WO2022254047A1 - Emodin derivatives and uses thereof - Google Patents
Emodin derivatives and uses thereof Download PDFInfo
- Publication number
- WO2022254047A1 WO2022254047A1 PCT/EP2022/065376 EP2022065376W WO2022254047A1 WO 2022254047 A1 WO2022254047 A1 WO 2022254047A1 EP 2022065376 W EP2022065376 W EP 2022065376W WO 2022254047 A1 WO2022254047 A1 WO 2022254047A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- emodin
- derivative according
- emodin derivative
- bromo
- Prior art date
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- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 154
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
- C07C205/46—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group the carbon skeleton containing carbon atoms of quinone rings
- C07C205/47—Anthraquinones containing nitro groups
- C07C205/48—Anthraquinones containing nitro groups the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/44—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing doubly-bound oxygen atoms bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
- C07C50/34—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having three rings
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/02—Hydroxy-anthraquinones; Ethers or esters thereof
- C09B1/06—Preparation from starting materials already containing the anthracene nucleus
- C09B1/10—Dyes containing halogen
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/02—Hydroxy-anthraquinones; Ethers or esters thereof
- C09B1/06—Preparation from starting materials already containing the anthracene nucleus
- C09B1/12—Dyes containing sulfonic acid groups
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D06M16/00—Biochemical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. enzymatic
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
- D06P1/00—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed
- D06P1/16—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed using dispersed, e.g. acetate, dyestuffs
- D06P1/20—Anthraquinone dyes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
Definitions
- the present invention generally relates to emodin derivatives of general structure (I), to pharmaceutical compositions comprising same and to their uses in medicine.
- the present invention further relates to textiles, comprising at least one emodin derivative of general structure (I).
- Emodin (3-methyl-l,6,8-trihydroxyanthraquinone) is a yellow plant anthraquinone dye belonging to family of anthraquinone dyes [1] It is also a potent bioactive molecule found in various plants [2-4] Pharmacological studies have shown that emodin is a tumor cell-growth inhibitor and has anti-inflammatory, diuretic, antioxidant, antimicrobial, hepatoprotective, DNA-binding, cathartic, vasorelaxing and anticancer activities.
- Emodin is secondary metabolite of several plants, especially in Rheum, Rhamnus and Polygonum. Rich source of emodin are rhizomes of Chinese rhubarb and Japanese knotweed, among others.
- Japanese knotweed (Fallopia Japonica) is one of the most invasive alien species in the world and poses a major ecological and environmental problem in Europe [7] Invasive alien plant species are not native, and are introduced outside of their natural habitat by human activities, either accidentally or deliberately. They have negative impacts on biodiversity, the ecosystem, human health, the economy, the environment [8, 9] One of the biggest challenges is to develop a successful circular economy model and to find new applications for invasive alien species.
- Natural colorants dye and pigments
- Natural colorants are increasingly attracting the attention of many researchers and are gaining an important role in the world due to their health benefits. Natural colorants are environmentally friendly, biodegradable, easily and safely accessible from different parts of the plants. They can be used in many areas, such as in the cosmetics industry, clothing, leather, textile dyeing, food processing and in the pharmaceutical industry [10, 11]
- the color obtained from raw plant materials could be permissible alternative to artificial colorants.
- emodin belongs to the quinonoids [10].
- the quinonoids colorants are classified into naphthoquinones, benzoquinones, anthraquinones etc.
- Emodin belongs to the group of anthraquinone colorants, based on a structure formed by three fused benzene rings [12].
- Anthraquinones can produce a wide range of colors (yellow, red, blue) due to their short conjugated chromophores. In simple form, they give yellow color, but in the presence of some donor or acceptor substituents on aromatic rings they can also produce red or blue hues [13]
- the present invention is based on the surprising finding that naturally extracted emodin from the rhizome of Japanese knotweed and chemically modified derivatives thereof show dyeing properties making them particularly suitable for dyeing different textiles without the use of mordants. Yellow colored emodin could be easily extracted from the rhizome with organic solvents. Aromatic rings of emodin provide an entry point for the introduction of various functional modifications, such as nitration, sulfonation, chlorination, bromination... With the use of emodin and its derivatives differently colored textiles were obtained - from yellow, orange, violet, red to brown-black.
- modification of emodin produces compounds with pronounced antibacterial activities, notably against S. aureus and E. faecalis. Furthermore, these compounds show also antiviral activity, notably against human coronavirus HCoV-NL63. Antibacterial activity was transferred also to textiles dyed with emodin derivatives with the best results on polyamide and wool.
- the present invention thus provides in a first aspect an emodin derivative of general structure (I) wherein Ri, R2, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, NO 2 , SO 3 H and COOR with R being H, Ci- 6 alkyl, C2-6 alkenyl or C2-6 alkynyl; with the proviso that at least one of Ri, R2, R3 and R4 is not hydrogen.
- the present invention provides in a further aspect an emodin derivative of the present invention for use in medicine, such as for use in the treatment of cancer, bacterial infection, fungal infection or viral infection.
- the present invention provides in a further aspect a pharmaceutical composition comprising at least one emodin derivative of the present invention.
- the present invention provides in a further aspect a textile comprising at least one emodin derivative of the present invention.
- the present invention provides in a further aspect the use of an emodin derivative of the present invention as a dye, such as a textile dye.
- the present invention provides in a further aspect the use of an emodin derivative of the present invention as a color sensor, for detecting inflammation of wounds based on the change of pH.
- Ri is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
- R2 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
- R3 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C2-6 alkenyl or C2-6 alkynyl; and
- R4 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C2-6 alkenyl or C2-6 alkynyl; with the proviso that at least one of Ri, R 2 , R 3 and R 4 is not hydrogen.
- composition comprising at least one emodin derivative according to any one of items 1 to 51 and at least one pharmaceutically acceptable excipient and/or carrier.
- Textile comprising at least one emodin derivative according to any one of items 1 to 51 or a pharmaceutical composition according to item 59.
- the textile according to item 60 which is a medical textile.
- the textile according to item 60 or 616 which is a bandage, plaster or compress.
- Figure 1 Structure of emodin (3-methyl-l,6,8-trihydroxyanthraquinone).
- FIG. 2 Emodin (E-H) and emodin derivatives (E-N02, E-S03H, E-l, E-31, E-2Br, E-4Br, E-2CI, E- NH2, E-OCH3, E-4Br-OCH3).
- Figure 3 Synthesis of modified emodins E-N02, E-S03H, E-l, E-31, E-2Br, E-4Br and E-2CI from emodin E-H.
- the present invention is based on the surprising finding that naturally extracted emodin from the rhizome of Japanese knotweed and chemically modified derivatives thereof show dyeing properties making them particularly suitable for dyeing different textiles without the use of mordants.
- Yellow colored emodin could be easily extracted from the rhizome with organic solvents.
- Aromatic rings of emodin provide an entry point for the introduction of various functional modifications, such as nitration, sulfonation, chlorination and bromination. With the use of emodin and its derivatives differently colored textiles were obtained - from yellow, orange, violet, red to brown-black.
- the present invention thus provides in a first aspect an emodin derivative of general structure (I) wherein
- Ri is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
- R2 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
- R3 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and R 4 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci- 6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; with the proviso that at least one of Ri, R 2 , R 3 and R 4 is not hydrogen.
- Ri is halogen
- Ri is bromo, chloro, iodo or fluoro. According to some embodiments, Ri is bromo.
- Ri is chloro
- Ri is iodo.
- Ri is fluoro
- Ri is hydrogen.
- R 2 is halogen or hydrogen.
- R 2 is halogen
- R 2 is bromo, chloro, iodo or fluoro.
- R 2 is bromo. According to some embodiments, R2 is chloro.
- R2 is iodo.
- R2 is fluoro
- R2 is hydrogen.
- R3 is halogen or hydrogen.
- R3 is halogen
- R3 is bromo, chloro, iodo or fluoro.
- R3 is bromo
- R3 is chloro. According to some embodiments, R3 is iodo.
- R3 is fluoro
- R3 is hydrogen
- R4 is halogen or hydrogen.
- R4 is halogen. According to some embodiments, R4 is bromo, chloro, iodo or fluoro.
- R4 is bromo
- R4 is chloro
- R4 is iodo.
- R4 is fluoro. According to some embodiments, R4 is hydrogen.
- Ri is halogen
- R2 is halogen or hydrogen
- R3 is halogen or hydrogen
- R4 is halogen or hydrogen
- Ri, R 2 , R 3 and R 4 are halogen, they are of the same kind, e.g. they are each bromo.
- Ri is bromo
- R 2 is bromo or hydrogen
- R 3 is bromo or hydrogen
- R 4 is bromo or hydrogen.
- Ri is bromo
- R 2 is bromo
- R 3 is bromo or hydrogen
- R 4 is bromo or hydrogen
- Ri is bromo
- R 2 is bromo
- R 3 is bromo
- R 4 is bromo
- Ri is bromo
- R 2 is bromo
- R 3 is hydrogen
- R 4 is hydrogen
- Ri is chloro
- R 2 is chloro or hydrogen
- R 3 is chloro or hydrogen
- R 4 is chloro or hydrogen
- Ri is chloro
- R 2 is chloro
- R 3 is chloro or hydrogen
- R 4 is chloro or hydrogen
- Ri is chloro
- R 2 is chloro
- R 3 is chloro
- R 4 is chloro
- Ri is chloro
- R 2 is chloro
- R 3 is hydrogen
- R 4 is hydrogen
- Ri is iodo
- R 2 is iodo or hydrogen
- R 3 is iodo or hydrogen
- R 4 is iodo or hydrogen.
- Ri is iodo
- R 2 is iodo
- R 3 is iodo or hydrogen
- R 4 is iodo or hydrogen.
- Ri is iodo
- R 2 is iodo
- R 3 is iodo
- R 4 is hydrogen
- Ri is iodo
- R 2 is hydrogen
- R 3 is hydrogen
- R 4 is hydrogen
- Ri is NO 2
- R 2 is NO 2 or hydrogen
- R 3 is NO 2 or hydrogen
- R 4 is N0 2 or hydrogen.
