Search

The present invention relates to a process for the extraction of valuable components from a tannin-rich bark raw-material, by carrying out an alkaline cooking step, followed by acid precipitation to separate the valuable components from the remaining bark pulp. The invention also relates to the use of said process on a bark side stream of a chemical pulping plant, whereby the liquor remaining after the extraction of the present process is returned to a stream of the wood pulping process, typically to a black liquor stream, while the spent pulp can be processed further, e.g. by bleaching to give dissolved pulp.Patent family as of 27.1.2022AU2019368701 AA 20210520 AU20190368701 20191023 BR112021007706 A2 20210727 BR20211107706 20191023 CA3116963 AA 20210419 CA20193116963 20191023 CL2021001038 A1 20211126 CL20210001038 20210422 CN113195729 A 20210730 CN201980070458 20191023 EP3870713 A1 20210901 EP20190797770 20191023 FI129347 B 20211215 FI20180005891 20181023 FI20185891 A 20200424 FI20180005891 20181023 ID2021PID08832 A 20211108 ID2021P0003643 20191023 JP2022505620 T2 20220114 JP20210522024T 20191023 US2021395466 AA 20211223 US20210287145 20191023 WO20084196 A1 20200430 WO2019FI50756 20191023Link to currentpatent family on right

The hepatic bile acid transporter Na+/taurocholate co-transporting polypeptide (NTCP) was identified in 2012 as the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Since then, this carrier has emerged as promising drug target for HBV/HDV virus entry inhibitors, but the synthetic peptide Hepcludex® of high molecular weight is the only approved HDV entry inhibitor so far. The present study aimed to identify small molecules as novel NTCP inhibitors with anti-viral activity. A ligand-based bioinformatic approach was used to generate and validate appropriate pharmacophore and QSAR (quantitative structure–activity relationship) models. Half-maximal inhibitory concentrations (IC50) for binding inhibition of the HBV/HDV-derived preS1 peptide (as surrogate parameter for virus binding to NTCP) were determined in NTCP-expressing HEK293 cells for 150 compounds of different chemical classes. IC50 values ranged from 2 µM up to &gt, 1000 µM. The generated pharmacophore and QSAR models were used for virtual screening of drug-like chemicals from the ZINC15 database (~11 million compounds). The 20 best-performing compounds were then experimentally tested for preS1-peptide binding inhibition in NTCP-HEK293 cells. Among them, four compounds were active and revealed experimental IC50 values for preS1-peptide binding inhibition of 9, 19, 20, and 35 µM, which were comparable to the QSAR-based predictions. All these compounds also significantly inhibited in vitro HDV infection of NTCP-HepG2 cells, without showing any cytotoxicity. The best-performing compound in all assays was ZINC000253533654. In conclusion, the present study demonstrates that virtual compound screening based on NTCP-specific pharmacophore and QSAR models can predict novel active hit compounds for the development of HBV/HDV entry inhibitors.

Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 &gt, 45 µM, SI &gt, 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p &lt, 0.05) and the mitochondrial membrane potential (p &lt, 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

White birches (Betula spp.) are utilized in huge quantities in the forest industry in northern latitudes of the world and low-value side-stream birch bark is burnt for energy. Outer birch bark is rich in (up to 30% dry weight) triterpene betulin and it can be easily isolated by solvent extraction. Betulin could be used as such or as starting material for more valuable products, fine chemicals and pharmaceuticals. In this work two sets of betulin derivatives were synthesized and screened as antiviral, antileishmanial and antibacterial agents. First set includes relatively easily synthesizable betulin derivatives, such as esters and various oxidation products. Second set includes novel heterocyclic betulin derivatives, where triazolo ring is fused by Diels-Alder reaction to the lupane skeleton of betulin. In the biological assays against human pathogens Semliki Forest virus; L. donovani parasites, which cause tropical disease leishmaniasis; and Gram-negative bacteria Chlamydia pneumoniae, several betulin derivatives displayed low-micromolar 50% growth inhibition values in vitro. In addition, most of the derivatives showed low cytotoxicity against the host cell lines. Metsäteollisuus käyttää koivua raaka-aineenaan suunnattomia määriä. Sivuotteena syntyvä koivunkuori poltetaan energian tuotantoon. Koivun ulkokuori sisältää runsaasti betuliini-nimistä triterpeeniä jopa 30 % kuivapainostaan. Betuliini voidaan helposti eristää kuoresta liuotinuutolla. Betuliinia voidaan käyttää sellaisenaan tai lähtöaineena muille tuotteille, hienokemikaaleille ja lääkeaineille. Tässä väitöskirjatyössä syntetisoitiin kaksi betuliinijohdannaisryhmää ja yhdisteiden tehokkuutta testattiin alfavirusten, Leishmania-suvun alkueläinten ja keuhkoklamydiabakteerin vastaisina yhdisteinä. Ensimmäinen ryhmä sisältää melko helposti valmistettavissa olevia johdannaisia, kuten betuliinin estereitä ja erilaisia hapetustuotteita. Toinen ryhmä sisältää uusia heterosyklisiä betuliinijohdannaisia, joissa triatsoli-rengas on fuusioitu betuliinin lupaanirakenteiseen hiilivetyrankaan. Testattaessa betuliinijohdannaisia ihmispatogeenejä vastaan, useat johdannaiset estivät taudinaiheuttajien kasvua mikromolaarisella konsentraatiolla. Lisäksi suurin osa betuliinijohdannaisista oli harmittomia isäntäsoluina käytettyjä solulinjoja vastaan.

The EU-project FORESTSPECS provides research based biological and technical understanding and solutions needed for upgrading wood related residues and humic substances to value-added chemicals and materials. Only through such knowledge-based approach it is possible to develop innovative applications to the potentially huge variety of bioactive substances available in these by-products, currently considered as waste. These substances represent a rich source of aromatic and other complex structures, whose upgrading to value-added speciality chemicals and materials pro-vides an opportunity to the forest sector to create new types of value chains. Application opportuni-ties include medical, pharmaceutical, agricultural, and environmental remediation uses. We focus our study on wood residues, such as the bark of Betula, Pinus, Picea, Larix, Abies and Populus, as well as on peat, as raw material. The work consists of innovative natural products chemistry, extraction and process technology; as well as basic research on the mode of action and the structure-function relationships in order to increase the knowledge-base, essential for the emerging bio-economy. Products arising from the use of these rapidly renewable natural raw mate-rials could replace petrochemical-based products not only in high value-added segments (e.g. med-icine, cosmetics, plant protection), but also in technical products such as adhesives, coatings, sur-factants and chelating agents. Furthermore, this project creates options for adding value to the total resource of processed wood and peat residues, e.g. in remediation and soil conditioning, so that no wastes remain, and the overall operations are environmentally sustainable and economically attractive. The outcomes of this project are expected to be of significant importance to the forest, farming, medical and pharmaceutical sectors, with major positive spin-off impacts to human health and the environment.