Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets.

TWIK-related acid-sensitive K+ (TASK) channels, including TASK-1, TASK-3, and TASK-5, are important members of the two-pore domain potassium (K2P) channel family. TASK-5 is not functionally expressed in the recombinant system. TASK channels are very sensitive to changes in extracellular pH and are active during all membrane potential periods. They are similar to other K2P channels in that they can create and use background-leaked potassium currents to stabilize resting membrane conductance and repolarize the action potential of excitable cells. TASK channels are expressed in both the nervous system and peripheral tissues, including excitable and non-excitable cells, and are widely engaged in pathophysiological phenomena, such as respiratory stimulation, pulmonary hypertension, arrhythmia, aldosterone secretion, cancers, anesthesia, neurological disorders, glucose homeostasis, and visual sensitivity. Therefore, they are important targets for innovative drug development. In this review, we emphasized the recent advances in our understanding of the biophysical properties, gating profiles, and biological roles of TASK channels. Given the different localization ranges and biologically relevant functions of TASK-1 and TASK-3 channels, the development of compounds that selectively target TASK-1 and TASK-3 channels is also summarized based on data reported in the literature.

Phytochemical library screening reveals betulinic acid as a novel Skp2-SCF E3 ligase inhibitor in non-small cell lung cancer.

Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome-dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant-derived Skp2 inhibitor, betulinic acid (BA), via high-throughput structure-based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non-small cell lung cancer (NSCLC) through targeting Skp2-SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H-bonds with residue Lys145, decreases its stability by disrupting Skp1-Skp2 interactions, thereby inhibiting the Skp2-SCF E3 ligase and promoting the accumulation of its substrates; that is, E-cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2-SCF E3 ligase and upregulating p27 and E-cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.

Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.

SPRY domain-containing SOCS box protein 2 (SPSB2) is a negative regulator of inducible nitric oxide synthase (iNOS) that modulates the lifetime of iNOS and thus the levels of nitric oxide (NO) production. Inhibitors that can disrupt the endogenous SPSB2-iNOS interaction and augment NO production have potential as novel antimicrobial and anticancer drugs. In this study, we have designed a cyclic peptide (cR8), containing an RGD motif and the SPSB2 binding motif (DINNNV). ITC and chemical shift perturbation showed that cR8 binds to the iNOS binding site on SPSB2 with a Kd of 671 nM, and saturation transfer difference NMR showed that cR8 binds to αvß3 integrin-expressing cells. Moreover, we determined the crystal structure of SPSB2 in complex with cR8, at a resolution of 1.34 Å. cR8 forms extensive hydrogen bonding with SPSB2 residues, but loss of an intramolecular hydrogen bond that is present in SPSB2-bound iNOS peptide may destabilize the bound conformation of cR8 and lead to a gentle reduction in SPSB2 binding affinity. These results serve as a useful basis for designing site-directed SPSB2 inhibitors in the future.

Skp1: Implications in cancer and SCF-oriented anti-cancer drug discovery.

In the last decade, the ubiquitin proteasome system (UPS), in general, and E3 ubiquitin ligases, in particular, have emerged as valid drug targets for the development of novel anti-cancer therapeutics. Cullin RING Ligases (CRLs), which can be classified into eight groups (CRL1-8) and comprise approximately 200 members, represent the largest family of E3 ubiquitin ligases which facilitate the ubiquitination-derived proteasomal degradation of a myriad of functionally and structurally diverse substrates. S phase kinase-associated protein 1 (Skp1)-Cullin1-F-Box protein (SCF) complexes are the best characterized among CRLs, which play crucial roles in numerous cellular processes and physiological dysfunctions, such as in cancer biology. Currently, there is growing interest in developing SCF-targeting anti-cancer therapies for clinical application. Indeed, the research in this field has seen some progress in the form of cullin neddylation- and Skp2-inhibitors. However, it still remains an underdeveloped area and needs to design new strategies for developing improved form of therapy. In this review, we venture a novel strategy that rational pharmacological targeting of Skp1, a central regulator of SCF complexes, may provide a novel avenue for SCF-oriented anti-cancer therapy, expected: (i) to simultaneously address the critical roles that multiple SCF oncogenic complexes play in cancer biology, (ii) to selectively target cancer cells with minimal normal cell toxicity, and (iii) to offer multiple chemical series, via therapeutic interventions at the Skp1 binding interfaces in SCF complex, thereby maximizing chances of success for drug discovery. In addition, we also discuss the challenges that might be posed regarding rational pharmacological interventions against Skp1.