- Ri is NO 2
- R 2 is NO 2
- R 3 is NO 2 or hydrogen
- R 4 is NO 2 or hydrogen.
- Ri is NO 2
- R 2 is NO 2
- R 3 is NO 2
- R 4 is NO 2 or hydrogen.
- Ri is NO 2
- R 2 is NO 2
- R 3 is NO 2
- R 4 is NO 2 .
- Ri is SO3H or hydrogen
- R2 is SO3H or hydrogen
- R3 is SO3H or hydrogen
- R4 is SO3H
- Ri is SO3H or hydrogen
- R2 is SO3H or hydrogen
- R3 is SO3H
- R4 is SO3H
- Ri is SO3H or hydrogen
- R2 is SO3H
- R3 is SO3H or hydrogen
- R 4 is SO3H
- Ri is SO3H
- R2 is SO3H or hydrogen
- R3 is SO3H or hydrogen
- R 4 is SO3H.
- modification of emodin produces compounds with pronounced antibacterial activities, notably against S. aureus and E. faecalis. Antibacterial activity was transferred also to textiles dyed with emodin derivatives with the best results on polyamide and wool. Furthermore, these compounds show also antiviral activity, notably against human coronavirus HCoV-NL63.
- the present invention provides in a further aspect an emodin derivative of the invention for use in medicine.
- the emodin derivative of the invention are useful in the treatment of an infection, such as a bacterial infection or viral infection, or in the treatment of cancer.
- the emodin derivative of the invention is for use in the treatment of an infection.
- the infection is a bacterial infection.
- the bacterial infection is caused by a bacterial pathogen selected from the group consisting of S. aureus, E. faecalis, P. aeruginosa, E. cloacae, B. laterosporus, B. subtilis, M. tuberculosis, K. pneumoniae, A. baumannii, E. coli and H. pylori.
- a bacterial pathogen selected from the group consisting of S. aureus, E. faecalis, P. aeruginosa, E. cloacae, B. laterosporus, B. subtilis, M. tuberculosis, K. pneumoniae, A. baumannii, E. coli and H. pylori.
- the infection is a fungal infection.
- the fungal infection is caused by a fungal pathogen selected from the group consisting of Candida albicans, Cryptococcus neoformans, Trichophyton mentagrophytes, Aspergillus fumigatus and Saprolegnia spp.
- a fungal pathogen selected from the group consisting of Candida albicans, Cryptococcus neoformans, Trichophyton mentagrophytes, Aspergillus fumigatus and Saprolegnia spp.
- the infection is a viral infection, such as an infection with a human virus.
- the human virus is a human DNA virus.
- the human DNA virus is selected from the group consisting of human papillomavirus, adenovirus, human herpes virus, including herpes simplex virus type 1 and type 2, varicella zoster virus, Epstein-Barr virus, human cytomegalovirus, molluscum contagiosum virus, orf virus, smallpox virus and vaccinia virus.
- the human virus is a RNA virus.
- the human RNA virus is selected from the group consisting of coronavirus, including SARS-CoV-2, Lassa virus, Hantavirus, Marburg virus, Ebola virus, Influenza virus, Mumps virus, human respiratory syncytial virus, Parainfluenza, Rabies, vesicular stomatitis virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Zika virus, Poliovirus, Rhinovirus, Hepatitis A virus and Rotavirus.
- coronavirus including SARS-CoV-2, Lassa virus, Hantavirus, Marburg virus, Ebola virus, Influenza virus, Mumps virus, human respiratory syncytial virus, Parainfluenza, Rabies, vesicular stomatitis virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Zika virus, Poliovirus, Rhinovirus, Hepatitis A virus and Rotavirus.
- the human virus is a coronavirus.
- the human virus is a coronavirus selected from severe acute respiratory syndrome related coronavirus, Middle East respiratory syndrome related coronavirus, HCoV-NL63, HCoV-HKUl, HCoV-229E and HCoV-OC43.
- the human virus is a severe acute respiratory syndrome related coronavirus, such as SARS-CoV-2.
- the emodin derivative of the invention is for use in the treatment a cancer.
- the cancer is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronch
- Another aspect of the invention refers to a pharmaceutical composition which comprises a least one emodin derivative of the invention and a pharmaceutically acceptable excipient and/or carrier.
- Suitable pharmaceutically acceptable excipient and carriers are well-known to the skilled person, and have been described in the literature, such as in Remington's Pharmaceutical Sciences, the Handbook of Pharmaceutical Additives or the Handbook of Pharmaceutical Excipients.
- suitable pharmaceutically acceptable excipients include diluents, fillers, binding agents, disintegrating agents, lubricants, fluidizers, granulating agents, coating materials, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweeting agents, flavoring agents, odor masking agents, coloring agents, anti-caking agents, chelating agents, plasticisers, viscosifiers, antioxidants, antiseptics, stabilizing agents, surfactants and buffer agents.
- compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
- the pharmaceutical composition is adapted for topical administration.
- the mentioned formulations can be prepared using standard methods such as those described or referred to in the European and US Pharmacopoeias and similar reference texts.
- Administration of the emodin derivative(s) or pharmaceutical composition(s) of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration.
- an effective administered amount of an emodin derivative of the present invention will depend on the relative efficacy of the derivative chosen, the severity of the disorder being treated and the weight of the sufferer.
- active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
- the emodin derivative(s) and pharmaceutical composition(s) of this invention may be used with other drugs to provide a combination therapy.
- the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
- Another aspect of the invention refers to the use of an emodin derivative in the manufacture of a medicament, particularly a medicament for use in the treatment of any one of the conditions mentioned above.
- Another aspect of this invention relates to a method of treating or preventing any one of the conditions mentioned above which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of an emodin derivative or a pharmaceutical composition of the invention.
- the present invention provides in a further aspect a textile comprising at least one emodin derivative according to the invention or a pharmaceutical composition according to the invention.
- a "textile" within the context of the present invention is a natural or man-made fiber, filament or yarn, or any fabric or cloth made of such fiber, filament or yarn, e.g., by weaving, felting, knitting, braiding or crocheting.
- the emodin derivative or pharmaceutical composition according to the invention may be applied to the textile as a coating or may be incorporated in the textile. According to some embodiments, the textile is coated with the emodin derivative or pharmaceutical composition according to the invention.
- the textile may be made of any suitable material.
- suitable material include cotton, wool, silk, polyester, polyamide, poly(lactic acid), olefin (such as polypropylen and polyethylen), viscose and polysulfone.
- the textile is made of cotton.
- the textile is made of wool.
- the textile is made of silk.
- the textile is made of polyester.
- the textile is made of polyamide.
- the textile is made of poly(lactic acid).
- the textile is made of olefin.
- the textile is made of viscose.
- the textile is made of polysulfone.
- the textile is a medical textile.
- a medical textile is a textile structure which has been designed and produced for use in any of a variety of medical applications, including implantable applications.
- medical textiles include, but are not limited to, dressings for wound care and hospital textiles.
- Non-limiting examples of specific medical textiles are bandages, plasters and compresses.
- the textile is a non-medical textile.
- the textile is a filter, such as a filter for air purification.
- the textile is a facemask.
- the present invention provides in a further aspect the use of an emodin derivative according to the invention as a dye, such as a textile dye.
- an emodin derivative according to the invention provides in a further aspect the use of an emodin derivative according to the invention as a color sensor.
- an emodin derivative according to the invention may be used for detecting inflammation of wounds based on the change of pH.
- Emodin purchased from Fluorochem was used as received. All the other reagents and solvents were of reagent-grade quality and obtained from commercial suppliers (Honeywell, Sigma-Aldrich). The Japanese knotweed rhizomes were collected and delivered by SNAGA d. o. o., washed with water to remove the dirt, air dried at room temperature and grounded into powder. TLC was performed on Merck-60-F 254 plates using mixtures of ethyl acetate:ethanol (10:1) or dichloromethane:ethanol (100:1). The crude products were purified by column chromatography on silica gel (63-200 pm, 70- 230 mesh ASTM; Fluka).
- the roots of Japanese knotweed were harvested in the area of Ljubljana. The roots were first water- rinsed, dried and chopped into 4 mm. The starting material of real sample (10 g) were extracted overnight in organic solvent dichloromethane (100 mL). The undissolved roots were filtrated, the crude product was evaporated in vacuum to provide yellow colour (400 mg, 4 %). The crude product was purified by silica gel column chromatography with mobile phase dichloromethane. Product was evaporated in vacuum to provide the pure emodin as yellow product (52 mg). X H NMR (500 MHz, DMSO) d 7.45 (s, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 6.57 (s, 1H), 2.40 (s, 3H).
- emodin offers an entry point for the introduction of different functional groups.
- the structures of emodin and emodin derivatives are shown in Figure 2.
- the dichloro emodin was formed and isolated in 71 % yield by treating emodin with NCS in TH F as solvent. All compounds were fully characterized by 1 FI and 13 C NMR spectroscopy, FIRMS and IR spectroscopy. The chemical structures and the positions of the functional groups on aromatic rings were confirmed by 2D NMR spectroscopy (FISQC and HMBC).
- Dyeing of wool (WO) and polyamide (PA) fabrics was performed in laboratory dyeing machine for exhaust dyeing at three temperatures 60, 80 and 95 °C, at liquor to goods ratio 40:1, for 30 min. The concentration of each dye was 0.125 g/l. After dyeing, the samples were washed with distilled water and dried at room temperature.
- AL* is a difference in lightness component
- Aa* is a difference in red-green component
- Ab* is a difference in blue-yellow component.
- the samples of WO and PA were measured for their color (on reflectance spectrometer Datacolor) before and after repetitive domestic washing (5-times) at 40 °C for 45 minutes.
- Table 1 and Table 2 summarize the color values of wool and polyamide fabrics dyed before and after five domestic washings. The durability to washing was good, especially on PA samples. In general, the washing fastness results were acceptable for all five dyes.
