Total Synthesis of Isohericerinol A and Its Analogues to Access Their Potential Neurotrophic Effects.

The secondary metabolites from Hericium erinaceus are well-known to have neurotrophic and neuroprotective effects. Isohericerinol A (1), isolated by our colleagues from its fruiting parts has a strong ability to increase the nerve growth factor secretion in C6 glioma cells. The current work describes the total synthesis of 1 and its regioisomer 5 in a few steps. We present two different approaches to 1 and a regiodivergent approach for both 1 and 5 by utilizing easily accessible feedstocks. Interestingly, the natural product 1, regioisomer 5, and their intermediates exhibited potent neurotrophic activity in in vitro experimental systems. Thus, these synthetic strategies provide access to a systematic structure-activity relationship study of natural product 1.

Death, Dying, and Bereavement Around the World: Theories, Varied Views, and Customs.

Although death is inevitable as a human being, talking about or planning for it may be an uncomfortable topic. Recently, due to the COVID-19 pandemic, we are witnessing an increase in deaths around us as well as globally, and health and social services professionals are more engaged in the death, dying, and bereavement services than ever. Dr. Eyetsemitan's book, Death, Dying, and Bereavement Around the World: Theories, Varied Views and Customs, would be a great textbook assisting health and social service professionals and students at both undergraduate and graduate levels to understand the concepts of death, dying, and bereavement across cultures. Additional relevant grief theories/models, diverse views, and customs/rituals in losses and grief provide useful supporting information.

Design, synthesis, and biological evaluation of potent 1,2,3,4-tetrahydroisoquinoline derivatives as anticancer agents targeting NF-κB signaling pathway.

The multifunctional transcription factor, nuclear factor-κB (NF-κB), is broadly involved in multiple human diseases, such as cancer and chronic inflammation, through abnormal modulations of the NF-κB signaling cascades. In patients with several types of cancer diseases, NF-κB is excessively activated, which could result in the stimulation of proliferation and/or suppression of apoptosis. Herein, we present a new series of 1,2,3,4-tetrahydroisoquinoline derivatives with good anticancer activities against various human cancer cell lines, which are rationally designed based on our novel NF-κB inhibitors. The SAR studies demonstrated that compound 5d with a methoxy group at the R3 position exhibits the most anti-proliferative activity with GI50 values, ranging 1.591 to 2.281 µM. Similar to KL-1156, the compound 5d (HSR1304) blocked NF-κB nuclear translocation step in LPS-stimulated MDA-MB-231 cells, probably leading to cytotoxic potency against tumor cells. Together with known potent NF-κB inhibitors containing diverse core heterocyclic moieties, the 1,2,3,4-tetrahydroisoquinoline derivatives can provide structural diversity, enhancing a potential for the development of a novel class of anticancer drugs.

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway.

Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.

Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway.

Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only N-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation.

Suppression of Pax3-MITF-M Axis Protects from UVB-Induced Skin Pigmentation by Tetrahydroquinoline Carboxamide.

Paired box gene 3 (Pax3) and cAMP responsive element-binding protein (CREB) directly interact with the cis-acting elements on the promoter of microphthalmia-associated transcription factor isoform M (MITF-M) for transcriptional activation in the melanogenic process. Tyrosinase (Tyro) is a target gene of MITF-M, and functions as a key enzyme in melanin biosynthesis. Tetrahydroquinoline carboxamide (THQC) was previously screened as an antimelanogenic candidate. In the current study, we evaluated the antimelanogenic activity of THQC in vivo and elucidated a possible mechanism. Topical treatment with THQC mitigated ultraviolet B (UVB)-induced skin pigmentation in guinea pig with decreased messenger RNA (mRNA) and protein levels of melanogenic genes such as MITF-M and Tyro. Moreover, THQC inhibited cAMP-induced melanin production in α-melanocyte-stimulating hormone (α-MSH)- or histamine-activated B16-F0 cells, in which it suppressed the expression of the MITF-M gene at the promoter level. As a mechanism, THQC normalized the protein levels of Pax3, a transcriptional activator of the MITF-M gene, in UVB-exposed and pigmented skin, as well as in α-MSH-activated B16-F0 culture. However, THQC did not affect UVB- or α-MSH-induced phosphorylation (activation) of CREB. The results suggest that suppression of the Pax3-MITF-M axis might be a potential strategy in the treatment of skin pigmentary disorders that are at high risk under UVB radiation.

Synthesis of N-arylindazole-3-carboxamide and N-benzoylindazole derivatives and their evaluation against α-MSH-stimulated melanogenesis.

