Spectroscopic studies of the interaction between phosphorus heterocycles and cytochrome P450 / 药物分析学报

P450 fatty acid decarboxylase OleT from Staphylococcus aureus (OleTsA) is a novel cytochrome P450 enzyme that catalyzes the oxidative decarboxylation of fatty acids to yield primarily terminal alkenes and CO2 or minor α-and β-hydroxylated fatty acids as side-products.In this work,the interactions between a series of cycloalkyl phosphorus heterocycles (CPHs) and OleTsA were investigated in detail by fluores-cence titration experiment,ultraviolet-visible (UV-vis) and 31p NMR spectroscopies.Fluorescence titration experiment results clearly showed that a dynamic quenching occurred when CPH-6,a repre-sentative CPHs,interacted with OleTsA with a binding constant value of 15.2 × 104 M-1 at 293 K.The thermodynamic parameters (△H,△S and △G) showed that the hydrogen bond and van der Waals force played major roles in the interaction between OleTsA and CPHs.The UV-vis and 31p NMR studies indicated the penetration of CPH-6 into the interior environment of OleTsA,which greatly affects the enzymatic activity of OleTsA.Therefore,our study revealed an effective way to use phosphorus hetero-cyclic compounds to modulate the activity of cvtochrome P450 enzymes.

Nanoestructuras de sílice, con diámetro y distribución de mesoporos variable, modificadas con ácido tungstofosfórico como catalizadores en la síntesis de quinoxalinas / Silica nanostructures, with variable diameter and mesopore size distribution, modified with tungstophosphoric acid as catalyst in the synthesis of quinoxalines / Nanoestruturas de sílica, com distribuição variável de diâmetro e tamanho de mesoporos, modificadas com ácido tungstofosfórico como catalisador na síntese de a síntese da quinoxalina

Resumen Se sintetizaron catalizadores (SNX#WPA) basados en ácido tungstofosfórico, en soportes de nanoestructuras de sílice (SNX), con distribución de diámetros y tamaños de mesoporos variables. Las SNX se prepararon en medio de octano/agua, usando poliestireno y bromuro de cetiltrimetilamonio como plantillas. Los materiales se caracterizaron por DRX, TEM y adsorción/desorción de nitrógeno. La relación octano/agua influyó tanto en la morfología y el tamaño de las SNX como en la distribución del tamaño de poro. Las SNX obtenidas utilizando relaciones OCT/H2O en el rango de 0,07-0,35, presentan mesoporos pequeños (5-6 nm) y grandes (28-34 nm), generados principalmente por poliestireno. Los mesoporos grandes y su contribución de volumen fueron claramente más altos que en las muestras SN1, SN2 y SN3. La estructura y la morfología de SNX#WPA fueron similares a las de las SNX usadas como soporte. Además, la caracterización de todos los materiales SNX#WPA por FT-IR y 31P NMR indicó la presencia de especies [PW12O40]3- y [H3-XPW12O40](3-X)- sin degradar. Según los resultados de la valoración potenciométrica, los sólidos presentaron sitios ácidos muy fuertes. Se evaluó la actividad de SNX#WPA como catalizadores en la síntesis de quinoxalinas, a partir de lo cual se obtuvieron altos rendimientos, sin formación de subproductos. De ello resultó que los materiales preparados son catalizadores altamente selectivos y reutilizables.

Abstract Tungstophosphoric acid supported on silica nanostructures (SNX#WPA) with variable diameter and mesopore size distribution were synthetized. Silica nanostructures (SNX) were prepared in octane/aqueous media using polystyrene and CTAB as organic templates. The materials were characterized by XRD, SEM, TEM and dinitrogen adsorption/ desorption isotherm analysis. The octane/ water ratio influenced the morphology and size of SNX prepared, as well as its pore size distribution. The SNX samples obtained using OCT/H2O ratios in the range 0.07-0.35 (SN4, SN5, and SN6 samples). present small (5-6 nm) and large (28-34 nm) mesopores (mainly generated by polystyrene). Large mesopores and their volume contribution were clearly higher than in the SN1, SN2, and SN3 samples. The structure and morphology of SNX#WPA samples were similar to those of the SNX. Furthermore, the characterization of all the SNX#WPA materials by FT-IR and 31P NMR indicated the presence of undegraded [PW12O40]3- and [H3-XPW12O40](3-X)-species. According to the potentiometric titration results, the solids presented very strong acid sites. The performance of SNX#WPA materials as catalysts in the synthesis of quinoxalines was evaluated. The yields achieved were high, without formation of by-products resulting from competitive reactions or decomposition products, so the prepared materials are highly selective and reusable catalysts.

Resumo Catalisadores (SNX#WPA) baseados em ácido tungsofosfórico suportado em nanoestruturas de sílica (SNX) foram sintetizados com distribuição de tamanhos e diâmetros variados de mesoporos. Os SNX foram preparados em meio octano/aquoso usando poliestireno e brometo de cetiltrimetilamônio como modelos orgânicos. Os materiais foram caracterizados por DRX, TEM e adsorção/ dessorção de nitrogénio. A razão octano/ agua influenciou a morfologia e o tamanho do SNX, bem como a distribuição do tamanho dos poros. O SNX obtido usando razões OCT/ H2O na faixa de 0,07-0,35, possui mesoporos pequenos (5-6 nm) e grandes (28-34 nm) (gerados principalmente por poliestireno). Mesoporos grandes e sua contribuição em volume foram claramente maiores do que nas amostras SN1, SN2 e SN3. A estrutura e a morfologia do SNX#WPA foram semelhantes às do SNX usado como suporte. Além disso, a caracterização de todos os materiais SNX#WPA por FT-IR e 31P NMR indicou a presença das espécies [PW12O40]3- e [H3-XPW12O40](3-X)- sem degradar. De acordo com os resultados da titulação potenciométrica, os sólidos apresentaram locais ácidos muito fortes. A atividade do SNX#WPA como catalisadores na síntese de quinoxalinas foi avaliada, produzindo altos rendimentos, sem formação de subprodutos, resultando em materiais catalisadores altamente seletivos e reutilizáveis.

Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells

Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T-acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with 10 μM up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to 1.94 μM. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer-related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.

Binding interaction of phosphorus heterocycles with bovine serum albumin:A biochemical study / 药物分析学报

Interaction between bovine serum albumin (BSA) and phosphorus heterocycles (PHs) was studied using multi-spectroscopic techniques. The results indicated the high binding a?nity of PHs to BSA as it quenches the intrinsic fluorescence of BSA. The experimental data suggested the fluorescence quenching mechanism between PHs and BSA as a dynamic quenching. From the UV–vis studies, the apparent association constant (Kapp) was found to be 9.25×102, 1.27×104 and 9.01×102 L/mol for the interaction of BSA with PH-1, PH-2 and PH-3, respectively. According to the F?rster's non-radiation energy transfer (FRET) theory, the binding distances between BSA and PHs were calculated. The binding distances (r) of PH-1, PH-2 and PH-3 were found to be 2.86, 3.03, and 5.12 nm, respectively, indicating energy transfer occurs between BSA and PHs. The binding constants of the PHs obtained from the fluorescence quenching data were found to be decreased with increase of temperature. The negative values of the thermodynamic parametersΔH,ΔS andΔG at different temperatures revealed that the binding process is spontaneous;hydrogen bonds and van der Waals interaction were the main force to stabilize the complex. The microenvironment of the protein-binding site was studied by synchronous fluorescence and circular dichroism (CD) techniques and data indicated that the conformation of BSA changed in the presence of PHs. Finally, we studied the BSA-PHs docking using AutoDock and results suggest that PHs is located in the cleft between the domains of BSA.

Synthesis and anti-HBV activity evaluation of Matijin-Su derivatives with aromatic heterocycles / 中国药科大学学报

@#Hepatitis B virus(HBV)-infected hepatitis is one of the most common infectious disease worldwide. To find novel effective anti-HBV agents, a series of Matijin-Su(MTS)derivatives with aromatic heterocycles were synthesized and evaluated for their anti- HBV activities in HepG2 2. 2. 15 cells. Among them, compounds 7a(IC50=2. 94 μmol/L)and 9a(IC50=2. 21 μmol/L)exhibited more potent inhibitory activity against the replication of HBV DNA in HepG2 2. 2. 15 cells than that of lead compound MTS(IC50=11. 16 μmol/L). Notably, both 7a and 9a displayed a high selective index(SI)of 146. 39 and > 250, respectively, which were also much higher than that of MTS(SI=10. 78). Therefore, compounds 7a and 9a may be promising anti-HBV agents with safety profile for HBV infection.

Synthesis of Some Novel Heterocyclic 1,2,4-triazolo [3,4-b][1,3,4] Thiadiazole Derivatives as Possible Antimicrobial Agents.

A series of 6-aryl-3- (3,4–dialkoxyphenyl) -[1,2,4]triazole [3,4-b][1,3,4] thiadiazole (7a-7o) were synthesized by condensing 4-amino-5-(3,4-dialkoxyphenyl)-4H-[1,2,4]- triazole-3-thiol (6) with various aromatic carboxylic acids in the presence of phosphorous oxychloride through one-pot reaction. The structures of these newly synthesized compounds were confirmed on the basis of IR, 1H NMR and mass spectral studies. All the synthesized compounds were screened for their antimicrobial activity against a variety of microorganisms.

Chemical constituents in endophytic fungus Verticillium sp. KY-18 isolated from Dendrobium officinale / 中草药

Objective: To study the chemical constituents in the endophytic fungus Verticillium sp. KY-18, isolated from Dendrobium candidum. Methods: The compounds were isolated and purified by means of chromatographic techniques and their structures were identified on the basis of spectral features. Results: Thirteen known compounds belong to oxygen heterocyclic compounds, named 2, 6-dihydroxy-2-methyl-7-(prop-1E-enyl)-1-benzofuran-3 (2H)-one (1), nigrosporapyrone D (2), oosponol (3), 2-methyl-4-pyrone (4), 5-(1E-butenyl)-6-methylpyran-2-one (5), penicisochroman D (6), verrucosapyrone B (7), (1S, 3S)-1, 8-dimethoxy-3, 5- dimethyl-6-hydroxyisochroman (8), phomopsinone A (9), pseudohalonectrin A (10), dictafolin-A (11), 2, 3-dihydro-5, 7-dihydroxy-2, 6, 8-trimethyl-4H-1-benzopyran-4-one (12), and 2-pyrone-4, 6-dicarboxylic acid (13). Conclusion: Compounds 2-10 are first isolated from the plants of Verticillium genus, and compounds 11-13 are first obtained from fungi.