- Yellow colored emodin was isolated from rhizomes of the Japanese knotweed. Four dyes were prepared from emodin, a yellow compound. The aromatic rings of emodin was chemically modified by nitration, sulfonation, chlorination and bromination. Emodin and its derivatives are the source of a wide range of colors (from yellow, orange, violet, red to brown-black).
- Various textile substrates cotton, polyester, wool and polyamide
- Example 3 Antimicrobial activity 3.1. Antibacterial activity of emodin and emodin derivatives
- MICs of the tested compound were determined by broth microdilution, according to CLSI guidelines [17]. Plates were incubated at 35 °C for 20 h and read visually. MICs were defined at the lowest concentration of antimicrobial agent inhibiting visible growth. For every species, and for the whole of organisms, MIC50 and MIC90 values were defined as the concentration inhibiting 50 % and 90 % of the corresponding numbers of tested strains.
- E-H and E-4Br are the most active.
- Emodin E-H showed antibacterial activity against S. aureus MRSA and different strains of S. aureus and E. faecalis.
- Emodin E-4Br showed potent antibacterial activity against S. aureus MRSA and different strains of S. aureus and E. faecalis.
- strains Escherichia coli ATCC11229 and Staphylococcus aureus ATCC 25923 were used.
- the strain Staphylococcus aureus ATCC 25923 was used for the determination of antibacterial activity of wool and polyamide samples coated with emodin.
- the Gram-positive bacteria S. aureus was transferred from TSA plate (Tryptic soy agar) to TSB liquid media (Tryptic soy broth) and cultivated overnight at 37°C, 100 rpm. Wool and polyamide samples functionalized with emodin were cut in 0,5 cm squares and placed in 96 well microtiter plate followed by UV sterilization for 15 min on each side.
- the overnight culture of S. aureus was adjusted with PBS to an optical density at 600 nm 0,1 which corresponds to an initial concentration of lxlO 5 cells/mL.
- Table 4 LogioCFU/mL after 18 hours incubation of S. aureus in presence of wool samples coated with emodin. * indicates significant differences among groups according to Anova test. The significance level adopted was 5%.
- Table 5 LogioCFU/mL after 18 hours incubation of S. aureus in presence of polyamide samples functionalized with emodin. * indicates significant differences among groups according to Anova test. The significance level adopted was 5%.
- Emodin and emodin derivatives were tested against human coronavirus NL63.
- the effect of compounds on viability of Vero cells was also assessed. Results were expressed as IC50 values in mM.
- Vero cells in EMEM medium supplemented with 10% FBS, were seeded into inner wells of 96-well white plates at 20,000 cells/well concentration. The next day, medium was removed and replaced with 50pL or lOOpL of EMEM with 2% FBS. 100 nL of compounds were added to wells using Mosquito pipetting device. Plates with 100 pL of medium werejncubated for 4 days at 33°C, 5% CO2, for cell viability assessment. To the plates in which 50 pL of the medium was added additional 50pL of medium with 5 times diluted FICoV-NL63 viral stock was added. Plates were then incubated for 4 days at 33°C, 5% CO2. Cell viability assessment
- Anti-viral effects of the compounds were expressed as % of live cells when compared to cells with and without virus added. IC50 values were calculated using GraphPad Prism 8 software. The results of the two parallels (NL63_1 and NL63_2) are shown in Table 6 below. Remdesivir and chloroquine were used as standards.
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Abstract
The invention generally relates to emodin derivatives of general structure (I), to pharmaceutical compositions comprising same and to their uses in medicine, especially in the treatment of bacterial or viral infections. The invention further relates to textiles, such as fabrics, comprising at least one emodin derivative of general structure (I). R1- R2- R3 and R4 are independently selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR; R is H, C1-6-alkyl, C2-6alkenyl or C2-6alkynyl; with the proviso that at least one of R1, R2, R3 and R4 is not hydrogen.
Description
Emodin derivatives and uses thereof
Technical field of the invention
The present invention generally relates to emodin derivatives of general structure (I), to pharmaceutical compositions comprising same and to their uses in medicine. The present invention further relates to textiles, comprising at least one emodin derivative of general structure (I).
Background of the invention
Emodin (3-methyl-l,6,8-trihydroxyanthraquinone) is a yellow plant anthraquinone dye belonging to family of anthraquinone dyes [1] It is also a potent bioactive molecule found in various plants [2-4] Pharmacological studies have shown that emodin is a tumor cell-growth inhibitor and has anti-inflammatory, diuretic, antioxidant, antimicrobial, hepatoprotective, DNA-binding, cathartic, vasorelaxing and anticancer activities. It has antitumor effects in various cancers such as leukemia, human tongue squamous cancer, lung cancer, gallbladder cancer, breast cancer, colon cancer and others [5, 6] Recent research show that it has potential antiviral activity against Sars-CoV-2. Emodin is secondary metabolite of several plants, especially in Rheum, Rhamnus and Polygonum. Rich source of emodin are rhizomes of Chinese rhubarb and Japanese knotweed, among others. Japanese knotweed (Fallopia Japonica) is one of the most invasive alien species in the world and poses a major ecological and environmental problem in Europe [7] Invasive alien plant species are not native, and are introduced outside of their natural habitat by human activities, either accidentally or deliberately. They have negative impacts on biodiversity, the ecosystem, human health, the economy, the environment [8, 9] One of the biggest challenges is to develop a successful circular economy model and to find new applications for invasive alien species.
Nowadays, there is renewed interest in the use of environmentally friendly natural products in everyday life. Natural colorants (dyes and pigments) are increasingly attracting the attention of many researchers and are gaining an important role in the world due to their health benefits. Natural colorants are environmentally friendly, biodegradable, easily and safely accessible from different parts of the plants. They can be used in many areas, such as in the cosmetics industry, clothing, leather, textile dyeing, food processing and in the pharmaceutical industry [10, 11] The color obtained from raw plant materials could be permissible alternative to artificial colorants.
According to its chemical structure, emodin belongs to the quinonoids [10]. The quinonoids colorants are classified into naphthoquinones, benzoquinones, anthraquinones etc. Emodin belongs to the group of anthraquinone colorants, based on a structure formed by three fused benzene rings [12]. Anthraquinones can produce a wide range of colors (yellow, red, blue) due to their short conjugated chromophores. In simple form, they give yellow color, but in the presence of some donor or acceptor substituents on aromatic rings they can also produce red or blue hues [13]
Some natural plant based dyes have a low affinity to textile materials. The use of mordant molecules can improve the affinity and fastness properties of the dye, but most of them are toxic [10]. In 2001, Hynninen and coworkers reported a high-temperature dyeing method for polyester fabrics and mordant dyeing of wool and polyamide with emodin [14, 15]. Ten years later, Ke and Wu were published, using the dyeing method of PLA fabrics with emodin using various metal salts as mordants [16]. Summary of the invention
The present invention is based on the surprising finding that naturally extracted emodin from the rhizome of Japanese knotweed and chemically modified derivatives thereof show dyeing properties making them particularly suitable for dyeing different textiles without the use of mordants. Yellow colored emodin could be easily extracted from the rhizome with organic solvents. Aromatic rings of emodin provide an entry point for the introduction of various functional modifications, such as nitration, sulfonation, chlorination, bromination... With the use of emodin and its derivatives differently colored textiles were obtained - from yellow, orange, violet, red to brown-black.
Moreover, the present inventors have found that modification of emodin produces compounds with pronounced antibacterial activities, notably against S. aureus and E. faecalis. Furthermore, these compounds show also antiviral activity, notably against human coronavirus HCoV-NL63. Antibacterial activity was transferred also to textiles dyed with emodin derivatives with the best results on polyamide and wool.
The present invention thus provides in a first aspect an emodin derivative of general structure (I)
wherein Ri, R2, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; with the proviso that at least one of Ri, R2, R3 and R4 is not hydrogen.
The present invention provides in a further aspect an emodin derivative of the present invention for use in medicine, such as for use in the treatment of cancer, bacterial infection, fungal infection or viral infection.
The present invention provides in a further aspect a pharmaceutical composition comprising at least one emodin derivative of the present invention.
The present invention provides in a further aspect a textile comprising at least one emodin derivative of the present invention.
The present invention provides in a further aspect the use of an emodin derivative of the present invention as a dye, such as a textile dye. The present invention provides in a further aspect the use of an emodin derivative of the present invention as a color sensor, for detecting inflammation of wounds based on the change of pH.
The present invention may be further characterized by the following items:
1. An emodin derivative of general structure (I)
wherein
Ri is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R2 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R3 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; and
R4 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; with the proviso that at least one of Ri, R2, R3 and R4 is not hydrogen.
