WO2020242051A1 - Composé, composition comprenant un composé et procédé de thérapie photodynamique pour inactiver ou tuer des cellules tumorales à l'aide de la composition - Google Patents

Composé, composition comprenant un composé et procédé de thérapie photodynamique pour inactiver ou tuer des cellules tumorales à l'aide de la composition Download PDF

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WO2020242051A1
WO2020242051A1 PCT/KR2020/005090 KR2020005090W WO2020242051A1 WO 2020242051 A1 WO2020242051 A1 WO 2020242051A1 KR 2020005090 W KR2020005090 W KR 2020005090W WO 2020242051 A1 WO2020242051 A1 WO 2020242051A1
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substituted
unsubstituted
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formula
compound
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윤주영
응웬반응이어
치수지
권나현
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주식회사 키텍바이오
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • It relates to a compound, a composition comprising the compound, and a photodynamic treatment method for inactivating or killing tumor cells using the composition.
  • Photodynamic therapy uses photosensitizers to absorb light of a specific wavelength and generate reactive oxygen species (ROS) through an energy transfer mechanism, and the reactive oxygen species thus generated inactivate target cells. It is a method of treating by making or killing.
  • ROS reactive oxygen species
  • One aspect is to provide novel compounds.
  • Another aspect is to provide a composition comprising the compound.
  • Another aspect is to provide a photodynamic treatment method for inactivating or killing tumor cells by using the composition.
  • R 1 , R 2 , R 6 , R 7 are independently of each other hydrogen, deuterium, hydroxy group, cyano group, nitro group, amidino group, hydrazino group, hydrazono group, substituted or unsubstituted C 1 -C 30 alkyl group , A substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, a substituted or unsubstituted C 1 -C 30 alkoxy group, a substituted or unsubstituted C 3 -C 20 Cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted C 3 -C 20 cycloalkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted a C 6
  • R 3 , R 4 , R 5 may each independently be one group selected from the groups represented by Formula 2 or Formula 3,
  • a 1 may be an oxygen (O) or sulfur (S) atom
  • R 8 in Formula 2 is hydrogen, deuterium, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted Or an unsubstituted C 1 -C 30 alkoxy group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 3 -C 20 cyclo Alkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted C 6 -C 50 aryl group, substituted or unsubstituted C 6 -C 50 aryloxy group, substituted or unsubstituted It may
  • a 2 may be a nitrogen (N) atom
  • R 9 and R 10 in Formula 3 are i) independently of each other hydrogen, deuterium, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted or unsubstituted C 1 -C 30 alkoxy group, substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted A substituted C 3 -C 20 cycloalkenyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, a substituted or unsubstituted C 6 -C 50 aryl group, a substituted or unsubstituted C 6 -C 50 aryl It may
  • compositions comprising one or more selected from solvents, acids, bases, and buffer solutions.
  • Irradiating with excitation light of an absorbable wavelength on the biological tumor cells in which the compound or a pharmaceutically acceptable salt thereof has been dispensed may include,
  • the composition provides a photodynamic treatment method for inactivating or killing tumor cells by generating reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • the compound according to an aspect provides a thionaphthalimide-based compound having an electron donating substituent at a specific position.
  • the composition comprising the thionaphthalimide-based compound or a pharmaceutically acceptable salt thereof is in a hypoxia state (hypoxia, 1% O 2 ), and in a normal state (normoxia, 20% O 2 ) effectively active oxygen species (ROS ) Can provide a photosensitizing agent. Therefore, the composition can provide a photodynamic treatment method for inactivating or killing tumor cells.
  • FIG. 1 schematically shows a mechanism that acts during photodynamic therapy for a composition according to an embodiment.
  • FIG. 2 schematically shows the progress of an intersystem crossing (ISC) process from a singlet excited state to a triplet excited state for the MANI-S compound prepared in Synthesis Example 2 I did it.