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists.

AIM: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. METHODS: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. RESULTS: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 µmol/L in AlphaScreen assay, and 0.82 µmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. CONCLUSION: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.

Fine-tuning pH sensor H98 by remote essential residues in the hydrogen-bond network of mTASK-3.

TASK-3 generates a background K+ conductance which when inhibited by acidification depolarizes membrane potential and increases cell excitability. These channels sense pH by protonation of histidine residue H98, but recent evidence revealed that several other amino acid residues also contribute to TASK-3 pH sensitivity, suggesting that the pH sensitivity is determined by an intermolecular network. Here we use electrophysiology and molecular modeling to characterize the nature and requisite role(s) of multiple amino acids in pH sensing by TASK-3. Our results suggest that the pH sensor H98 and consequently pH sensitivity is influenced by remote amino acids that function as a hydrogen-bonding network to modulate ionic conductivity. Among the residues in the network, E30 and K79 are the most important for passing external signals near residue S31 to H98. The hydrogen-bond network plays a key role in selectivity or pH sensing in mTASK-3, and E30 and S31 in the network can modulate the conductive properties (E30) or reverse the pH sensitivity and selectivity of the channel (S31). Molecular dynamics simulations and pK1/2 calculation revealed that double mutants involving H98 + S31 primarily regulate the structure stability of the pore selectivity filter and pore loop regions, further strengthen the stability of the cradle suspension system, and alter the ionization state of E30 and K79, thereby preventing pore conformational change that normally occurs in response to varying extracellular pH. These results demonstrate that crucial residues in the hydrogen-bond network can remotely tune the pH sensing of mTASK-3 and may be a potential allosteric regulatory site for therapeutic molecule development.

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets.

More than two decades of research has revealed a combination of proteases that determine cartilage degradation in osteoarthritis. These include metalloproteinases, which degrade the major macromolecules in cartilage, aggrecan and type II collagen, serine proteases, and cysteine proteases, for example cathepsin K. This review summarizes the function of proteases in osteoarthritis progression, as revealed by studies of genetically engineered mouse models. A brief overview of the biochemical characteristics and features of several important proteases is provided, with the objective of increasing understanding of their function. Published data reveal at least three enzymes to be major targets for osteoarthritis drug development: ADAMTS-5, MMP-13, and cathepsin K. In surgical models of osteoarthritis, mice lacking these enzymes are protected from cartilage damage and, to varying degrees, from bone changes. In-vivo studies targeting these proteases with selective small-molecule inhibitors have been performed for a variety of animal models. Mouse models will provide opportunities for future tests of the therapeutic effect of protease inhibitors, both on progression of structural damage to the joint and on associated pain.

Fluostatins I-K from the South China Sea-derived micromonospora rosaria SCSIO N160.

The strain SCSIO N160 was isolated from a South China Sea sediment sample and was characterized as a Micromonospora rosaria species on the basis of its 16S rRNA gene sequence. Three new fluostatins, I-K (1-3), were isolated from the culture of M. rosaria SCSIO N160, together with six known compounds, fluostatins C-F (4-7), rabelomycin (8), and phenanthroviridone (9). The structure of fluostatin D (5) was confirmed by an X-ray crystallographic study. The absolute configuration of 1 and 3 was assigned by electronic circular dichroism calculations. Compounds 8 and 9 exhibited good antimicrobial activities against Staphylococcus aureus ATCC 29213 with MIC values of 1.0 and 0.25 µg/mL, respectively. Compound 9 also exhibited significant in vitro cytotoxic activities toward SF-268 (IC50 0.09 µM) and MCF-7 (IC50 0.17 µM).

A small-molecule Skp1 inhibitor elicits cell death by p53-dependent mechanism.

