Synthesis of Symmetrical and Unsymmetrical <i>N</i>,<i>N</i>′-Diaryl Guanidines via Copper/<i>N</i>-Methylglycine-Catalyzed Arylation of Guanidine Nitrate

CuI/<i>N</i>-methylglycine-catalyzed coupling reaction of guanidine nitrate with both aryl iodides and bromides takes place at 70–100 °C, affording symmetrical <i>N</i>,<i>N</i>′-diaryl guanidines with good to excellent yields. Unsymmetrical <i>N</i>,<i>N</i>′-diaryl guanidines can be assembled via monoarylation of guanidine nitrate with aryl iodides bearing a strong electron-withdrawing group and subsequent coupling with another aryl iodide

Highly Asymmetric Bromocyclization of Tryptophol: Unexpected Accelerating Effect of DABCO-Derived Bromine Complex

Highly asymmetric bromocyclization of tryptophol by using chiral anionic phase-transfer catalyst and DABCO-derived brominating reagent is described. Optimization of the reaction conditions revealed that the reaction rate was accelerated together with improvement of enantioselectivity by addition of catalytic DABCO-derived brominating reagent. From tryptophol, 3-bromofuroindoline could be directly obtained in excellent enantioselectivities by employing this novel methodology

Synthesis of CDDO–Amino Acid–Nitric Oxide Donor Trihybrids as Potential Antitumor Agents against Both Drug-Sensitive and Drug-Resistant Colon Cancer

Seventeen CDDO–amino acid–NO donor trihybrids (<b>4a</b>–<b>q</b>) were designed and synthesized. Biological evaluation indicated that the most active compound <b>4c</b> produced high levels of NO and inhibited the proliferation of drug-sensitive (HCT-8, IC₅₀ = 0.294 μM) and drug-resistant (HCT-8/5-FU, IC₅₀ = 0.232 μM) colon cancer cells, which were attenuated by an NO scavenger or typical substrate of PepT1. Furthermore, <b>4c</b> triggered HCT-8 and HCT-8/5-FU cell apoptosis more strongly than CDDO-Me, inhibited the HIF-1α, Stat3, AKT, and ERK signaling, and induced the nitration of P-gp, MRP1, and BCRP proteins in HCT-8/5-FU cells. Finally, <b>4c</b> had 4.36–5.53-fold less inhibitory activity against nontumor colon epithelial-like cells (CCD841, IC₅₀ = 1.282 μM) in vitro and inhibited the growth of implanted human drug-resistant colon cancers in mice more potently than CDDO-Me. Together, <b>4c</b> is a novel trihybrid with potent antitumor activity and may be a promising candidate for the treatment of drug-resistant colon cancer

Ethylene Glycol-Linked Amino Acid Diester Prodrugs of Oleanolic Acid for PepT1-Mediated Transport: Synthesis, Intestinal Permeability and Pharmacokinetics

