The syntheses of some naturally derived naphthoquinones

Bibliography: pages 193-195.The synthesis of the naphthalene core of the ansamycin antibiotics, 8-acetyl-3-acetylamino-5,7-dihydroxy-1,4-naphthoquinone from benzoquinone by means of simple reactions including, Diels-Alder adduct formation, mild acetylation, oxime formation and Beckmann rearrangement in five steps with an overall yield of 22% is described in Chapter 1. The synthesis of the naturally occurring naphthoquinone derivative, possessing anti tumour and antiprotozoal properties, bikaverin is described in Chapter 2. Starting from vanillin the key intermediate 2-(2'-benzyloxy-6'-methyl-4'-methoxybenzoyl)-1,4,5,6,8-pentamethoxynaphthalene was prepared in six simple steps in an overall yield of 18%. This key intermediate was converted into bikaverin utilizing two independent routes. In the first route the benzyl group was removed from the key intermediate by hydrogenolysis followed by oxidative spiro ring formation , with 2,3-dichloro-5,6-dicyanobenzoquinone. After effecting xanthone ring formation and removal of two methyl groups with lithium iodide, bikaverin was produced in six steps in an overall yield of 32%. In the second route the key intermediate was first oxidised by silver (II) oxide this was followed by removal of the benzyl group and two methyl groups peri- to the quinone with boron trichloride, which led to spontaneous spiro ring formation, ultimately bikaverin was produced in three steps in an overall of 34%. The syntheses of the naturally occurring product ventiloquinone E and its trans-isomer as well as an isomer of the naturally occurring ventiloquinone J and its trans-isomer are described in Chapter 3. Starting from 1,2,4,5,8-pentamethoxynaphthalene, the synthesis of which has been described in Chapter 2, ventiloquinone E was prepared in nine steps in an overall yield of 7%. Similarly an isomer of ventiloquinone J was also prepared from 1,2,4,5,8-pentamethoxynaphthalene in ten steps in an overall yield of 6%. In both cases a mixture of cis-and trans-isomers was obtained, a successful resolution of both mixtures was accomplished by thin layer chromatography. By two other methods the trans-isomer of ventiloquinone E could be prepared in either nine steps in an overall yield of 23% or in six steps with an overall yield of 30% starting from the same pentamethoxynaphthalene

Agro-waste as source of fine and industrial chemicals: synthesis of 2-formyl-6 hydroxybenzoic acid and 4-methoxyisobenzofuran-1,3-dione from cashew nut shell liquid

This paper reports on the synthesis of 2-formyl-6-hydroxybenzoic acid (8) and 4 methoxyisobenzofuran-1,3-dione (10) from a renewable natural material Cashew Nut Shell Liquid (CNSL) achieved in five and seven steps, respectively. Anacardic acid was isolated from CNSL, dimethoxylated into (E)-methyl 2-methoxy-6-(pentadec-8-enyl)benzoate which was subsequently hydrogenated into methyl 2-methoxy-6-pentadecylbenzoate. Benzylic bromination of the methoxyester, and dehydrobromination afforded (E)-methyl 2-methoxy-6-(pentadec-1-enyl)benzoate which upon ozonolysis gave methyl 2-formyl-6-methoxybenzoate. Oxidation and dehydration of 8 formed methoxyphthalic anhydride (10). The work reported in this paper has further demonstrated the resourcefulness of cashew nut shell liquid as a renewable natural resource for synthesis of fine and industrial chemicals.Keywords: Anacardium occidentale, Cashew Nut Shell Liquid, Anacardic acid, 2 formyl-6-methoxybenzoate, methoxyphthalic anhydrid

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.Supporting Information File 1 Experimental procedures and copies of NMR spectra.This work is based on research supported by the National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the WitwatersrandThe National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the Witwatersrand.http://www.sherpa.ac.uk/romeo/issn/1860-5397/am2017Chemistr

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.Supporting Information File 1 Experimental procedures and copies of NMR spectra.This work is based on research supported by the National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the WitwatersrandThe National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the Witwatersrand.http://www.sherpa.ac.uk/romeo/issn/1860-5397/am2017Chemistr

Potent antitrypanosomal activities of 3-aminosteroids against African trypanosomes: investigation of cellular effects and of cross-resistance with existing drugs. Molecules

Treatment of animal African trypanosomiasis (AAT) requires urgent need for safe, potent and affordable drugs and this has necessitated this study. We investigated the trypanocidal activities and mode of action of selected 3-aminosteroids against Trypanosoma brucei brucei. The in vitro activity of selected compounds of this series against T. congolense (Savannah-type, IL3000), T. b. brucei (bloodstream trypomastigote, Lister strain 427 wild-type (427WT)) and various multi-drug resistant cell lines was assessed using a resazurin-based cell viability assay. Studies on mode of antitrypanosomal activity of some selected 3-aminosteroids against Tbb 427WT were also carried out. The tested compounds mostly showed moderate-to-low in vitro activities and low selectivity to mammalian cells. Interestingly, a certain aminosteroid, holarrhetine (10, IC50 = 0.045 ± 0.03 µM), was 2 times more potent against T. congolense than the standard veterinary drug, diminazene aceturate, and 10 times more potent than the control trypanocide, pentamidine, and displayed an excellent in vitro selectivity index of 2130 over L6 myoblasts. All multi-drug resistant strains of T. b. brucei tested were not significantly cross-resistant with the purified compounds. The growth pattern of Tbb 427WT on long and limited exposure time revealed gradual but irrecoverable growth arrest at ≥ IC50 concentrations of 3-aminosteroids. Trypanocidal action was not associated with membrane permeabilization of trypanosome cells but instead with mitochondrial membrane depolarization, reduced adenosine triphosphate (ATP) levels and G2/M cell cycle arrest which appear to be the result of mitochondrial accumulation of the aminosteroids. These findings provided insights for further development of this new and promising class of trypanocide against African trypanosomes