  • ISC intersystem crossing
  • FIG. 3 schematically shows a process in which the MANI-S compound prepared in Synthesis Example 2 is dissolved in water to form a self-assembled nanostructure, and is decomposed upon contact with a target protein.
  • FIG. 4A is an SEM image of a self-assembled nanostructure formed from a composition (10 ⁇ M) dissolved in water of the MANI-S compound prepared in Synthesis Example 2.
  • FIG. 4A is an SEM image of a self-assembled nanostructure formed from a composition (10 ⁇ M) dissolved in water of the MANI-S compound prepared in Synthesis Example 2.
  • Figure 4b is a composition diluted to 10 ⁇ M by adding water to a mixture obtained by dissolving the MANI-S compound prepared in Synthesis Example 2 in dimethyl sulfoxide (DMSO) after 30 minutes and aging in the dark for 1 week After that, each of the dynamic light scattering (DLS) analysis results.
  • DMSO dimethyl sulfoxide
  • FIG. 5A shows the NI-O compound, the NI-S compound, the MONI-O compound, the MONI-S compound, and the MANI-O compound and the MANI-S compound used or prepared in Synthesis Example 2 This is the result of analyzing the UV/Vis absorption spectrum for each composition (10 ⁇ M) dissolved in a toluene solvent.
  • Figure 6a is a 30 ⁇ M 2',7'-dichlorofluorescein diacetate (DCFH-DA) aqueous solution control sample (control), 10 ⁇ M methylene blue aqueous solution sample (MB), the MANI-S compound prepared in Synthesis Example 2
  • DCFH-DA aqueous solution control sample
  • MB 10 ⁇ M methylene blue aqueous solution sample
  • the 10 ⁇ M MANI-S self-assembled nanostructure-containing aqueous solution sample (NanoMANI-S) dissolved in DCFH-DA and diluted with water, and the 10 ⁇ M MANI-S self-assembled nanostructure-containing aqueous solution sample (NanoMANI-S) were added to albumin (albumin).
  • Figure 6b is a 50 ⁇ M dihydroethidium (DHE) aqueous solution control sample (control), 10 ⁇ M methylene blue aqueous solution sample (MB), 10 ⁇ M MANI obtained by dissolving the MANI-S compound prepared in Synthesis Example 2 in DHE and diluting with water.
  • DHE dihydroethidium
  • MB methylene blue aqueous solution sample
  • DMSO dimethylsulfoxide
  • albumin albumin
  • Figure 7 (a), (b) is a dark state, hypoxic state (hypoxia, 1% O 2 ), and after incubation for 16 hours in a normal state (normoxia, 20% O 2 ) 0 ⁇ M, 0.125 ⁇ M, 0.25 ⁇ M, 0.50 ⁇ M concentration of methylene blue (MB) and the MANI-S compound prepared in Synthesis Example 2 were cultured for 2 hours each, and the hypoxia state (1% O 2 ) environment, and normal state (20% O 2 ) HeLa cells cultured under the environment were irradiated with a white light source (0.1 W/cm 2 halogen lamp) for 10 minutes, and then the survival rate of HeLa cells cultured for 24 hours was measured by MTT (3-(4, 5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay results;
  • MTT 3-(4, 5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazol
  • pharmaceutically acceptable salt is a concentration that is relatively non-toxic and harmless to patients, and side effects caused by this salt are represented by Formula 1, which does not degrade the beneficial efficacy of the compound represented by Formula 1. It means any organic or inorganic addition salt of a compound.
  • inorganic acids and organic acids can be used as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc.
  • inorganic acids can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fu Marine acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethane Sulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid, and the like can be used.
  • these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salt (calcium salt, magnesium salt, etc.), and the like.
  • alkali metal salts sodium salt, potassium salt, etc.
  • alkaline earth metal salt calcium salt, magnesium salt, etc.