2. The emodin derivative according to item 1, wherein Ri is halogen.
3. The emodin derivative according to item 1, wherein Ri is bromo, chloro, iodo or fluoro.
4. The emodin derivative according to item 1, wherein Ri is bromo.
5. The emodin derivative according to item 1, wherein Ri is chloro.
6. The emodin derivative according to item 1, wherein Ri is iodo.
7. The emodin derivative according to item 1, wherein Ri is fluoro.
8. The emodin derivative according to any one of items 1 to 7, wherein R2 is halogen or hydrogen.
9. The emodin derivative according to any one of items 1 to 7, wherein R2 is halogen.
10. The emodin derivative according to any one of items 1 to 7, wherein R2 is bromo, chloro, iodo or fluoro.
11. The emodin derivative according to any one of items 1 to 7, wherein R2 is bromo.
12. The emodin derivative according to any one of items 1 to 7, wherein R2 is chloro.
13. The emodin derivative according to any one of items 1 to 7, wherein R2 is iodo.
14. The emodin derivative according to any one of items 1 to 7, wherein R2 is fluoro.
15. The emodin derivative according to item 1 to 7, wherein R2 is hydrogen.
16. The emodin derivative according to any one of items 1 to 15, wherein R3 is halogen or hydrogen.
17. The emodin derivative according to any one of items 1 to 15, wherein R3 is halogen.
18. The emodin derivative according to any one of items 1 to 15, wherein R3 is bromo, chloro, iodo or fluoro.
19. The emodin derivative according to any one of items 1 to 15, wherein R3 is bromo.
20. The emodin derivative according to any one of items 1 to 15, wherein R3 is chloro.
21. The emodin derivative according to any one of items 1 to 15, wherein R3 is iodo.
22. The emodin derivative according to any one of items 1 to 15, wherein R3 is fluoro.
23. The emodin derivative according to item 1 to 15, wherein R3 is hydrogen.
24. The emodin derivative according to any one of items 1 to 23, wherein R4 is halogen or hydrogen.
25. The emodin derivative according to any one of items 1 to 23, wherein R4 is halogen.
26. The emodin derivative according to any one of items 1 to 23, wherein R4 is bromo, chloro, iodo or fluoro.
27. The emodin derivative according to any one of items 1 to 23, wherein R4 is bromo.
28. The emodin derivative according to any one of items 1 to 23, wherein R4 is chloro.
29. The emodin derivative according to any one of items 1 to 23, wherein R4 is iodo.
30. The emodin derivative according to any one of items 1 to 23, wherein R4 is fluoro.
31. The emodin derivative according to item 1 to 20, wherein R4 is hydrogen.
32. The emodin derivative according to item 1, wherein Ri is bromo, R2 is bromo or hydrogen, R3 is bromo or hydrogen, and R4 is bromo or hydrogen.
33. The emodin derivative according to item 1, wherein Ri is bromo, R2 is bromo, R3 is bromo or hydrogen, and R4 is bromo or hydrogen.
34. The emodin derivative according to item 1, wherein Ri is bromo, R2 is bromo, R3 is bromo, and R4 is bromo.
35. The emodin derivative according to item 1, wherein Ri is bromo, R2 is bromo, R3 is hydrogen, and R4 is hydrogen.
36. The emodin derivative according to item 1, wherein Ri is chloro, R2 is chloro or hydrogen, R3 is chloro or hydrogen, and R4 is chloro or hydrogen.
37. The emodin derivative according to item 1, wherein Ri is chloro, R2 is chloro, R3 is chloro or hydrogen, and R4 is chloro or hydrogen.
38. The emodin derivative according to item 1, wherein Ri is chloro, R2 is chloro, R3 is chloro, and R4 is chloro.
39. The emodin derivative according to item 1, wherein Ri is chloro, R2 is chloro, R3 is hydrogen, and R4 is hydrogen.
40. The emodin derivative according to item 1, wherein Ri is iodo, R2 is iodo or hydrogen, R3 is iodo or hydrogen, and R4 is iodo or hydrogen.
41. The emodin derivative according to item 1, wherein Ri is iodo, R2 is iodo, R3 is iodo or hydrogen, and R4 is iodo or hydrogen.
42. The emodin derivative according to item 1, wherein Ri is iodo, R2 is iodo, R3 is iodo, and R4 is hydrogen.
43. The emodin derivative according to item 1, wherein Ri is iodo, R2 is hydrogen, R3 is hydrogen, and R4 is hydrogen.
44. The emodin derivative according to item 1, wherein Ri is NO2, R2 is NC or hydrogen, R3 is NO2 or hydrogen, and R4 is NO2 or hydrogen.
45. The emodin derivative according to item 1, wherein Ri is NO2, R2 is NO2, R3 is NC or hydrogen, and R4 is NO2 or hydrogen.
46. The emodin derivative according to item 1, wherein Ri is NO2, R2 is NO2, R3 is NO2, and R4 is NC or hydrogen.
47. The emodin derivative according to item 1, wherein Ri is NO2, R2 is NO2, R3 is NO2, and R4 is NO2.
48. The emodin derivative according to item 1, wherein Ri is SO3H or hydrogen, R2 is SO3H or hydrogen, R3 is SO3H or hydrogen, and R4 is SO3H.
49. The emodin derivative according to item 1, wherein Ri is SO3H or hydrogen, R2 is SO3H or hydrogen, R3 is SO3H, and R4 is SO3H.
50. The emodin derivative according to item 1, wherein Ri is SO3H or hydrogen, R2 is SO3H, R3 is SO3H or hydrogen, and R4 is SO3H.
51. The emodin derivative according to item 1, wherein Ri is SO3H, R2 is SO3H or hydrogen, R3 is SO3H or hydrogen, and R4 is SO3H.
52. The emodin derivative according to any one of items 1 to 51 for use in medicine.
53. The emodin derivative according to any one of items 1 to 52 for use in the treatment of an infection.
54. The emodin derivative for use according to item 53, wherein the infection is a bacterial infection.
55. The emodin derivative for use according to item 53, wherein the infection is a fungal infection.
56. The emodin derivative for use according to item 53, wherein the infection is a viral infection.
57. The emodin derivative for use according to item 56, wherein the viral infection is coronavirus infection.
58. The emodin derivative according to any one of items 1 to 51 for use in the treatment of a cancer.
59. Pharmaceutical composition comprising at least one emodin derivative according to any one of items 1 to 51 and at least one pharmaceutically acceptable excipient and/or carrier.
60. Textile comprising at least one emodin derivative according to any one of items 1 to 51 or a pharmaceutical composition according to item 59.
61. The textile according to item 60, which is a medical textile.
62. The textile according to item 60 or 616, which is a bandage, plaster or compress.
63. The textile according to item 60, which is a filter.
64. The textile according to any one of items 60 to 63, which is made of cotton, wool, silk, polyamide or polyester.
65. The textile according to any one of items 60 to 63, which is made of polyamide.
66. The textile according to any one of items 60 to 65, for use in medical therapy.
67. The textile according to any one of items 60 to 65, for non-medical use.
68. Use of an emodin derivative according to any one of items 1 to 51 as a dye, such as a textile dye.
69. Use of an emodin derivative according to any one of items 1 to 51 as a color sensor.
70. Use of an emodin derivative according to any one of items 1 to 51 for detecting inflammation of wounds based on the change of pH.
Brief description of the figures
Figure 1: Structure of emodin (3-methyl-l,6,8-trihydroxyanthraquinone).
Figure 2: Emodin (E-H) and emodin derivatives (E-N02, E-S03H, E-l, E-31, E-2Br, E-4Br, E-2CI, E- NH2, E-OCH3, E-4Br-OCH3).
Figure 3: Synthesis of modified emodins E-N02, E-S03H, E-l, E-31, E-2Br, E-4Br and E-2CI from emodin E-H.
The present invention is now described in more detail below.
Detailed description of the invention
As noted above, the present invention is based on the surprising finding that naturally extracted emodin from the rhizome of Japanese knotweed and chemically modified derivatives thereof show dyeing properties making them particularly suitable for dyeing different textiles without the use of mordants. Yellow colored emodin could be easily extracted from the rhizome with organic solvents. Aromatic rings of emodin provide an entry point for the introduction of various functional modifications, such as nitration, sulfonation, chlorination and bromination. With the use of emodin and its derivatives differently colored textiles were obtained - from yellow, orange, violet, red to brown-black.
The present invention thus provides in a first aspect an emodin derivative of general structure (I)
wherein
Ri is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R2 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R3 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; and R4 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; with the proviso that at least one of Ri, R2, R3 and R4 is not hydrogen.
According to some embodiments, Ri is halogen.
According to some embodiments, Ri is bromo, chloro, iodo or fluoro. According to some embodiments, Ri is bromo.
According to some embodiments, Ri is chloro.
According to some embodiments, Ri is iodo.
According to some embodiments, Ri is fluoro.
According to some embodiments, Ri is hydrogen. According to some embodiments, R2 is halogen or hydrogen.
According to some embodiments R2 is halogen.
According to some embodiments, R2 is bromo, chloro, iodo or fluoro.
According to some embodiments, R2 is bromo.
According to some embodiments, R2 is chloro.
According to some embodiments, R2 is iodo.
According to some embodiments, R2 is fluoro.
According to some embodiments, R2 is hydrogen. According to some embodiments, R3 is halogen or hydrogen.
According to some embodiments, R3 is halogen.
According to some embodiments, R3 is bromo, chloro, iodo or fluoro.
According to some embodiments, R3 is bromo.
According to some embodiments, R3 is chloro. According to some embodiments, R3 is iodo.
According to some embodiments, R3 is fluoro.
According to some embodiments, R3 is hydrogen.
According to some embodiments, R4 is halogen or hydrogen.
According to some embodiments, R4 is halogen. According to some embodiments, R4 is bromo, chloro, iodo or fluoro.
According to some embodiments, R4 is bromo.
According to some embodiments, R4 is chloro.
According to some embodiments, R4 is iodo.
According to some embodiments, R4 is fluoro. According to some embodiments, R4 is hydrogen.
According to some embodiments, Ri is halogen, R2 is halogen or hydrogen, R3 is halogen or hydrogen, and R4 is halogen or hydrogen.
According to some embodiments, if two or more of Ri, R2, R3 and R4 are halogen, they are of the same kind, e.g. they are each bromo.
According to some embodiments, Ri is bromo, R2 is bromo or hydrogen, R3 is bromo or hydrogen, and R4 is bromo or hydrogen.
According to some embodiments, Ri is bromo, R2 is bromo, R3 is bromo or hydrogen, and R4 is bromo or hydrogen.
According to some embodiments, Ri is bromo, R2 is bromo, R3 is bromo, and R4 is bromo.
According to some embodiments, Ri is bromo, R2 is bromo, R3 is hydrogen, and R4 is hydrogen.
According to some embodiments, Ri is chloro, R2 is chloro or hydrogen, R3 is chloro or hydrogen, and R4 is chloro or hydrogen.
According to some embodiments, Ri is chloro, R2 is chloro, R3 is chloro or hydrogen, and R4 is chloro or hydrogen.
According to some embodiments, Ri is chloro, R2 is chloro, R3 is chloro, and R4 is chloro.
