Electron-Withdrawing β‑Substituent, Ring-Strain, and Ortho Effects on Reactivity, Selectivity, and Stability of <i>o</i>‑Alkoxybenzyl Carbocations

<i>o</i>-Alkoxybenzyl carbocations <b>1</b> and <b>2</b> were generated by laser flash photolysis of the corresponding <i>o</i>-alkoxybenzyl alcohols <b>3</b> and <b>4</b> to understand how the electron-withdrawing β-substituent, the ring-strain, and the ortho effects affect the reactivity (electrophilicity), selectivity, and stability of <b>1</b> and <b>2</b>, and to fit the electrophilicity of <b>1</b> and <b>2</b> into the current carbocation electrophilicity scale (<i>E</i>). Our finding is that both the electron-withdrawing β-substituent and the ring-strain effects make <b>1</b> less stable than <b>2</b> by 3.0 kcal/mol. These effects plus the ortho effect of <b>2</b> make <b>1</b> more reactive than <b>2</b>, but the selectivity of <b>1</b> and <b>2</b> toward amine nucleophiles is almost the same within experimental errors. The electrophilicity of <b>1</b> and <b>2</b> has been fit into the current carbocation electrophilicity scale (<i>E</i>) quite well

Chemical Constituents of the Rhizomes of <i>Bletilla formosana</i> and Their Potential Anti-inflammatory Activity

Nine new phenanthrenes (<b>1</b>–<b>9</b>) and a new benzyl glycoside (<b>10</b>) together with 45 known compounds were isolated from the rhizomes of <i>Bletilla formosana</i>. The structures of <b>1</b>–<b>10</b> were elucidated primarily on the basis of their 1D and 2D NMR spectroscopic data. Most of the isolated compounds were evaluated for their anti-inflammatory activities. The results showed that IC₅₀ values for the inhibition of superoxide anion generation and elastase release ranged from 0.2 to 6.5 μM and 0.3 to 5.7 μM, respectively. Structure–activity relationships of the isolated compounds were also investigated. The inhibitory potencies were determined as phenanthrenes > bibenzyls > biphenanthrenes

Novel Pyrazole Derivatives Effectively Inhibit Osteoclastogenesis, a Potential Target for Treating Osteoporosis

As human beings live longer, age-related diseases such as osteoporosis will become more prevalent. Intolerant side effects and poor responses to current treatments are observed. Therefore, novel effective therapeutic agents are greatly needed. Here, pyrazole derivatives were designed and synthesized, and their osteoclastogenesis inhibitory effects both <i>in vitro</i> and <i>in vivo</i> were evaluated. The most promising compound <b>13</b> with a 2-(dimethylamino)­ethyl group inhibited markedly <i>in vitro</i> osteoclastogenesis as well as the bone resorption activity of osteoclasts. Compound <b>13</b> affected osteoclast’s early proliferation and differentiation more than later fusion and maturation stages. In ovariectomized (OVX) mice, compound <b>13</b> can inhibit the loss of trabecular bone volume, trabecular bone number, and trabecular thickness. Moreover, compound <b>13</b> can antagonize OVX-induced reduction of serum bone resorption marker and then compensatory increase of the bone formation marker. To sum up, compound <b>13</b> has high potential to be developed into a novel therapeutic agent for treating osteoporosis in the future

Antitumor Agents. 293. Nontoxic Dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) Analogues Chemosensitize Multidrug-Resistant Cancer Cells to Clinical Anticancer Drugs

Novel dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogues were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine-resistant nasopharyngeal carcinoma) cells, a multidrug resistant cell line overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2′-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives <b>16</b> and <b>23</b> showed 5–10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analogue <b>6</b> also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogues against both non-MDR and MDR cells, suggesting that DDB analogues serve as novel lead compounds for the development of chemosensitizers to overcome the MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogues dramatically elevated the cellular concentration of anticancer drugs

Application of flow cytometry for evaluating clinical prognosis and histopathological grade of human glioma