We have designed and synthesized twenty-six N-arylindazole-3-carboxamide (3a-p) and N-benzoylindazole (6a-j) derivatives to discover with excellent inhibition activities of α-MSH-stimulated melanogenesis. In the bio evaluation studies of these compounds, we discovered eighteen compounds, out of twenty-six exhibited more potent inhibition than the positive control arbutin. From the SAR studies, we identified 3k and 6g as lead compounds which displayed almost 5 and 9 times more potent inhibition of α-MSH-stimulated melanogenesis respectively than the reference arbutin. It is also evident the presence of electron withdrawing group at para position (R3) for the compounds (3a-p) and presence of +M group at ortho position (R5) for the compounds (6a-j) were crucial for their excellent inhibition activities of α-MSH-stimulated melanogenesis.

Transition metal-free synthesis of quinazolinones using dimethyl sulfoxide as a synthon.

Biologically important quinazolinones have been synthesized from 2-aminobenzamides and DMSO. The key feature of the reaction is the utilization of DMSO as a methine source for intramolecular oxidative annulation. The CNS depressant drug methaqualone has also been synthesized by our methodology. The present method involves the synthesis of quinazolinones with a broad substrate scope and a good yield.

Development of 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and their salts as potent cytotoxic agents and topoisomerase I/IIα inhibitors.

A novel series of 35 angularly fused pentacyclic 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 28, 30, 34, 35, 46, 48, 52, and 53 compounds exhibited potent cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and IIα inhibition. Among them, the compound 48 exhibited dual Topoisomerase I and IIα inhibition especially at 20 µM concentrations the compound 48 exhibited 1.25 times more potent Topoisomerase IIα inhibitory activity (38.3%) than the reference drug etoposide (30.6%). The compound 52 also exhibited excellent (88.4%) topoisomerase I inhibition than the reference drug camptothecin (66.7%) at 100 µM concentrations. Molecular docking studies of the compounds 48 and 52 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 48 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 52 have with Arg364, Thr718, and Asn722 residues. Both the compounds 48 and 52 have π-π stacking interactions with the stacked DNA bases. The docking studies of the compound 48 with topo IIα explored that it was bound to the topo IIα DNA cleavage site where etoposide was situated. The benzo[f]chromeno[4,3-b][1,7]naphthyridine ring of the compound 48 was stacked between the DNA bases of the cleavage site with π-π stacking interactions and there were no hydrogen bond interactions with topo IIα.

Antioxidant and Neuroprotective Effects of N-((3,4-Dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline in Primary Cultured Rat Cortical Cells: Involvement of ERK-CREB Signaling.

Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer's disease (AD). In the present study, we investigated the effect of N-((3,4-dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to that of memantine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist clinically used to treat AD. We found that BL-M inhibited glutamate- or N-methyl-d-aspartate (NMDA)-induced excitotoxic cell damage. The IC50 value of BL-M against NMDA toxicity was comparable to that of memantine. BL-M potently inhibited intracellular reactive oxygen species generated by glutamate or NMDA. Additionally, it inhibited the formation of 1,1-diphenyl-2-picryl-hydrazyl radicals in vitro and lipid peroxidation in rat brain homogenates. In contrast, memantine showed minimal or negligible antioxidant activity. Western blotting and immunocytochemical analyses showed that BL-M, not memantine, increased the ERK1/2 phosphorylation and subsequent phosphorylation of cAMP response element-binding protein (CREB). The inhibition of NMDA toxicity by BL-M was dramatically reversed by U0126, a well-known MEK inhibitor, suggesting that ERK1/2-mediated CREB phosphorylation is required for the neuroprotective action. Collectively, in this study, we demonstrated the neuroprotective effect of a newly synthesized chromene derivative BL-M and its underlying action mechanism(s). In contrast to memantine, BL-M exhibited marked antioxidant activity. Furthermore, it enhanced the ERK-mediated phosphorylation of CREB, which plays a crucial neuroprotective role. Our findings suggest that BL-M may be beneficial for AD and other neurodegenerative disorders associated with excitotoxicity as well as oxidative stress.

Cytokine-induced killer cells hunt individual cancer cells in droves in a mouse model.

Cytotoxicity of cytokine-induced killer (CIK) cells depends mainly on their encounters with target cells, but how many CIK cells are required to kill an individual cancer cell is unknown. Here we used time-lapse imaging to quantify the critical effector cell number required to kill an individual target cell. CIK cells killed MHC-I-negative and MHC-I-positive cancer cells, but natural killer (NK) cells destroyed MHC-I-negative cells only. The average threshold number of CIK cells required to kill an individual cancer cell was 6.7 for MHC-I-negative cells and 6.9 for MHC-I-positive cells. That of NK cells was 2.4 for MHC-I-negative cells. Likely due to the higher threshold numbers, killing by CIK cells was delayed in comparison with NK cells: 40% of MHC-negative target cells were killed after 5 h when co-cultured with CIK cells and after 2 h with NK cells. Our data have implications for the rational design of CIK cell-based immunotherapy of cancer patients.