According to some embodiments, Ri is chloro, R2 is chloro, R3 is hydrogen, and R4 is hydrogen.
According to some embodiments, Ri is iodo, R2 is iodo or hydrogen, R3 is iodo or hydrogen, and R4 is iodo or hydrogen.
According to some embodiments, Ri is iodo, R2 is iodo, R3 is iodo or hydrogen, and R4 is iodo or hydrogen.
According to some embodiments, Ri is iodo, R2 is iodo, R3 is iodo, and R4 is hydrogen.
According to some embodiments, Ri is iodo, R2 is hydrogen, R3 is hydrogen, and R4 is hydrogen.
According to some embodiments, Ri is NO2, R2 is NO2 or hydrogen, R3 is NO2 or hydrogen, and R4 is N02 or hydrogen.
According to some embodiments, Ri is NO2, R2 is NO2, R3 is NO2 or hydrogen, and R4 is NO2 or hydrogen.
According to some embodiments, Ri is NO2, R2 is NO2, R3 is NO2, and R4 is NO2 or hydrogen.
According to some embodiments, Ri is NO2, R2 is NO2, R3 is NO2, and R4 is NO2.
According to some embodiments, Ri is SO3H or hydrogen, R2 is SO3H or hydrogen, R3 is SO3H or hydrogen, and R4 is SO3H.
According to some embodiments Ri is SO3H or hydrogen, R2 is SO3H or hydrogen, R3 is SO3H, and R4 is SO3H.
According to some embodiments, Ri is SO3H or hydrogen, R2 is SO3H, R3 is SO3H or hydrogen, and R4 is SO3H. According to some embodiments, Ri is SO3H, R2 is SO3H or hydrogen, R3 is SO3H or hydrogen, and R4 is SO3H.
Particular embodiments of the emodin derivative of the invention are shown in the table below:
R 1 R2 R3 R 4
E-N02 NOz NOz NOz NOz
E-S03H H H H SOsH
E-l I H H H
E-31 I I I H
E-2Br Br Br H H
E-4Br Br Br Br Br
E-2CI Cl Cl H H
As noted above, the present inventors have found that modification of emodin produces compounds with pronounced antibacterial activities, notably against S. aureus and E. faecalis. Antibacterial activity was transferred also to textiles dyed with emodin derivatives with the best results on polyamide and wool. Furthermore, these compounds show also antiviral activity, notably against human coronavirus HCoV-NL63.
Accordingly, the present invention provides in a further aspect an emodin derivative of the invention for use in medicine.
Particularly, the emodin derivative of the invention are useful in the treatment of an infection, such as a bacterial infection or viral infection, or in the treatment of cancer.
According to some embodiments, the emodin derivative of the invention is for use in the treatment of an infection.
According to some embodiments, the infection is a bacterial infection.
According to some embodiments, the bacterial infection is caused by a bacterial pathogen selected from the group consisting of S. aureus, E. faecalis, P. aeruginosa, E. cloacae, B. laterosporus, B. subtilis, M. tuberculosis, K. pneumoniae, A. baumannii, E. coli and H. pylori.
According to some embodiments, the infection is a fungal infection.
According to some embodiments, the fungal infection is caused by a fungal pathogen selected from the group consisting of Candida albicans, Cryptococcus neoformans, Trichophyton mentagrophytes, Aspergillus fumigatus and Saprolegnia spp.
According to some embodiments, the infection is a viral infection, such as an infection with a human virus.
According to some embodiments, the human virus is a human DNA virus.
According to some embodiments, the human DNA virus is selected from the group consisting of human papillomavirus, adenovirus, human herpes virus, including herpes simplex virus type 1 and type 2, varicella zoster virus, Epstein-Barr virus, human cytomegalovirus, molluscum contagiosum virus, orf virus, smallpox virus and vaccinia virus.
According to some embodiments, the human virus is a RNA virus.
According to some embodiments, the human RNA virus is selected from the group consisting of coronavirus, including SARS-CoV-2, Lassa virus, Hantavirus, Marburg virus, Ebola virus, Influenza virus, Mumps virus, human respiratory syncytial virus, Parainfluenza, Rabies, vesicular stomatitis virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Zika virus, Poliovirus, Rhinovirus, Hepatitis A virus and Rotavirus.
According to some embodiments, the human virus is a coronavirus.
According to some embodiments, the human virus is a coronavirus selected from severe acute respiratory syndrome related coronavirus, Middle East respiratory syndrome related coronavirus, HCoV-NL63, HCoV-HKUl, HCoV-229E and HCoV-OC43.
According to some embodiments, the human virus is a severe acute respiratory syndrome related coronavirus, such as SARS-CoV-2.
According to some embodiments, the emodin derivative of the invention is for use in the treatment a cancer.
According to some embodiments, the cancer is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma and retinoblastoma.
Another aspect of the invention refers to a pharmaceutical composition which comprises a least one emodin derivative of the invention and a pharmaceutically acceptable excipient and/or carrier.
Suitable pharmaceutically acceptable excipient and carriers are well-known to the skilled person, and have been described in the literature, such as in Remington's Pharmaceutical Sciences, the Handbook of Pharmaceutical Additives or the Handbook of Pharmaceutical Excipients. Non-limiting examples of suitable pharmaceutically acceptable excipients include diluents, fillers, binding agents, disintegrating agents, lubricants, fluidizers, granulating agents, coating materials, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweeting agents, flavoring agents, odor masking agents, coloring agents, anti-caking agents, chelating agents, plasticisers, viscosifiers, antioxidants, antiseptics, stabilizing agents, surfactants and buffer agents.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration. According to some embodiments, the pharmaceutical composition is adapted for topical administration.
The mentioned formulations can be prepared using standard methods such as those described or referred to in the European and US Pharmacopoeias and similar reference texts.
Administration of the emodin derivative(s) or pharmaceutical composition(s) of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration.
Generally an effective administered amount of an emodin derivative of the present invention will depend on the relative efficacy of the derivative chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
The emodin derivative(s) and pharmaceutical composition(s) of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
Another aspect of the invention refers to the use of an emodin derivative in the manufacture of a medicament, particularly a medicament for use in the treatment of any one of the conditions mentioned above.
Another aspect of this invention relates to a method of treating or preventing any one of the conditions mentioned above which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of an emodin derivative or a pharmaceutical composition of the invention.
The present invention provides in a further aspect a textile comprising at least one emodin derivative according to the invention or a pharmaceutical composition according to the invention.
A "textile" within the context of the present invention is a natural or man-made fiber, filament or yarn, or any fabric or cloth made of such fiber, filament or yarn, e.g., by weaving, felting, knitting, braiding or crocheting.
The emodin derivative or pharmaceutical composition according to the invention may be applied to the textile as a coating or may be incorporated in the textile. According to some embodiments,
the textile is coated with the emodin derivative or pharmaceutical composition according to the invention.
The textile may be made of any suitable material. Non-limiting examples of a suitable material include cotton, wool, silk, polyester, polyamide, poly(lactic acid), olefin (such as polypropylen and polyethylen), viscose and polysulfone.
According to some embodiments, the textile is made of cotton.
According to some embodiments, the textile is made of wool.
According to some embodiments, the textile is made of silk.
According to some embodiments, the textile is made of polyester.
According to some embodiments, the textile is made of polyamide.
According to some embodiments, the textile is made of poly(lactic acid).
According to some embodiments, the textile is made of olefin.
According to some embodiments, the textile is made of viscose.
According to some embodiments, the textile is made of polysulfone.
According to some embodiments, the textile is a medical textile. A medical textile is a textile structure which has been designed and produced for use in any of a variety of medical applications, including implantable applications. Generally, medical textiles include, but are not limited to, dressings for wound care and hospital textiles. Non-limiting examples of specific medical textiles are bandages, plasters and compresses.
According to some embodiments, the textile is a non-medical textile.
According to some embodiments, the textile is a filter, such as a filter for air purification.
According to some embodiments, the textile is a facemask.
The present invention provides in a further aspect the use of an emodin derivative according to the invention as a dye, such as a textile dye.
The present invention provides in a further aspect the use of an emodin derivative according to the invention as a color sensor. Particularly, an emodin derivative according to the invention may be used for detecting inflammation of wounds based on the change of pH.
Having generally described this invention, a further understanding can be obtained by reference to certain specific examples, which are provided herein for purposes of illustration only, and are not intended to be limiting unless otherwise specified.
Examples
Example 1 - General
1.1 Materials and instruments
Emodin purchased from Fluorochem was used as received. All the other reagents and solvents were of reagent-grade quality and obtained from commercial suppliers (Honeywell, Sigma-Aldrich). The Japanese knotweed rhizomes were collected and delivered by SNAGA d. o. o., washed with water to remove the dirt, air dried at room temperature and grounded into powder. TLC was performed on Merck-60-F254 plates using mixtures of ethyl acetate:ethanol (10:1) or dichloromethane:ethanol (100:1). The crude products were purified by column chromatography on silica gel (63-200 pm, 70- 230 mesh ASTM; Fluka). Products were characterized using 1H, 13C and 2D (HSQC, HBMC) NMR spectra, HRMS and IR analysis. 1H, 13C and 2D NMR spectra were recorded on Bruker Avance III 500 instruments, IR spectra were recorded on Spectrum BX FTIR Perkin-Elmer. HR-MS were recorded on LC MS system Agilent 6224 Accurate Mass TOF LC/MS.
1.2 Synthesis
1.2.1 Isolation of emodin (E-H) from roots of Japanese knotweed.
The roots of Japanese knotweed were harvested in the area of Ljubljana. The roots were first water- rinsed, dried and chopped into 4 mm. The starting material of real sample (10 g) were extracted overnight in organic solvent dichloromethane (100 mL). The undissolved roots were filtrated, the crude product was evaporated in vacuum to provide yellow colour (400 mg, 4 %). The crude product was purified by silica gel column chromatography with mobile phase dichloromethane. Product was evaporated in vacuum to provide the pure emodin as yellow product (52 mg). XH NMR (500 MHz, DMSO) d 7.45 (s, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 6.57 (s, 1H), 2.40 (s, 3H).
