Synthesis of benzonaphthofuroquinones and benzoylnaphthindolizinediones by reactions of flavonoids with dichlone under basylous, oxygenous and aqueous conditions: Their cytotoxic and apoptotic activities

© 2020 The Royal Society of Chemistry. Using flavonoids and dichlone as substrates, benzonaphthofuroquinones (1, 2, 3, 5, 6, novel; 4 new) and benzoylnaphthindolizinediones (7, 8, known; 9, new) were synthesized through common base-catalyzed method and a new method of combining base-catalyzed with O2/H2O exposing. The possible reaction mechanisms may involve the process like isomerization, hydration, oxidation, decomposition and intermolecular condensation. Benzonaphthofuroquinones (2, 3, 4, 5) were found to exhibit potent cytotoxicity against carcinoma cell lines and low toxicity to normal cell lines. The compounds 4 and 5 not only expressed a significant late-stage-apoptosis against human leukemia and melanoma, but also promoted the cleavage of caspase-3 and PARP in human leukemia, which suggested that the late-stage-apoptosis and caspase-3 pathway may be responsible for the cytotoxicities of these benzonaphthofuroquinones. The replacement of the furan ring with pyrrole system in benzoylnaphthindolizinediones (7, 8, 9) resulted in the loss of anticancer activity

Analysis of five deep-sequenced trio-genomes of the Peninsular Malaysia Orang Asli and North Borneo populations

BackgroundRecent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated.ResultsWe analyzed the whole-genome deep sequencing data (30x) of five native trios from Peninsular Malaysia and North Borneo, and characterized the genomic variants, including single nucleotide variants (SNVs), small insertions and deletions (indels) and copy number variants (CNVs). We discovered approximately 6.9 million SNVs, 1.2 million indels, and 9000 CNVs in the 15 samples, of which 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify de novo variants and estimated the autosomal mutation rates to be 0.81x10(-8) - 1.33x10(-8), 1.0x10(-9) - 2.9x10(-9), and 0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example is a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples.ConclusionOur study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia

Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation

A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 μM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro

Design, Synthesis, and Bioactive Screen In Vitro of Cyclohexyl (<i>E</i>)-4-(Hydroxyimino)-4-Phenylbutanoates and Their Ethers for Anti-Hepatitis B Virus Agents

A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 &#177; 6.26 &#956;M, SI = 13.41) and HBeAg (IC50 = 49.39 &#177; 4.17 &#956;M, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 &#177; 17.17 &#956;M, SI = 2.2) and HBeAg (IC50 = 249.9 &#177; 21.51 &#956;M, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18&#8722;27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening

Design, Synthesis and Bioactive Evaluation of Oxime Derivatives of Dehydrocholic Acid as Anti-Hepatitis B Virus Agents

Oxime derivatives of dehydrocholic acid and its esters were designed for anti-hepatitis B virus (HBV) drugs according to principles of assembling active chemical fragments. Twelve compounds were synthesized from dehydrocholic acid by esterification and oxime formation, and their anti-hepatitis B virus (HBV) activities were evaluated with HepG 2.2.15 cells. Results showed that 5 compounds exhibited more effective inhibition of HBeAg than positive control, among them 2b-3 and 2b-1 showed significant anti-HBV activities on inhibiting secretion of HBeAg (IC50 (2b-3) = 49.39 &plusmn; 12.78 &mu;M, SI (2b-3) = 11.03; IC50 (2b-1) = 96.64 &plusmn; 28.99 &mu;M, SI (2b-1) = 10.35) compared to the Entecavir (IC50 = 161.24 &mu;M, SI = 3.72). Molecular docking studies showed that most of these compounds interacted with protein residues of heparan sulfate proteoglycan (HSPG) in host hepatocyte and bile acid receptor

Real-time cyber−physical system co-simulation testbed for microgrids control

This study presents a real-time cyber−physical system co-simulation testbed for microgrids. The proposed testbed consists of two parts, a power simulator and a communication simulator, which has the capacity to emulate a physical micro-grid with large numbers of power electronic devices and its cyber system at real time. Furthermore, an interaction interface approach based on Ethernet is presented to synchronise data between two distinct simulation systems, as well as establishing the mapping relationship between corresponding nodes of power systems and communication systems. Through the detailed models of microgrids and accurate emulation of the cyber system, the developed testbed provides a simulation environment for the verification of the microgrids control algorithm and the influence of cyber events on microgrids performance. A case study is provided to explain the complete simulation process and demonstrate the ability of the testbed

A new anthraquinone and eight constituents from <i>Hedyotis caudatifolia</i> Merr. et Metcalf: isolation, purification and structural identification

<p><i>Hedyotis caudatifolia</i> Merr. et Metcalf. (HC), a folk medicine in Yao nationalities areas in China, was used to investigate the chemical constituents. Through silica gel and Sephadex LH-20 column chromatography, nine compounds were isolated and purified. By physical and chemical properties, IR, MS (EI-MS, high resolution EI-MS), 1D NMR (¹H NMR, ¹³C NMR) and 2D NMR (HSQC, ¹H–¹H COSY, HMBC), their structures were identified as β-sitosterol (<b>1</b>), stigmasterol (<b>2</b>), scopolin (<b>3</b>), 2-hydroxy-1,7,8-trimethoxyanthracene-9,10-dione (<b>4</b>), oleanolic acid (<b>5</b>), ursolic acid (<b>6</b>), methyl barbinervate (<b>7</b>), β-daucosterol (8) and p-Hydroxybenzoic acid (<b>9</b>). These compounds were isolated from HC for the first time, and <b>4</b> a new anthraquinone whose biological activities are worth to be investigated in future. These compounds may contribute to the HC’s pharmacological effects on treating diseases, and may be used as candidates for control index in establishing the quality control standard of HC.</p