The purposes of this study were to expand the structure of parent drugs selected for peptide transporter 1 (PepT1)-targeted ester prodrug design and to improve oral bioavailability of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug. Through an ethoxy linker the carboxylic acid group of OA was conjugated with the carboxylic acid group of different amino acid promoieties to form six diester prodrugs. The effective permeability (<i>P</i>_eff) of prodrugs was screened by in situ rat single-pass intestinal perfusion (SPIP) model in two buffers with different pH (6.0 and 7.4) as PepT1 employs a proton-gradient as the driving force. Compared to OA, 2.5-fold, 2.3-fold, 2.2-fold, 2.1-fold, and 1.9-fold enhancement of <i>P</i>_eff in buffer with pH 6.0 was observed for l-Phe ester (<b>5c</b>), l-Val ester (<b>5a</b>), l-Lys ester (<b>5e</b>), d-Phe ester (<b>5d</b>), and d-Val ester (<b>5b</b>), respectively. Furthermore, <i>P</i>_eff of <b>5a</b>, <b>5c</b>, <b>5d</b> and <b>5e</b> in pH 6.0 was significantly higher than that in pH 7.4 (<i>p</i> < 0.01), respectively. These results showed that the H⁺ concentration of perfusion solution had great effect on the transport of the prodrugs across intestinal membrane. For the further evaluation of affinity to PepT1, inhibition studies were performed by coperfusing 0.1 mM prodrug with 50 mM glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1). It turned out that the <i>P</i>_eff of <b>5a</b>, <b>5b</b>, <b>5c</b> and l-Tyr ester (<b>6f</b>) significantly reduced in the presence of Gly-Sar (1.7-fold, 2.2-fold, 1.9-fold, and 1.4-fold, respectively). We supposed that it may be attributed to PepT1 mediated transport of these prodrugs. <b>5a</b> and <b>6f</b> were selected as the optimal target prodrugs for oral absorption <i>in vivo</i>. Following intragastric administration of 300 mg/kg (calculated as OA) <b>5a</b>, <b>6f</b> and OA in three groups of rats, compared with group OA, <i>C</i>_max for the group of <b>5a</b> and <b>6f</b> was enhanced by 1.56-fold and 1.54-fold, respectively. <i>F</i>_app of group <b>5a</b> and <b>6f</b> was 2.21- and 2.04-fold increased, respectively, indicating that <b>5a</b> and <b>6f</b> had better oral absorption than OA. The combined results also suggest that diester prodrugs which conjugated two carboxylic acid groups of proper amino acid promoieties and parent drug through a linker can be used for PepT1-targeted prodrug design. With this strategy, oral bioavailability of OA in rats could be improved significantly

Hybrid Molecule from <i>O</i>²‑(2,4-Dinitrophenyl)diazeniumdiolate and Oleanolic Acid: A Glutathione <i>S</i>‑Transferase π‑Activated Nitric Oxide Prodrug with Selective Anti-Human Hepatocellular Carcinoma Activity and Improved Stability

A series of hybrids from <i>O</i>²-(2,4-dinitrophenyl)­diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione <i>S</i>-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, <b>21</b>, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, <b>21</b> exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of <b>21</b> occurred in the presence of GSTπ and was much more effective than in glutathione <i>S</i>-transferase α. Additionally, <b>21</b> induced apoptosis in HepG2 cells by arresting the cell cycle at the G2/M phase, activating both the mitochondrion-mediated pathway and the MAPK pathway and enhancing the intracellular production of ROS

Total Synthesis of (−)-Conolutinine

The first enantioselective synthesis of (−)-conolutinine was achieved in 10 steps. The synthesis featured a catalytic asymmetric bromocyclization of tryptamine to forge the tricycle intermediate. Hydration of an alkene catalyzed by Co­(acac)₂ was also employed as a key step to diastereoselectively introduce the tertiary alcohol moiety. The absolute configuration of (−)-conolutinine was established to be (2<i>S</i>,5<i>aS</i>,8<i>aS</i>,13<i>aR</i>) based on this asymmetric total synthesis

Discovery of a Potential Anti-Inflammatory Agent: 3‑Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile

Fifteen novel derivatives of glycyrrhetinic acid (GA) were synthesized and evaluated for anti-inflammatory activities. It was found that the introduction of 1-en-3-one and 9(11),12-diene and 2,20-dinitrile functionalities into the scaffold of GA led to the discovery of potent compound <b>19</b> for inhibition of LPS-induced NO production. Furthermore, <b>19</b> effectively inhibited the protein and mRNA expression of inducible NO synthase (iNOS) and the mRNA expression of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 macrophages. Mechanistically, <b>19</b> exerted inhibitory effects on the activation of the three main MAPKs and phosphorylation and degradation of IκB-α, as well as the ratio of nuclear/cytosolic content of p65. Importantly, <b>19</b> significantly decreased the mortality rate in the mouse model of LPS-induced sepsis shock. It is noteworthy that inhibitory effect of <b>19</b> on NO production was not blocked by the glucocorticoid receptor antagonist mifepristone, indicating that it does not act through the glucocorticoid receptor