Skp1 overexpression promotes tumor growth, whereas reduced Skp1 activity is also linked with genomic instability and neoplastic transformation. This highlights the need to gain better understanding of Skp1 biology in cancer settings. To this context, potent and cellularly active small-molecule Skp1 inhibitors may be of great value. Using a hypothesis-driven, structure-guided approach, we herein identify Z0933M as a potent Skp1 inhibitor with KD ∼0.054 µM. Z0933M occupies a hydrophobic hotspot (P1) - encompassing an aromatic cage of two phenylalanines (F101 and F139) - alongside C-terminal extension of Skp1 and, thus, hampers its ability to interact with F-box proteins, a prerequisite step to constitute intact and active SCF E3 ligase(s) complexes. In cellulo, Z0933M disrupted SCF E3 ligase(s) functioning, recapitulated previously reported effects of Skp1-reduced activity, and elicited cell death by a p53-dependent mechanism. We propose Z0933M as valuable tool for future efforts toward probing Skp1 cancer biology, with implications for cancer therapy.

Research on the Application Value of Intelligent Heating Box in Newborn Nursing.

The aim of this study was to explore the application effect of intelligent incubator in neonatal care. We selected the period from January 1, 2018, to December 31, 2020, where there were 100 full-term and premature babies born in a hospital and transferred to the neonatal intensive care unit (NICU) within 1 hour after birth. Before the improved heat preservation, 100 full-term infants in the control group and 100 full-term infants in the intervention group of the intelligent warming box were formed into a full-term infant group for a comparative study. Statistics and comparison of the two groups of term infants and premature infants admitted to the hospital were carried out to assess body temperature and the changes in the incidence of each system. The research found that on comparison of admission body temperature between the control group and the intervention group, with the intervention group in the intelligent heating box, the incidence of hypothermia was significantly lower than that of the control group (95% vs. 37% of full-term infants; 98% vs. 49% of premature babies; there is a statistical significance (P < 0.05)). The intelligent heating box can reduce the fluctuation of the newborn's body temperature, keep the internal environment of newborns stable, and provide suitable conditions for the rapid growth of newborns, suitable for clinical promotion and application.

Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma.

Aberrant activation of the Hedgehog (Hh) pathway is implicated in the pathogenesis and development of multiple cancers, especially Hh-driven medulloblastoma (MB). Smoothened (SMO) is a promising therapeutic target of the Hh pathway in clinical cancer treatment. However, SMO mutations frequently occur, which leads to drug resistance and tumor relapse. Novel inhibitors that target both the wild-type and mutant SMO are in high demand. In this study, we identified a novel Hh pathway inhibitor, pseudolaric acid B (PAB), which significantly inhibited the expression of Gli1 and its transcriptional target genes, such as cyclin D1 and N-myc, thus inhibiting the proliferation of DAOY and Ptch1+/- primary MB cells. Mechanistically, PAB can potentially bind to the extracellular entrance of the heptahelical transmembrane domain (TMD) of SMO, based on molecular docking and the BODIPY-cyclopamine binding assay. Further, PAB also efficiently blocked ciliogenesis, demonstrating the inhibitory effects of PAB on the Hh pathway at multiple levels. Thus, PAB may overcome drug-resistance induced by SMO mutations, which frequently occurs in clinical setting. PAB markedly suppressed tumor growth in the subcutaneous allografts of Ptch1+/- MB cells. Together, our results identified PAB as a potent Hh pathway inhibitor to treat Hh-dependent MB, especially cases resistant to SMO antagonists.

Isolation, expression, and biochemical characterization: nitrite reductase from Bacillus cereus LJ01.

Biological remediation of toxic oxygen-containing anions such as nitrate that are common in the environment is of great significance. Therefore, it is necessary to understand the specific role of nitrate and nitrite reductase in the bioremediation process. Bacillus cereus LJ01, which was isolated from traditional Chinese soybean paste, effectively degraded nitrite (such as NaNO2) at 0-15 mmol L-1 in LB medium. Moreover, the nitrite-degrading active substance (ASDN) was isolated and purified from B. cereus LJ01. The nitrite-degrading activity of nitrite reductase (named LJ01-NiR) was 4004.89 U mg-1. The gene encoding the assimilation of nitrite reductase in B. cereus LJ01 was cloned and overexpressed in E. coli. The purified recombinant LJ01-NiR has a wide range of activities under temperature (20-60 °C), pH (6.5-8.0) and metal ions (Fe3+, Fe2+, Cu2+, Mn2+, and Al3+). Kinetic parameters of LJ01-NiR, including the values of K m and V max were 1.38 mM and 2.00 µmol g-1 min-1, respectively. The results showed that LJ01-NiR could degrade nitrite with or without an electron donor. In addition, sequence analysis revealed that LJ01-NiR was a ferredoxin-dependent nitrite reductase given the presence of conserved [Fe4-S4] cluster and heme-binding domain. The nitrite ion binds to the LJ01-NiR active site by forming three hydrogen bonds with the residues ASN72, ALA133 and ASN140. Due to its high nitrite-degrading activity, LJ01-NiR could potentially be used for environmental pollution treatment.