<p><b>Objectives:</b> Flow cytometry was applied to predict the biological parameters of tumor behavior based on the DNA content distribution of tumors. We used flow cytometry to determine the number of cell cycles for the characterization of intracranial gliomas and its possible prognostic role.</p> <p><b>Methods:</b> Flow cytometric analysis of the DNA content was performed for 37 fresh operative glioma specimens. The expression of Ki-67 in glioma specimens was detected using immunohistochemistry staining. The check points of G2/M-phase fractions, cyclin B, and pCdk1 (Y15) were analyzed using Western immunoblotting.</p> <p><b>Results:</b> Compared to low-grade (grade I/II) gliomas, significant differences in the Ki-67, cyclin B, G2/M-phase, and S+G2/M-phase expressions were found in high-grade (grade III/IV) gliomas. Furthermore, receiver operating characteristic (ROC) analysis indicated optimal cutoff points for the G2/M-phase and S+G2/M-phase fractions of 13.47 and 17.26%, respectively, which can be used to differentiate cases with low- and high-grade gliomas. Additionally, both G2/M-phase and S+G2/M-phase fractions had significant association with the expression of Ki-67 in the gliomas. The gliomas were classified by the DNA content. We found that patients with high-grade glioma had worse survival rate than patients with low-grade glioma. Meanwhile, ROC curve analysis gave cutoffs for G2/M-phase of 9.4% and for S+G2/M-phase fractions of 15.04% as best predicting survival. The patients with glioma had poor survival when the levels of G2/M-phase and S+G2/M-phase were more than 9.4 and 15.04%, respectively. In contrast, no significant association between the DNA content of glioma patients and their age, tumor recurrence, and tumor size was found.</p> <p><b>Discussion:</b> Our results indicate that flow cytometry analysis for G2/M-phase and S+G2/M-phase fractions can be used for tumor grading for rapidly differentiating low- from high-grade gliomas.</p

Anti-inflammatory Flavan-3-ol-dihydroretrochalcones from <i>Daemonorops draco</i>

Four A-type flavan-3-ol-dihydroretrochalcone dimers, dragonins A–D (<b>1</b>–<b>4</b>), were characterized from the traditional Chinese medicine Sanguis Draconis. The structures of <b>1</b>–<b>4</b> were elucidated by spectroscopic and spectrometric analyses. Compounds <b>1</b> and <b>2</b> exhibited significant inhibition of fMLP/CB-induced superoxide anion and elastase. The signaling pathways accounting for the inhibitory effects of compound <b>2</b> were also elucidated. These purified A-type flavan-3-ol-dihydroretrochalcones are new potential leads for the development of anti-inflammatory drugs

Dragonbloodin A1 and A2: Flavan Trimers and Anti-inflammatory Principles from Sanguis Draconis

Two flavan trimers, dragonbloodin A1 (<b>1</b>) and A2 (<b>2</b>), were isolated as diastereomers from sanguis draconis, a traditional Chinese medicine for regulating blood. The structures of <b>1</b> and <b>2</b> were elucidated by spectroscopic analysis and X-ray diffraction. Possible interactions between <b>1</b> and <b>2</b> were discussed, and possible biosynthesis pathways were deduced. Compounds <b>1</b>, <b>2</b>, and their racemic mixture all exhibited inhibition of human neutrophil elastase in a dose-dependent manner

Chemical Constituents and Anti-inflammatory Principles from the Fruits of <i>Forsythia suspensa</i>

Fifty compounds were isolated from the fruits of <i>Forsythia suspensa</i>, including 13 new compounds characterized as eight new diterpenoids (<b>1</b>–<b>8</b>), three new lignans (<b>9</b>–<b>11</b>), a new iridoid (<b>12</b>), and a new triterpenoid (<b>13</b>). Their structures were established on the basis of spectroscopic and spectrometric analysis. Most of the isolated compounds were examined for their anti-inflammatory activity in vitro. The results showed that several compounds displayed significant inhibition of fMLP/CB-induced superoxide anion generation and elastase release, with IC₅₀ values ranging from 0.6 ± 0.1 to 8.6 ± 0.8 μg/mL and from 0.8 ± 0.3 to 7.3 ± 1.1 μg/mL, respectively

Dragonbloodin A1 and A2: Flavan Trimers and Anti-inflammatory Principles from Sanguis Draconis

Two flavan trimers, dragonbloodin A1 (<b>1</b>) and A2 (<b>2</b>), were isolated as diastereomers from sanguis draconis, a traditional Chinese medicine for regulating blood. The structures of <b>1</b> and <b>2</b> were elucidated by spectroscopic analysis and X-ray diffraction. Possible interactions between <b>1</b> and <b>2</b> were discussed, and possible biosynthesis pathways were deduced. Compounds <b>1</b>, <b>2</b>, and their racemic mixture all exhibited inhibition of human neutrophil elastase in a dose-dependent manner

γ- and δ‑Lactams from the Leaves of <i>Clausena lansium</i>

Eight new clausenamides, including three γ-lactams (<b>1</b>–<b>3</b>), four δ-lactams (<b>4</b>–<b>7</b>), and an amide (<b>8</b>), and seven known lactams, including compounds <b>9</b>–<b>11</b>, which were purified from natural sources for the first time, were characterized from the leaves of <i>Clausena lansium</i>. Their structures were elucidated using spectroscopic methods, and the absolute configurations were determined using electronic circular dichroism and single-crystal X-ray diffraction analyses with Cu Kα radiation. Compound <b>2</b> (50 μM) protected 22.24% of cortical neurons against Aβ_25–35-induced cell death