1.2.2 l,3,8-trihydroxy-6-methyl-2,4,5,7-tetranitroanthracene-9,10-dione (E-N02).
To a mixture of the emodin (270 mg, 1.0 mmol) and concentrated H2SO4 (4 mL) at 0 °C concentrated HNO3 (5 mL) was added dropwise over 10 min. The reaction mixture was stirred at 0 °C for 30 min and 4 h at room temperature. The mixture was poured onto ice and extracted with ethyl acetate (3x30 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was evaporated under vacuum. The crude reaction was purified by column chromatography using ethyl acetate/ethanol (10/1) mobile phase. The solvent was evaporated in vacuum to provide the product (408 mg, 91 %) as an orange-red solid. 4H NMR (500 MHz, DMSO-ds, 25 °C): d = 2.21 (s, 3H, CHs) ppm. 13C NMR (126 MHz, DMSO-ds, 25 °C): d = 183.8, 177.3, 161.0, 156.6, 151.9, 143.2, 140.4, 139.9, 134.8, 128.8, 124.3, 122.4, 117.0, 96.7, 12.3 ppm. IR: 3351, 1638, 1538, 1369, 1170 cm4. HRMS (ESI+): m/z calcd for Ci5H6N40i3451.0004 [M+H]+, found: 451.0002 [M+H]+.
1.2.3 l,3,8-trihydroxy-6-methyl-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid (E-S03H).
To emodin (270 mg, 1.0 mmol) was added dropwise oleum (8 mL) over 15 min. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured onto ice and extracted with ethyl acetate (3x30 mL). The organic layer was dried over anhydrous Na2SC>4 and the solvent was evaporated under vacuum. The crude reaction product was macerated in MeCN and hexane and then purified by column chromatography using ethyl acetate/ethanol (10/1) mobile phase. The solvent was evaporated in vacuum to provide the product (266.2 mg, 76 %) as a black solid. 4H NMR (500 MHz, DMSO-de, 25 °C): d = 7.35 (d, J = 1.9 Hz, 1H, ArH), 7.14 (d, J = 1.9 Hz, 1H, ArH), 6.75 (s, 1H, ArH), 2.38 (s, 3H, CH3) ppm. 13C NMR (126 MHz, DMSO-ds, 25 °C): d = 158.2, 151.1, 146.8, 139.7, 134.7, 133.5, 126.7, 121.4, 112.1, 110.6, 109.4, 108.9, 105.0, 96.7, 14.6 ppm. IR: 3451, 1738, 1600, 1426, 1367, 1202, 1094 cm4. HRMS (ESI-): m/z calcd for CisHioOgS 349.0024 [M-H] , found: 349.0032 [M-H]\
1.2.4. l,3,8-trihydroxy-2-iodo-6-methylanthracene-9,10-dione (E-l).
To a stirred solution of emodin (135 mg, 0.5 mmol) in 2-MeTHF (5 mL) was added iodine (510 mg, 2.0 mmol) and 30% H2O2 (4 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC (CH2Cl2:EtOH=100:l). After reaction was complete, the reaction mixture was washed with NaHSC>3 and extracted with dichloromethane (3x30 mL). The organic layer was washed with water (1x30 mL), dried over anhydrous Na2SC>4 and evaporated under vacuum. The crude reaction product was washed with hexane (5 mL) and acetonitrile (5 mL) to remove
soluble impurities. The product was dried in vacuum to provide the product (184.2 mg, 93 %) as orange solid. 4H NMR (500 MHz, DMSO-ds, 25 °C): d = 7.47 (s, 1H, ArH), 7.21 (s, 1H, ArH), 7.16 (s, 1H, ArH), 2.41 (s, 3H, CH3) ppm. 13C NMR (126 MHz, DMSO-ds, 25 °C): d = 189.4, 181.2, 165.2, 163.5,
161.4. 148.6, 134.2, 132.7, 124.3, 120.6, 113.1, 108.5, 106.8, 83.2, 21.6 ppm. IR: 3339, 1665, 1615, 1473, 1379, 1263, 1168, 949 cm4. HRMS (ESI-): m/z calcd for C15H9IO5 394.9422 [M-H] , found: 394.9428 [M-H] .
1.2.5. 2,4,5-trihydroxy-l,3,6-triiodo-7-methylanthracene-9,10-dione (E-31)
To a stirred solution of emodin (135 mg, 0.5 mmol) in THF (13 mL) and water (13 mL) was added iodine (8 g, 32.0 mmol) at 0 °C. NaHC03 (3.5 g, 42.0 mmol) was then added stepwise. The reaction mixture was stirred for 24 h at room temperature. The reaction was monitored by TLC (CH2Cl2:EtOH=100:l). After completion of the reaction, the reaction mixture was extracted with dichloromethane (3x30 mL). The organic layer was washed with water (1x30 mL), dried over anhydrous Na2SC>4 and evaporated under vacuum. The crude reaction product was washed with hexane (5 mL) and acetonitrile (3x5 mL) to remove soluble impurities. The product was dried in vacuum to provide the product (262.4 mg, 81 %) as an orange-brown solid. 4H NMR (500 MHz, DMSO-de, 25 °C): d = 7.47 (s, 1H, ArH), 2.48 (s, 3H, CH3) ppm. 13C NMR (126 MHz, DMSO-ds, 25 °C): d = 187.2, 180.2, 165.1, 163.8, 159.5, 151.8, 133.3, 132.0, 120.4, 111.8, 110.0, 101.3, 84.1, 82.5, 29.3 ppm. IR: 3359, 1614, 1377, 1236, 1111, 1043 cm4. HRMS (ESI-): m/z calcd for Ci5H7l305 646.7355 [M-H] , found: 646.7380 [M-H] .
1.2.6. l,3-dibromo-2,4,5-trihydroxy-7-methylanthracene-9,10-dione (E-2Br).
To a stirred solution of emodin (135 mg, 0.5 mmol) in TFE (5 mL) was added HBr (48 %, 2.5 mmol) and 30 % H2O2 (313 pL, 4 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC (CH2Cl2:EtOH=100:l). After completion of the reaction, the reaction mixture was washed with NaHS03 and extracted with CH2CI2 (3x30 mL). The organic layer was washed with water (1x30 mL), dried over anhydrous Na3S04 and evaporated under vacuum. The crude reaction product was washed with hexane (5 mL) and acetonitrile (5 mL) to remove soluble impurities. The product was dried in vacuum to provide the product (194.7 mg, 91 %) as an orange solid. 4H NMR (500 MHz, DMSO-ds, 25 °C): d = 7.42 (d, J = 0.6 Hz, 1H, ArH), 7.09 (d, J = 0.6 Hz, 1H, ArH), 2.40 (s, 3H, CH3) ppm. 13C NMR (126 MHz, DMSO-ds, 25 °C): d = 188.8, 181.2, 161.1,
160.7, 149.2, 134.0, 130.5, 123.9, 121.1, 113.2, 110.6, 106.6, 105.7, 67.5, 22.1 ppm. IR: 3346, 1664, 1376, 1289, 1250, 1213, 1114 cm4. HRMS (ESI-): m/z calcd for CisHgB^Os 424.8666 [M-H] , found: 424.8667 [M-H] .
1.2.7 l,3,6,8-tetrabromo-2,4,5-trihydroxy-7-methylanthracene-9,10-dione (E-4Br).
/V-Bromosuccinimide (890 mg, 5.0 mmol) was added to a solution of emodin (270 mg, 1.0 mmol) in THF (5 mL) and stirred for 24 h at 60 °C. After completion of the reaciton, the reaction mixture was extracted with ethyl acetate (3x30 mL). The organic layer was dried over anhydrous Na S and the solvent was evaporated under vacuum. The crude reaction product was washed with hexane (5 mL) and acetonitrile (3x5 mL) to remove soluble impurities. The product was dried in vacuum to provide the product (486 mg, 83 %) as an orange solid. 4H NMR (500 MHz, DMSO-ds, 25 °C): d = 2.72 (s, 1H) ppm.13C NMR (126 MHz, DMSO-ds, 25 °C): d= 185.4, 183.0, 162.5, 159.5, 156.3, 147.3, 133.5, 132.5,
119.7, 115.6, 113.4, 107.9, 106.8, 103.8, 25.6 ppm. IR: 3302, 1679, 1621, 1566, 1379, 1223, 1161, 1129, 1049, 805, 760. IR: 3404, 1666, 1617, 1368, 1315, 1231, 1205, 1123, 1046 cm4. HRMS (ESI-): m/z calcd for CisHeB^Os 580.6876 [M-H] , found: 580.6886 [M-H] .
1.2.8 l,3-dichloro-2,4,5-trihydroxy-7-methylanthracene-9,10-dione (E-2CI).
To a stirred solution of emodin (135 mg, 0.5 mmol) in MeCN (5 mL) was added HCI (0.5 mL) and 30 % H O (313 pL, 4 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC (CH2Cl2:EtOH=100:l). After completion of the reaciton, the reaction mixture was washed with NaHSC and extracted with dichloromethane (3x30 mL). The organic layer was washed with water (3x20 mL), dried over anhydrous Na SC and evaporated under vacuum. The crude reaction product was washed with hexane (5 mL) and acetonitrile (5 mL) to remove soluble impurities. The product was dried in vacuum to provide the product (301.8 mg, 89 %) as an orange solid. 4H NMR (500 MHz, DMSO-ds, 25 °C): d = 7.37 (s, 1H, ArH), 7.03 (s, 1H, ArH), 2.37 (s, 3H, CHs) ppm. 13C NMR (126 MHz, DMSO-ds, 25 °C): d = 185.0, 182.0, 165.6, 160.7, 160.2, 147.2, 133.9, 127.5, 123.4, 122.3, 120.3, 113.5, 112.6, 104.2, 22.0 ppm. IR: 3312, 1622, 1536, 1379, 1199, 1162, 1100 cm4. HRMS (ESI-): m/z calcd for C H CI O 336.9676 [M-H] , found: 336.9686 [M-H] .