Synthesis and biological evaluation of caffeic acid derivatives as potent inhibitors of α-MSH-stimulated melanogenesis.

We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities.

Synthesis, biological evaluation, and metabolic stability of chlorogenic acid derivatives possessing thiazole as potent inhibitors of α-MSH-stimulated melanogenesis.

A series of catechol and dioxolane analogs containing thiazole CGA derivatives have been synthesized and evaluated for their inhibitory activity against α-MSH. The inhibitory activity was improved by replacing an α,ß-unsaturated carbonyl of previously reported caffeamides with thiazole motif. Surprisingly, compound 7d, one of the derivatives of dioxolane analogs, displayed the most potent inhibitory activity with an IC50 of 0.90µM. Further studies on metabolic stability and bioactivation potential were also accomplished.

Design, synthesis and biological evaluation of 1,3-diphenylbenzo[f][1,7]naphthyrdines.

A novel series of twenty 1,3-diphenylbenzo[f][1,7]benzonaphthyrdine derivatives were designed and synthesized through intermolecular imino Diels-Alder reaction. Their in vitro cytotoxic activities were evaluated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Majority of synthesized compounds exhibited significant cytotoxic activities against all tested human cancer cell lines. Among them 4l, 4m, and 4o derivatives exhibited most promising cytotoxic activities. Furthermore these compounds were evaluated against human Topoisomerase IIα inhibition. Interestingly, the compound 4l exhibited 1.3 and 1.2 times more potent human Topoisomerase IIα inhibition than the reference drug etoposide in both 100µM and 20µM concentrations respectively. Molecular docking studies for the compound 4l have also been executed by Sybyl X-2.1 in which it reveals the binding site of the compound 4l with topo IIα DNA cleavage site where etoposide was situated. The benzo[f][1,7]naphthyridine ring was stacked between the DNA bases of the cleavage site.

The emotional eating and negative food relationship experiences of obese and overweight adults.

Overweight and obesity pose serious public health problems, affecting 68.8% of Americans. Previous research indicated that psychological factors played important roles in an individual's motivation to consume food. In particular, emotional eating, defined as overeating in response to negative affect, has received particular attention as a risk factor for obesity. This study explored and addressed the emotional factors involved in the development of emotional eating. A total of 10 Midwestern American male and female adults, previously diagnosed as medically overweight and obese, were recruited via online and print advertisement using maximum variation and snowball sampling methods. Using a semi-structured, face-to-face interview format, participants shared their perspectives about the development and persistence of emotional eating. The interviews were transcribed and Atlas.ti software was used to assist in thematic analysis of emotional eating. Study results yielded themes, such as emotional triggers, food cravings, comfort from foods, mindless eating, and childhood experiences. Findings indicated that participants generally lacked emotional self-care, but desired to decrease their emotional eating behaviors. Implications are discussed to construct creative, evidence-based treatments for the overweight and obese emotional eaters.

Anti-cancer effect of N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-carboxamide, a novel synthetic compound.

Naphthofuran compounds have been known to regulate HNF 4α which is associated with proliferation, progression and metastasis of HCC. In this study, we investigated whether N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-carboxamide (NHDC), a novel synthetic naphthofuran compound inhibits liver tumor growth through activation of HNF 4α. Treatment with different concentrations (1-10.8 µM) of NHDC for various periods (0-72 h) inhibited liver cancer cells (HepG2, Hep3B) growth as well as colony formation followed by induction of apoptosis in a concentration dependent manner. NHDC also induced expression of the apoptosis regulating genes as well as inhibiting the action of STAT3. These inhibitory effects were associated with enhancement of expression and DNA binding activity of HNF 4α. In vivo study confirmed that liver tumor growth was prevented with NHDC (5 mg/kg), and its effect was also related with inhibition of STAT3 pathway through enhancement of expression and DNA binding activity of HNF 4α. Moreover, siRNA of HNF 4α abolished NHDC-induced cell growth inhibition as well as DNA binding activity and phosphorylation of STAT3. Pull down assay docking prediction analysis proved that NHDC directly binds to hydrophobic fatty acid ligand binding site of HNF 4α. A novel naphthofuran compound, NHDC inhibited liver tumor growth by inactivating of STAT3 through direct biding to HNF 4α.

A novel synthetic compound MCAP suppresses LPS-induced murine microglial activation in vitro via inhibiting NF-kB and p38 MAPK pathways.