Effective Virtual Screening Strategy toward Covalent Ligands: Identification of Novel NEDD8-Activating Enzyme Inhibitors

The NEDD8-activating enzyme (NAE) is an emerging target for cancer therapy, which regulates the degradation and turnover of a variety of cancer-related proteins by activating the cullin-RING E3 ubiquitin ligases. Among a limited number of known NAE inhibitors, the covalent inhibitors have demonstrated the most potent efficacy through their covalently linked adducts with NEDD8. Inspired by this unique mechanism, in this study, a novel combined strategy of virtual screening (VS) was adopted with the aim to identify diverse covalent inhibitors of NAE. To be specific, a docking-enabled pharmacophore model was first built from the possible active conformations of chosen covalent inhibitors. Meanwhile, a dynamic structure-based phamacophore was also established based on the snapshots derived from molecular dynamic simulation. Subsequent screening of a focused ZINC database using these pharmacophore models combined with covalent docking discovered three novel active compounds. Among them, compound <b>LZ3</b> exhibited the most potent NAE inhibitory activity with an IC₅₀ value of 1.06 ± 0.18 μM. Furthermore, a cell-based washout experiment proved the proposed covalent binding mechanism for compound <b>LZ3</b>, which confirmed the successful application of our combined VS strategy, indicating it may provide a viable solution to systematically discover novel covalent ligands

Learning in adaptive collaborative management of community forests: lessons from Indonesia

This paper describes CIFOR’s experiences in implementing ACM research in two sites in Indonesia; East Kalimantan and Jambi. The focus of this paper is on how joint (or social) learning is designed, implemented and institutionalized in every stage of the research. The methodology of the research was participatory action research (PAR) that allowed the research team to carry out two concurrent roles: at the same time they were involved in action (introducing and facilitating the development of ACM) and in observing the process and results for an outside audience (research). It was found that the most important factor in learning was a “trigger” that was a major concern to all stakeholders. A trigger can be an issue or problem. In East Kalimantan case major problems faced by stakeholders were lack of trust among stakeholders, ineffective communication and information exchange within a particular stakeholder group and among stakeholder groups. Meanwhile, in Jambi the major problem was unclear village boundaries. In both cases, inter and intra stakeholders dialogues were used as platform for learning. Along the processes component of learning and learning issues were jointly identified. Learning occurred not only horizontally but also vertically. Some important outcomes of learning are knowledge construction, knowledge sharing, trust building, joint action and also a sense of ownership

Synthesis and Biological Evaluation of Novel Olean-28,13β-lactams as Potential Antiprostate Cancer Agents

γ-Lactam is an important structural motif in a large number of biologically active natural products and synthetic small pharmaceutical molecules. However, there is currently no effective approach to construct γ-lactam ring directly from natural rigid polycyclic amides. Herein, we report a facile methodology for synthesis of a new group of olean-28,13β-lactams (<b>10a</b>–<b>j</b>) from their corresponding amides, promoted by an easily available reagent 2,3-dichloro-5,6-dicyanobenzo­quinone (DDQ), through an intramolecular dehydrogenative C–N coupling reaction via a radical ion mechanism. Biological evaluation indicated that the most active lactam <b>10h</b> displayed potent antiproliferative activity against human cancer cells but 13.84- to 16.92-fold less inhibitory activity on noncancer cells in vitro. In addition, <b>10h</b> significantly inhibited the growth of implanted prostate cancer in vivo. Furthermore, <b>10h</b> induced cell cycle arrest and apoptosis and down-regulated the AKT/mTOR signaling in DU-145 cells. Finally, <b>10h</b> was more stable in rat plasma and human liver microsomes than CDDO-Me and had little hERG channel inhibitory activity. Collectively, <b>10h</b> may be a potential antiprostate cancer agent for further investigation