1.3 Results and discussion
We developed a simple and effective method to isolate emodin (E-H) from the rhizomes of the Japanese knotweed. The roots of Japanese knotweed were harvested in the Ljubljana area. The roots were first rinsed with water, dried and chopped to 4 mm. The starting material of the real sample was extracted overnight in organic solvent dichloromethane, filtrated and evaporated on vacuum. After extraction we obtain a yellow coloured extract with a yield of 4 %. Pure yellow emodin was isolated by column chromatography with 0,52 % yield relative to the initial biomass or 13 % yield relative to the extract. We determined the amount of emodin in the extract by 1H NMR spectroscopy. We have found that the extract contains 15 % emodin.
The natural product emodin offers an entry point for the introduction of different functional groups. We investigated nitration, halogenation (bromination, chlorination) and sulfonation. The structures of emodin and emodin derivatives are shown in Figure 2.
The synthetic route to access modified emodin from emodin is shown in Figure 3. We prepared a nitrated product with four NO2 functional groups using the standard procedure in the presence of FI2SO4 and FINO3. Nitro emodin was synthesized with a good yield of 91 %. Sulfonated product with a sulfonyl group was prepared from a mixture of emodin and oleum in 24 hours. Flalogenated emodins are biologically activated molecules. We synthesized tetrabromo emodin using NBS reagents in TH F in up to 83 % isolated yield. The dichloro emodin was formed and isolated in 71 % yield by treating emodin with NCS in TH F as solvent. All compounds were fully characterized by 1FI and 13C NMR spectroscopy, FIRMS and IR spectroscopy. The chemical structures and the positions of the functional groups on aromatic rings were confirmed by 2D NMR spectroscopy (FISQC and HMBC).
Example 2 - Dyeing and colour measurement 2.1 Dyeing
Dyeing of wool (WO) and polyamide (PA) fabrics was performed in laboratory dyeing machine for exhaust dyeing at three temperatures 60, 80 and 95 °C, at liquor to goods ratio 40:1, for 30 min. The concentration of each dye was 0.125 g/l. After dyeing, the samples were washed with distilled water and dried at room temperature.
2.2 Durability to domestic washing
Wash fastness test of dyed samples was performed in a laboratory washing machine Gyrowash according to the ISO 105-C06:2010 standard method. The samples were washed repetitively five times at 40 °C for 45 min. The washing solution contained 4 g/l of SDC standard detergent. After washing, the samples were rinsed twice for 1 min in distilled water at 40 °C and then air dried at room temperature.
2.3 Colour measurements
The colour (CIELAB values) of dyed samples was measured on reflectance spectrophotometer (Datacolor Spectraflash SF 600 PLUS-CT). All measurements were performed using 4 layers of fabric with a 3 mm aperture, wherein the specular component was included under D65 illumination and 10° standard observer. An average of ten measurements was recorded on each sample. Colour difference (AEat,*) between unwashed and washed samples was calculated according to equation 1:
Where AL* is a difference in lightness component, Aa* is a difference in red-green component and Ab* is a difference in blue-yellow component.
2.4 Results and discussion
Different textile substrates were dyed at different temperatures with emodin and its modifications. As textile materials we used cotton (CO), polyester (PES), wool (WO) and polyamide (PA). All materials were dyed at three different temperatures of 60, 80 and 95 °C for 30 minutes. Brominated (E-4Br) and chlorinated (E-CI) emodin were also dyed at 20 °C. The results of dyeing textile materials with colorants E-H, E-N02 and E-S03H show that polyester had a poor adsorption capacity against all three dyes. Cotton had good adsorption to emodin (E-H), while it had poor adsorption to nitrated emodin (E-N02) and sulfonated emodin (E-S03H). For this reason, the CO and PES samples were not measured for color and no tests were performed.
All dyes had excellent adsorption on wool (WO) and polyamide (PA) (data not shown). By using emodin and its derivatives we obtained textiles of different colors. With yellow emodin (E-H) we obtained an orange coloration on textile material, with orange nitrated emodin (E-N02) we
obtained violet, with black sulfonated emodin (E-S03H) we obtained a brown coloration, with orange bominated product (E-4Br) we obtained a pink and violet coloration and with yellow chlorinated emodin (E-CI) we also observed a pink and violet coloration on wool and polyamide. shows that the dyeing temperature increases the color shade of dyed samples. Dyed samples become darker at 95 °C, which is visible from decreased CIEL* value.
The samples of WO and PA were measured for their color (on reflectance spectrometer Datacolor) before and after repetitive domestic washing (5-times) at 40 °C for 45 minutes. Table 1 and Table 2 summarize the color values of wool and polyamide fabrics dyed before and after five domestic washings. The durability to washing was good, especially on PA samples. In general, the washing fastness results were acceptable for all five dyes.
Table 1. CIELAB colour values of wool (WO) and polyamide (PA) fabrics dyed at three temperatures (60, 80 and 95 °C) with emodin (E-H), nitrated emodin (E-N02), sulfonated emodin (E-S03H), brominated emodin (E-4Br) and chlorinated emodin (E-CI) dyes.
Table 2. CIELAB colour values of wool (WO) and polyamide (PA) fabrics dyed at three temperatures (60, 80 and 95 °C) with emodin (E-H), nitrated emodin (E-N02), sulfonated emodin (E-S03H), brominated emodin (E-4Br) and chlorinated emodin (E-CI) dyes after five domestic washings.
Yellow colored emodin was isolated from rhizomes of the Japanese knotweed. Four dyes were prepared from emodin, a yellow compound. The aromatic rings of emodin was chemically modified by nitration, sulfonation, chlorination and bromination. Emodin and its derivatives are the source of a wide range of colors (from yellow, orange, violet, red to brown-black). Various textile substrates (cotton, polyester, wool and polyamide) were dyed with emodin and with emodin derivatives. Polyester had a low adsorption capacity against all dyes. Cotton had good adsorption capacity for emodin, whereas it had a poor one for nitrated and sulfonated emodin. All dyes had excellent absorption on wool and polyamide. The samples of wool and polyamide were measured for color before and after repetitive domestic washing. Wool and polyamide dyed with the natural dye emodin and emodin modifications have a very good washing stability. The results show that natural dyes (emodin and its modifications) are suitable for dyeing various textile materials, preferably wool and polyamide.
Example 3 - Antimicrobial activity 3.1. Antibacterial activity of emodin and emodin derivatives
Antimicrobial assay:
MICs of the tested compound were determined by broth microdilution, according to CLSI guidelines [17]. Plates were incubated at 35 °C for 20 h and read visually. MICs were defined at the lowest concentration of antimicrobial agent inhibiting visible growth. For every species, and for the whole
of organisms, MIC50 and MIC90 values were defined as the concentration inhibiting 50 % and 90 % of the corresponding numbers of tested strains.
Table 3. Antibacterial activity of emodin and emodin derivatives in pg/ml on different microorganisms.
The above results show that compounds E-H and E-4Br are the most active. Emodin E-H showed antibacterial activity against S. aureus MRSA and different strains of S. aureus and E. faecalis. Emodin E-4Br showed potent antibacterial activity against S. aureus MRSA and different strains of S. aureus and E. faecalis.
3.2. Determination of antibacterial activity of fabric samples coated with emodin
For the determination of antibacterial activity of wool and polyamide samples functionalized with emodin, strains Escherichia coli ATCC11229 and Staphylococcus aureus ATCC 25923 were used.
Antimicrobial assay:
For the determination of antibacterial activity of wool and polyamide samples coated with emodin, the strain Staphylococcus aureus ATCC 25923 was used. The Gram-positive bacteria S. aureus was transferred from TSA plate (Tryptic soy agar) to TSB liquid media (Tryptic soy broth) and cultivated overnight at 37°C, 100 rpm. Wool and polyamide samples functionalized with emodin were cut in 0,5 cm squares and placed in 96 well microtiter plate followed by UV sterilization for 15 min on each side. The overnight culture of S. aureus was adjusted with PBS to an optical density at 600nm 0,1 which corresponds to an initial concentration of lxlO5 cells/mL. 200 pL of cell suspension was added to each well and the microtiter plate was incubated for 18h, at 37°C, 300 rpm. After incubation serial dilutions have been performed and 10 pL of each dilution was spoted on agar plate (spot assay). Plates were incubated at 37°C, 24h and based on dilutions and colony enumeration on TSA agar, CFU (colony forming units) per mL was calculated.
Reduction of Staphylococcus aureus growth on wool samples functionalized with emodin
Table 4: LogioCFU/mL after 18 hours incubation of S. aureus in presence of wool samples coated with emodin. * indicates significant differences among groups according to Anova test. The significance level adopted was 5%.
Reduction of Staphylococcus aureus growth on polyamide samples functionalized with emodin
Table 5: LogioCFU/mL after 18 hours incubation of S. aureus in presence of polyamide samples functionalized with emodin. * indicates significant differences among groups according to Anova test. The significance level adopted was 5%.
The above results show that the antibacterial activity of emodin derivatives is preserved when they are used as dyes for textile. Polyamide textile dyed with emodin derivatives showed the highest antibacterial activity with the broader structural set of emodin derivatives.
Example 4 - Antiviral activity
Activity of emodin and emodin derivatives against human coronavirus NL63
Emodin and emodin derivatives were tested against human coronavirus NL63. The activity of 11 compounds against human corona virus HCoV-NL63. In parallel, the effect of compounds on viability of Vero cells was also assessed. Results were expressed as IC50 values in mM.