Suppression of Musashi­2 by the small compound largazole exerts inhibitory effects on malignant cells.

RNA­binding protein Musashi­2 (MSI2) serves as a regulator of numerous pivotal biological processes associated with cancer initiation, development and resistance to treatment, and may represent a promising drug target. However, whether MSI2 inhibition is of value in antitumor treatment remains to be determined. The present study demonstrated that MSI2 was upregulated in non­small cell lung cancer (NSCLC) and was inversely associated with the clinical outcome of the patients. Molecular docking analysis demonstrated that the small compound largazole binds to and may be a potential inhibitor of MSI2. Largazole markedly decreased the protein and mRNA levels of MSI2 and suppressed its downstream mammalian target of rapamycin signaling pathway. Largazole also inhibited the proliferation and induced apoptosis of NSCLC and chronic myeloid leukemia (CML) cells (including bone marrow mononuclear cells harvested from CML patients). These results indicate that MSI2 is an emerging therapeutic target for NSCLC and CML, and the MSI2 inhibitor largazole may hold promise as a treatment for these malignancies.

Phloretin ameliorates hyperuricemia-induced chronic renal dysfunction through inhibiting NLRP3 inflammasome and uric acid reabsorption.

BACKGROUND: Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown. PURPOSE: This study aims to evaluate the therapeutic effect of phloretin on HUA-induced renal injury in mice and to reveal its underlying mechanism. METHODS: Mice were induced hyperuricemic by oral gavage of adenine/potassium oxonate. The effects of phloretin on renal function, fibrosis, oxidative stress, inflammation, and UA metabolism in HUA mice were evaluated. The effect of phloretin on NLRP3 pathway was analyzed in human renal tubular cell lines (HK-2). RESULTS: HUA mice showed renal dysfunction with increased renal fibrosis, inflammation and mitochondrial stress. By contrast, phloretin reduced the level of serum blood urea nitrogen (BUN), urinary albumin to creatinine ratio (UACR), tubular necrosis, extracellular matrix (ECM) deposition and interstitial fibroblasts in HUA mice. The renal infiltration of inflammatory cells, cytokines such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1ß (IL-1ß) release, mitochondrial reactive oxygen species (ROS) and morphological lesions in HUA mice also decreased. Furthermore, phloretin partly inhibited renal glucose transporter 9 (GLUT9) and promoted urinary UA excretion in HUA mice. In vitro, phloretin suppressed the NLPR3 pathway under LPS or UA stimulation in HK-2 cells. CONCLUSIONS: Phloretin could effectively attenuate UA-induced renal injury via co-inhibiting NLRP3 and UA reabsorption, and thus it might be a potential therapy to hyperuricemia-related renal diseases.

Silencing Of MAGI1 Promotes The Proliferation And Inhibits Apoptosis Of Glioma Cells Via The Wnt/ß-Catenin And PTEN/AKT Signaling Pathways.

BACKGROUND: Membrane-associated guanylate kinase (MAGUK) with inverted orientation protein 1 (MAGI1) is a novel member of the MAGUK family with a vital role in tumor progression related to invasion and metastasis. However, the function of MAGI1 in glioma is currently unknown. We therefore analyzed the expression of MAGI1 protein in human glioma samples, glioma cell lines and glioma stem cells (GSCs), and explored its effects on glioma cell proliferation and apoptosis. METHODS: MAGI1 expression in glioma tissues was examined by Western blotting and real-time polymerase chain reaction and its relationships with clinical pathological features were analyzed. The effects of MAGI1 knockdown on the proliferation of glioma cell lines and GSCs were detected by CCK8 and colony-formation assays, and apoptosis was assessed by flow cytometry. We also investigated the effects of MAGI1 silencing on protein expression levels of epithelial-mesenchymal transition biomarkers, as well as ß-catenin, cyclin D1, PTEN and phospho-Akt by Western blotting. RESULTS: MAGI1 was significantly downregulated in glioma tissues and its expression was related to cancer progression. Silencing of MAGI1 in both glioma cell lines and GSCs enhanced proliferation and inhibited apoptosis. MAGI1 knockdown also significantly increased the expression levels of N-cadherin, vimentin, ß-catenin, cyclin D1 and phospho-Akt and reduced the expression of E-cadherin and PTEN. CONCLUSIONS: Our results indicated that MAGI1 might play a vital role in glioma progression and may represent a potential therapeutic target for the treatment of glioma.