AIM: To investigate the anti-neuroinflammatory activity of a novel synthetic compound, 7-methylchroman-2-carboxylic acid N-(2-trifluoromethyl) phenylamide (MCAP) against LPS-induced microglial activation in vitro. METHODS: Primary mouse microglia and BV2 microglia cells were exposed to LPS (50 or 100 ng/mL). The expression of iNOS and COX-2, proinflammatory cytokines, NF-κB and p38 MAPK signaling molecules were analyzed by RT-PCR, Western blot and ELISA. The morphological changes of microglia and nuclear translocation of NF-ĸB were visualized using phase contrast and fluorescence microscopy, respectively. RESULTS: Pretreatment with MCAP (0.1, 1, 10 µmol/L) dose-dependently inhibited LPS-induced expression of iNOS and COX-2 in BV2 microglia cells. Similar results were obtained in primary microglia pretreated with MCAP (0.1, 0.5 µmol/L). MCAP dose-dependently abated LPS-induced release of TNF-α, IL-6 and IL-1ß, and mitigated LPS-induced activation of NF-κB by reducing the phosphorylation of IκBα in BV2 microglia cells. Moreover, MCAP attenuated LPS-induced phosphorylation of p38 MAPK, whereas SB203580, a p38 MAPK inhibitor, significantly potentiated MCAP-caused inhibition on the expression of MEF-2 (a transcription factor downstream of p38 MAPK). CONCLUSION: MCAP exerts anti-inflammatory effects in murine microglia in vitro by inhibiting the p38 MAPK and NF-κB signaling pathways and proinflammatory responses. MCAP may be developed as a novel agent for treating diseases involving activated microglial cells.

Design, synthesis, and biological evaluation of benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives as anticancer agents and inhibitors of NF-κB.

With the aim of developing novel scaffolds as anticancer agents and inhibitors of NF-κB activity, 60 novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives (1a-s, 2a-k, 3a-s, and 4a-k) were designed and synthesized from the reference lead compound KL-1156, which is an inhibitor of NF-κB translocation to the nucleus in LPS-stimulated RAW 264.7 macrophage cells. The novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxamide derivatives exhibited potent cytotoxic activities (measured by the sulforhodamine B assay) at low micromolar concentrations against six human cancer cell lines: ACHN (renal), HCT15 (colon), MM231 (breast), NUGC-3 (gastric), NCI-H23 (lung), and PC-3 (prostate). In addition, these compounds also inhibited LPS-induced NF-κB transcriptional activity. The +M effect and hydrophobic groups on the N-phenyl ring potentiated the anticancer activity and NF-κB inhibitory activity, respectively. However, according to the results of structure-activity relationship studies, only benzofuran-2-carboxylic acid N-(4'-hydroxy)phenylamide (3m) was the lead scaffold with both an outstanding anticancer activity and NF-κB inhibitory activity. This novel lead scaffold may be helpful for investigation of new anticancer agents that act through inactivation of NF-κB.

Antioxidant and Anti-inflammatory Activities of N-((3,4-Dihydro-2H-benzo[h]chromene-2-yl)methyl)-4-methoxyaniline in LPS-Induced BV2 Microglial Cells.

Microglial activation is known to cause inflammation resulting in neurotoxicity in several neurological diseases. N-((3,4-Dihydro-2H-benzo[h]chromene-2-yl)methyl)-4-methoxyaniline (BL-M), a chromene derivative, was originally synthesized with the perspective of inhibiting nuclear factor-kappa B (NF-κB), a key regulator of inflammation. The present study evaluated the antioxidant and anti-inflammatory potential of BL-M in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Our results demonstrated that BL-M significantly inhibited the formation of 1,1-diphenyl-2-picrylhydrazyl radicals, as well as lipid peroxidation in rat brain homogenate in a concentration-dependent manner. In addition, it suppressed the generation of intracellular reactive oxygen species, and the levels of pro-inflammatory mediators including nitric oxide, tumor necrosis factor-α, and interleukin-6 in LPS-induced BV2 cells. Western blotting analyses revealed the inhibition of inhibitor of kappa B alpha (IκBα) phosphorylation and NF-κB translocation by BL-M in LPS-activated cells. Therefore, our study highlights marked antioxidant and anti-inflammatory activities of BL-M, and suggests that this compound may have a beneficial impact on various neurodegenerative diseases associated with inflammation.

Concise Synthesis of Broussonone A.

A concise and expeditious approach to the total synthesis of broussonone A, a p-quinol natural compound, has been developed. The key features of the synthesis include the Grubbs II catalyst mediated cross metathesis of two aromatic subunits, and a chemoselective oxidative dearomatizationin the presence of two phenol moieties. Especially, optimization associated with the CM reaction of ortho-alkoxystyrenes was also studied, which are known to be ineffective for Ru-catalyzed metathesis reactions under conventional reaction conditions because ortho-alkoxy group could coordinate to the ruthenium center, resulting in the potential complication of catalyst inhibition.