Viral infection
Vero cells, in EMEM medium supplemented with 10% FBS, were seeded into inner wells of 96-well white plates at 20,000 cells/well concentration. The next day, medium was removed and replaced with 50pL or lOOpL of EMEM with 2% FBS. 100 nL of compounds were added to wells using Mosquito pipetting device. Plates with 100 pL of medium werejncubated for 4 days at 33°C, 5% CO2, for cell viability assessment. To the plates in which 50 pL of the medium was added additional 50pL of medium with 5 times diluted FICoV-NL63 viral stock was added. Plates were then incubated for 4 days at 33°C, 5% CO2. Cell viability assessment
After 4days of incubation, 50 pL/well of Cyto Tox-Fluor reagent was added to the plates infected with FICoV-NL63 virus. Plates were incubated for 1 hour and dead-cell protease activity was measured by measurement of fluorescent product (480/520) using Spectra Max i3 instrument. In parallel, to the plates used for Vero cell viability assessment, 50pL/well of Cell Titer-Glo Luminescent reagent was added and luminescence proportional to ATP cell content was measured after 5 minutes of incubation, using Spectra Max i3 instrument.
Anti-viral effects of the compounds were expressed as % of live cells when compared to cells with and without virus added. IC50 values were calculated using GraphPad Prism 8 software.
The results of the two parallels (NL63_1 and NL63_2) are shown in Table 6 below. Remdesivir and chloroquine were used as standards.
Table 6. Anti HCoV-NL63 effects of tested compounds (IC50 in mM)
The above results show that emodin derivatives show sub-micromolar IC5o values against HCoV- NL63 with the best candidates being more potent than remdesivir.
List of references cited in the description
1. Bechtold, T., Natural Colorants - Quinoid, Naphthoquinoid and Anthraquinoid Dyes. 2009; pp 151-182.
2. Izhaki, I., Emodin - a secondary metabolite with multiple ecological functions in higher plants. New Phytologist 2002, 155 (2), 205-217.
3. Chen, H. G.; Tuck, T.; Ji, X. H.; Zhou, X.; Kelly, G.; Cuerrier, A.; Zhang, J. Z., Quality Assessment of Japanese Knotweed (Fallopia japonica) Grown on Prince Edward Island as a Source of Resveratrol. J. Agric. Food Chem. 2013, 61 (26), 6383-6392.
4. Benova, B.; Adam, M.; Pavlikova, P.; Fischer, J., Supercritical fluid extraction of piceid, resveratrol and emodin from Japanese knotweed. J. Supercrit. Fluids 2010, 51 (3), 325-330.
5. Dong, X.; Fu, J.; Yin, X.; Cao, S.; Li, X.; Lin, L.; Huyiligeqi; Ni, J., Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics. Phytotherapy Research 2016, 30 (8), 1207- 1218.
6. Hsu, S.-C.; Chung, J.-G., Anticancer potential of emodin. BioMedicine 2012, 2 (3), 108-116.
7. Bashtanova, U. B.; Beckett, K. P.; Flowers, T. J., Review: Physiological Approaches to the Improvement of Chemical Control of Japanese Knotweed (Fallopia japonica). Weed Sci. 2009, 57 (6), 584-592.
8. Cororaton, C.; Orden, D.; Peterson, E., A Review of Literature on the Economics of Invasive Species. 2009.
9. Kumar Rai, P.; Singh, J. S., Invasive alien plant species: Their impact on environment, ecosystem services and human health. Ecological Indicators 2020, 111, 106020.
10. Nambela, L.; Haule, L. V.; Mgani, Q., A review on source, chemistry, green synthesis and application of textile colorants. J. Clean Prod. 2020, 246, 14.
11. Yusuf, M.; Shabbir, M.; Mohammad, F., Natural Colorants: Historical, Processing and Sustainable Prospects. Natural Products and Bioprospecting 2017, 7 (1), 123-145.
12. Indumathy, K.; Kannan, K. P., Eco-benign fungal colorants: sources and applications in textiles. J. Text. Inst., 7.
13. Gordon, P. F.; Gregory, P., Anthraquinone Dyes. In Organic Chemistry in Colour, Gordon, P. F.; Gregory, P., Eds. Springer Berlin Heidelberg: Berlin, Heidelberg, 1987; pp 163-199.
14. Raisanen, R.; Nousiainen, P.; Hynninen, P. H., Emodin and dermocybin natural anthraquinones as mordant dyes for wool and polyamide. Text. Res. J. 2001, 71 (11), 1016- 1022.
Raisanen, R.; Nousiainen, P.; Hynninen, P. H., Emodin and dermocybin natural anthraquinones as high-temperature disperse dyes for polyester and polyamide. Text. Res. J. 2001, 71 (10), 922-927. Wu, J.; Ke, J., Dyeability of PLA Fabric with Natural Dye Emodin. Advanced Materials Research 2011, 183-185, 2000-2004. CLSI, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - CLSI document M07-A8, 8th ed., Clinical and Laboratory Standards Institute, Wayne, PA, 2009.
Claims
1. An emodin derivative of general structure (I)
wherein
Ri is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R2 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; R3 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; and
R4 is selected from the group consisting of hydrogen, halogen, NO2, SO3H and COOR with R being H, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; with the proviso that at least one of Ri, R2, R3 and R4 is not hydrogen.
2. The emodin derivative according to claim 1, wherein Ri is halogen.
3. The emodin derivative according to claim 1 or 2, wherein R2 is halogen or hydrogen.
4. The emodin derivative according to claim 1 or 2, wherein R2 is halogen.
5. The emodin derivative according to any one of claims 1 to 4, wherein R3 is halogen or hydrogen.
6. The emodin derivative according to any one of claims 1 to 4, wherein R3 is halogen.
7. The emodin derivative according to any one of claims 1 to 6, wherein R4 is halogen or hydrogen.
8. The emodin derivative according to any one of claims 1 to 7, wherein R4 is halogen.
9. The emodin derivative according to claims 1 to 7, wherein R4 is hydrogen.
10. The emodin derivative according to claim 1, wherein Ri is bromo, R2 is bromo or hydrogen, R3 is bromo or hydrogen, and R4 is bromo or hydrogen.
11. The emodin derivative according to claim 1, wherein Ri is bromo, R2 is bromo, R3 is bromo or hydrogen, and R4 is bromo or hydrogen.
12. The emodin derivative according to claim 1, wherein Ri is bromo, R2 is bromo, R3 is bromo, and R4 is bromo.
13. The emodin derivative according to claim 1, wherein Ri is bromo, R2 is bromo, R3 is hydrogen, and R4 is hydrogen.
14. The emodin derivative according to claim 1, wherein Ri is chloro, R2 is chloro or hydrogen, R3 is chloro or hydrogen, and R4 is chloro or hydrogen.
15. The emodin derivative according to claim 1, wherein Ri is chloro, R2 is chloro, R3 is chloro or hydrogen, and R4 is chloro or hydrogen.
16. The emodin derivative according to claim 1, wherein Ri is chloro, R2 is chloro, R3 is chloro, and R4 is chloro.
17. The emodin derivative according to claim 1, wherein Ri is chloro, R2 is chloro, R3 is hydrogen, and R4 is hydrogen.
18. The emodin derivative according to claim 1, wherein Ri is iodo, R2 is iodo or hydrogen, R3 is iodo or hydrogen, and R4 is iodo or hydrogen.
19. The emodin derivative according to claim 1, wherein Ri is iodo, R2 is iodo, R3 is iodo or hydrogen, and R4 is iodo or hydrogen.
20. The emodin derivative according to claim 1, wherein Ri is iodo, R2 is iodo, R3 is iodo, and R4 is hydrogen.
21. The emodin derivative according to claim 1, wherein Ri is iodo, R2 is hydrogen, R3 is hydrogen, and R4 is hydrogen.
22. The emodin derivative according to claim 1, wherein Ri is NO2, R2 is NO2 or hydrogen, R3 is NO2 or hydrogen, and R4 is NO2 or hydrogen.
23. The emodin derivative according to claim 1, wherein Ri is NO2, R2 is NO2, R3 is NO2 or hydrogen, and R4 is NC or hydrogen.
24. The emodin derivative according to claim 1, wherein Ri is NO2, R2 is NO2, R3 is NO2, and R4 is NC or hydrogen.
25. The emodin derivative according to claim 1, wherein Ri is NO2, R2 is NO2, R3 is NO2, and R4 is NO2.
26. The emodin derivative according to claim 1, wherein Ri is SO3H or hydrogen, R2 is SO3H or hydrogen, R3 is SO3H or hydrogen, and R4 is SO3H.
27. The emodin derivative according to claim 1, wherein Ri is SO3H or hydrogen, R2 is SO3H or hydrogen, R3 is SO3H, and R4 is SO3H.
28. The emodin derivative according to claim 1, wherein Ri is SO3H or hydrogen, R2 is SO3H, R3 is SO3H or hydrogen, and R4 is SO3H.
29. The emodin derivative according to claim 1, wherein Ri is SO3H, R2 is SO3H or hydrogen, R3 is SO3H or hydrogen, and R4 is SO3H.
30. The emodin derivative according to any one of claims 1 to 29 for use in medicine.
31. The emodin derivative according to any one of claims 1 to 29 for use in the treatment of an infection.
32. The emodin derivative for use according to claim 31, wherein the infection is a bacterial infection.
33. The emodin derivative for use according to claim 31, wherein the infection is a viral infection.
34. The emodin derivative for use according to claim 33, wherein the viral infection is coronavirus infection.
35. Pharmaceutical composition comprising at least one emodin derivative according to any one of claims 1 to 29 and at least one pharmaceutically acceptable excipient and/or carrier.
36. Textile comprising at least one emodin derivative according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 35.
37. Use of an emodin derivative according to any one of claims 1 to 29 as a dye, such as a textile dye.
38. Use of an emodin derivative according to any one of claims 1 to 29 as a color sensor.
39. Use of an emodin derivative according to any one of claims 1 to 29 for detecting inflammation of wounds based on the change of pH.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116172994A (en) * | 2023-04-28 | 2023-05-30 | 四川大学华西医院 | Application of anthraquinone derivative in preparation of anti-pancreatitis medicine |
| CN116172994B (en) * | 2023-04-28 | 2023-07-04 | 四川大学华西医院 | Application of anthraquinone derivative in preparation of anti-pancreatitis medicine |
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