CXCL13/CXCR5 signaling axis in cancer.

The tumor microenvironment comprises stromal and tumor cells which interact with each other through complex cross-talks that are mediated by a variety of growth factors, cytokines, and chemokines. The chemokine ligand 13 (CXCL13) and its chemokine receptor 5 (CXCR5) are among the key chemotactic factors which play crucial roles in deriving cancer cell biology. CXCL13/CXCR5 signaling axis makes pivotal contributions to the development and progression of several human cancers. In this review, we discuss how CXCL13/CXCR5 signaling modulates cancer cell ability to grow, proliferate, invade, and metastasize. Furthermore, we also discuss the preliminary evidence on context-dependent functioning of this axis within the tumor-immune microenvironment, thus, highlighting its potential dichotomy with respect to anticancer immunity and cancer immune-evasion mechanisms. At the end, we briefly shed light on the therapeutic potential or implications of targeting CXCL13/CXCR5 axis within the tumor microenvironment.

4-Aryl Pyrrolidines as Novel Orally Efficacious Antimalarial Agents. Part 2: 2-Aryl-N-(4-arylpyrrolidin-3-yl)acetamides.

Malaria is caused by infection from the Plasmodium parasite and kills hundreds of thousands of people every year. Emergence of new drug resistant strains of Plasmodium demands identification of new drugs with novel chemotypes and mechanisms of action. As a follow up to our evaluation of 4-aryl-N-benzylpyrrolidine-3-carboxamides as novel pyrrolidine-based antimalarial agents, we describe herein the structure-activity relationships of the reversed amide homologues 2-aryl-N-(4-arylpyrrolidin-3-yl)acetamides. Unlike their carboxamide homologues, acetamide pyrrolidines do not require a third chiral center to be potent inhibitors of P. falciparum and have good pharmacokinetic properties and improved oral efficacy in a mouse model of malaria. Compound (-)-32a (CWHM-1552) has an in vitro IC50 of 51 nM in the P. falciparum 3D7 assay and an in vivo ED90 of <10 mg/kg/day and ED99 of 30 mg/kg/day in a murine P. chabaudi model. Remarkably, the absolute stereochemical preference for this acetamide series (3S,4R) is opposite of that determined for the homologous carboxamide series. Lead compounds for this class have modest affinities for the hERG channel and inhibit CYP 3A4. Additional optimization is needed in order to eliminate these undesired properties from this otherwise promising series of antimalarial compounds.

4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides.

Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases. Extensive profiling of the two terminal aryl rings revealed a structure-activity relationship in which relatively few substituents are tolerated at the benzylic position, but the 3-aryl position tolerates a range of hydrophobic groups and some heterocycles. Out of this effort, we identified (+)-54b (CWHM-1008) as a lead compound. 54b has EC50 values of 46 and 21 nM against drug-sensitive Plasmodium falciparum 3D7 and drug-resistant Dd2 strains, respectively. Furthermore, 54b has a long half-life in mice (4.4 h) and is orally efficacious in a mouse model of malaria (qd; ED99 ∼ 30 mg/kg/day). Thus, the 4-aryl- N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.

Enantioselective Synthesis of Planar Chiral Pyridoferrocenes via Palladium-Catalyzed Imidoylative Cyclization Reactions.

A highly efficient synthesis of planar chiral pyrido[3,4- b] ferrocenes by a palladium-catalyzed enantioselective isocyanide insertion/desymmetric C(sp2)-H bond activation reaction was developed. Various planar chiral pyridoferrocenes were obtained in high yields with good to excellent enantioselectivity under mild conditions (up to 99% yield, 99% ee), enabled by a unique SPINOL-derived phosphoramidite ligand.