In vitro analysis of the combinatory effects of novel aminonaphthoquinone derivatives and curcumin on breast cancer progression

CITATION: Pereira, Melanie C. et al. 2020. In vitro analysis of the combinatory effects of novel aminonaphthoquinone derivatives and curcumin on breast cancer progression. Anticancer Research, 40(1):229-238, doi:10.21873/anticanres.13944.The original publication is available at: https://pubmed.ncbi.nlm.nih.govBackground/aim: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells. Materials and methods: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel. Results: Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations. Conclusion: Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.Publisher's versio

Towards Increased Recovery of Critical Raw Materials from WEEE– evaluation of CRMs at a component level and pre-processing methods for interface optimisation with recovery processes

Increasing recovery of critical raw materials (CRMs) from waste electrical and electronic equipment (WEEE) is a strategic priority to mitigate supply risks. Today, CRM recovery rates are generally low, with increases requiring new recovery processes and interface optimisation with pre-processing to ensure appropriate material flows for efficient recovery are generated. Here, results from an industrial trial to increase CRM recovery from WEEE are presented to inform development of pre-processing strategies which generate such material flows. Au, Ag, Co, Ga, Mg, Nb, Ru, Pd, Ir, Y, Nd, Sb, Ta and W are identified with XRF in components of a range of WEEE samples including within individual printed circuit board (PCB) components. CRM distribution in PCBs is mapped by visual inspection with reference to this data. Cost-effective methods to disassemble WEEE; isolate CRM bearing components, and upgrade/concentrate CRMs are evaluated for industrial adoption. A guillotine is found most suitable for LCD disassembly and separation of Au edge-contacts from PCBs, while cryocracking is best for isolation of internal components of digital media devices. Thermal PCB disassembly with a solder bath for simultaneous SMD removal and subsequent sieving to sort SMDs thereby concentrating CRMs for recovery is a promising approach. Microwave ashing of PCBs to concentrate CRMs is promising although off-gas treatment would be required. Recovery potential of identified CRMs from material streams generated is found to be poor due to lack of suitable recovery infrastructure except for precious and platinum group metals in PCBs, but available pyrometallurgical recovery permanently dissipates other CRMs present

A novel miniature in-line load-cell to measure in-situ tensile forces in the tibialis anterior tendon of rats.

Direct measurements of muscular forces usually require a substantial rearrangement of the biomechanical system. To circumvent this problem, various indirect techniques have been used in the past. We introduce a novel direct method, using a lightweight (~0.5 g) miniature (3 x 3 x 7 mm) in-line load-cell to measure tension in the tibialis anterior tendon of rats. A linear motor was used to produce force-profiles to assess linearity, step-response, hysteresis and frequency behavior under controlled conditions. Sensor responses to a series of rectangular force-pulses correlated linearly (R2 = 0.999) within the range of 0-20 N. The maximal relative error at full scale (20 N) was 0.07% of the average measured signal. The standard deviation of the mean response to repeated 20 N force pulses was ± 0.04% of the mean response. The step-response of the load-cell showed the behavior of a PD2T2-element in control-engineering terminology. The maximal hysteretic error was 5.4% of the full-scale signal. Sinusoidal signals were attenuated maximally (-4 dB) at 200 Hz, within a measured range of 0.01-200 Hz. When measuring muscular forces this should be of minor concern as the fusion-frequency of muscles is generally much lower. The newly developed load-cell measured tensile forces of up to 20 N, without inelastic deformation of the sensor. It qualifies for various applications in which it is of interest directly to measure forces within a particular tendon causing only minimal disturbance to the biomechanical system

Genome-Wide Analysis Reveals a Complex Pattern of Genomic Imprinting in Mice

Parent-of-origin–dependent gene expression resulting from genomic imprinting plays an important role in modulating complex traits ranging from developmental processes to cognitive abilities and associated disorders. However, while gene-targeting techniques have allowed for the identification of imprinted loci, very little is known about the contribution of imprinting to quantitative variation in complex traits. Most studies, furthermore, assume a simple pattern of imprinting, resulting in either paternal or maternal gene expression; yet, more complex patterns of effects also exist. As a result, the distribution and number of different imprinting patterns across the genome remain largely unexplored. We address these unresolved issues using a genome-wide scan for imprinted quantitative trait loci (iQTL) affecting body weight and growth in mice using a novel three-generation design. We identified ten iQTL that display much more complex and diverse effect patterns than previously assumed, including four loci with effects similar to the callipyge mutation found in sheep. Three loci display a new phenotypic pattern that we refer to as bipolar dominance, where the two heterozygotes are different from each other while the two homozygotes are identical to each other. Our study furthermore detected a paternally expressed iQTL on Chromosome 7 in a region containing a known imprinting cluster with many paternally expressed genes. Surprisingly, the effects of the iQTL were mostly restricted to traits expressed after weaning. Our results imply that the quantitative effects of an imprinted allele at a locus depend both on its parent of origin and the allele it is paired with. Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life