spiked with different levels of imatinib. The background of the assay was also determined by measuring >100 NHP blank samples. Immunoassay selectivity was characterized by testing metabolites including N-desmethylimatinib and other structure-related compounds of imatinib for cross-reactivity at relevant physiological concentrations. Results: With a quantitative range from 100 to 4,000 ng/mL and instrument auto-dilution, plasma samples with imatinib concentrations up to 10,000 ng/mL could be determined using this assay. Time-to-first result was 11 minutes and 400 samples per hour could be measured using a stored calibration curve. The total imprecision of NHP pools spiked with imatinib at four concentrations across the assay range was <10% CV and the assay was linear from 100 to 4,000 ng/mL. The background of the assay was <50 ng/mL. The assay cross-reactivities to N-desmethylimatinib and other cross-reactants were determined to have insignificant impact on the quantitation of imatinib. Conclusion: This immunoassay is suitable for determining imatinib concentrations in plasma with the advantages of speed, small sample size, no sample pretreatment and application on automated instrumentation, providing a tool for optimization of imatinib plasma trough levels with pharmacokinetic-guided dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5441. doi:10.1158/1538-7445.AM2011-5441

Synthesis and application of a novel molecularly imprinted polymer‐coated stir bar for microextraction of triazole fungicides in soil

The preparation, characteristics and application of a sorptive stir bar coated with molecularly imprinted polymer (MIP) using triadimefon as the template molecule are described here. Raw glass capillary was coated with MIP through chemical bonding. The synthesis method was effective and reproducible with the batch-to-batch RSD within 7.8%. Scanning electron micrographs of the stir bar revealed a highly porous coating with average thickness of 15 μm. The synthesized stir bar was proved to be highly stable in most of the solvent for use. Extraction performance showed the fabricated stir bar has excellent molecular recognition abilities for triadimefon and the structure-related compounds, such as triadimenol, diniconazole, flutriafol, hexaconazole, tebuconazole, paclobutrazol and uniconazole, and thus can be applied for simultaneous determination of these triazole fungicides from complex samples by coupling with high-performance liquid chromatography. The variables that influence extraction were optimized with 10.0 μg/L standard solutions of triazole fungicides, and the analytical method was established for the determination of triazole fungicides in soil. The detection limits were in the range of 0.14-0.34 μg/L, and the recoveries were from 86.7 to 114.6% for spiked soil sample.

Diethyldithiocarbamate and structurally-related compounds and the uptake and release of noradrenaline in the heart of the rat.

Journal Article Diethyldithiocarbamate and structurally-related compounds and the uptake and release of noradrenaline in the heart of the rat Get access W Lippmann, W Lippmann Biogenic Amines Laboratory, Ayerst Laboratories, Montreal, Quebec, Canada Search for other works by this author on: Oxford Academic Google Scholar K Lloyd K Lloyd Biogenic Amines Laboratory, Ayerst Laboratories, Montreal, Quebec, Canada Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 21, Issue 11, November 1969, Pages 780–781, https://doi.org/10.1111/j.2042-7158.1969.tb08171.x Published: 12 April 2011 Article history Received: 25 July 1969 Published: 12 April 2011

Rat Liver Cytochrome P450-mediated Metabolic Activation of Methoxsalen and Structurally Related Compounds and its Relation to Enzyme Inhibition

Abstract The metabolic activation and enzyme inhibition characteristics of methoxsalen were investigated in rat liver microsomes obtained from untreated animals and those treated with a number of prototypic inducers of cytochrome P450. Glutathione depletion assays have been carried out which show reactive metabolite generation to be markedly increased following phenobarbitone and β-naphthoflavone induction. Moreover, isoniazid induction led to levels of glutathione depletion significantly higher than those seen with other forms of induction, suggesting an important role for the cytochrome P4502E1 isozyme in the metabolic activation process. Methoxsalen was shown to be an extremely potent inhibitor of 7-ethoxycoumarin-O-de-ethylase activity, with inhibition constants of the order of μm with microsomes obtained from untreated, phenobarbitone- and β-aphthoflavone-induced animals. In contrast, constants obtained with microsomes obtained from isoniazid-induced animals were found to be markedly higher. Comparisons of the inhibition of 7-ethoxy and 7-pentoxyresorufin-O-dealkylase activities by methoxsalen and a number of structurally-related compounds have shown that a complete tricyclic ring system and an unsaturated 4′,5′-bond are structural prerequisites in the formation of reactive metabolites which inhibit cytochrome P450. These data implicate the furan ring system as the source of these metabolites and rule out the involvement of the pyrone ring system in the inhibition process.

Determination of unknown protein function using crystallographic screening of metabolite cocktail binding

An estimated 30–40% of sequenced bacterial genes, and an even higher fraction of genes in archaea and eukaryotes, encode for proteins that lack an assigned function. Identification of unknown protein functions is a high‐priority task in our efforts to understand cellular processes. Here, we applied crystallographic screening to assess the binding of compounds in a metabolite library to proteins in two families. These two families are the YjeF_N family of unknown function represented by a mouse apolipoprotein‐I binding protein and the N‐terminal domain of Tm0922 from Thermotoga maritima, and the PF01256 family, previously annotated as a family of small molecule kinases, represented by YxkO from Bacillus subtilis and the C‐terminal domain of Tm0922. The selective binding of several structurally‐related compounds observed for each protein provides the basis for identification of the likely ligands of the proteins. Subsequently, the PF01256 proteins are shown to catalyze ATP‐dependent NAD(P)H‐hydrate dehydration, the previously described orphan activity. The YjeF_N proteins interact with an adenosine diphosphoribose‐related (ADPR) substrate and most likely serve as ADPR transferases. Metabolite library screening may be used as an efficient tool for the functional studies of uncharacterized proteins. The funding was provided by the NIH grants U01‐HD060491, U54‐GM74492, U54‐GM074942 and R01‐GM53163.