  • the compound according to an embodiment may be represented by the following Formula 1:
  • R 1 , R 2 , R 6 , R 7 are independently of each other hydrogen, deuterium, hydroxy group, cyano group, nitro group, amidino group, hydrazino group, hydrazono group, substituted or unsubstituted C 1 -C 30 alkyl group , A substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, a substituted or unsubstituted C 1 -C 30 alkoxy group, a substituted or unsubstituted C 3 -C 20 Cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted C 3 -C 20 cycloalkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted a C 6
  • R 3 , R 4 , R 5 may each independently be one group selected from the groups represented by Formula 2 or Formula 3,
  • a 1 may be an oxygen (O) or sulfur (S) atom
  • R 8 in Formula 2 is hydrogen, deuterium, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted Or an unsubstituted C 1 -C 30 alkoxy group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 3 -C 20 cyclo Alkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted C 6 -C 50 aryl group, substituted or unsubstituted C 6 -C 50 aryloxy group, substituted or unsubstituted It may
  • a 2 may be a nitrogen (N) atom
  • R 9 and R 10 in Formula 3 are i) independently of each other hydrogen, deuterium, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted or unsubstituted C 1 -C 30 alkoxy group, substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted A substituted C 3 -C 20 cycloalkenyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, a substituted or unsubstituted C 6 -C 50 aryl group, a substituted or unsubstituted C 6 -C 50 aryl It may
  • the C 3 -C 50 CY1 heterocyclic group of Formula 3 may be a group represented by any one of the following Formulas 3-1 to 3-20:
  • R 1 is a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, a substituted or unsubstituted A C 1 -C 30 alkoxy group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 3 -C 20 cycloalkenyl group, A substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, a substituted or unsubstituted C 6 -C 50 aryl group, a substituted or unsubstituted C 6 -C 50 aryloxy group, a substituted or unsubstituted
  • Each of R 2 , R 6 , and R 7 may be hydrogen.
  • a 1 may be an oxygen (O) atom
  • R 8 is a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted or unsubstituted C 1 -C 30 alkoxy group, substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted Or an unsubstituted C 3 -C 20 cycloalkenyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, a substituted or unsubstituted C 6 -C 50 aryl group, a substituted or unsubstituted C 6 -C 50 aryloxy group, a substituted or or un
  • the R 9 and R 10 are i) independently of each other a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted or unsubstituted C 1 -C 30 alkoxy group, substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted C 3 -C 20 cycloalkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted C 6 -C 50 aryl group, substituted or unsubstituted C 6 -C 50 aryloxy group, It may be a substituted or unsubstituted C 1
  • R 9 and R 10 are i) independently of each other a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 6 -C 50 aryl group, a substituted or unsubstituted C 6 -C 50 aryloxy group, a substituted or unsubstituted C 6 -C 50 arylthio group, a substituted or unsubstituted a C 1 -C 50 heteroaryl group, or is a combination thereof, ii) R 9 is a C (R '1) and R 10 is C (R' 2), wherein the R '1 and R' 2 combined with each other C 3 -C 30 CY1 may form a heterocyclic group.
  • R 3 and R 5 may each be hydrogen, and R 4 may be one group selected from groups represented by Formula 2 or Formula 3.
  • the compound may be a compound represented by the following Formula 1-1:
  • R a is a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, a substituted or unsubstituted C 1 -C 30 alkoxy group, substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted C 3 -C 20 cycloalkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted C 6 -C 50 aryl group, substituted or unsubstituted C 6 -C 50 aryloxy group, substituted or unsubstituted C 6 -C 50 arylthio group , A
  • R b may be one group selected from groups represented by Formula 2-1 or Formula 3-1,
  • R c is hydrogen, deuterium, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group , A substituted or unsubstituted C 1 -C 30 alkoxy group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 3 -C 20 Cycloalkenyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, substituted or unsubstituted C 6 -C 50 aryl group, substituted or unsubstituted C 6 -C 50 aryloxy group, substituted or unsubstituted
  • R d and R e are independently of each other hydrogen, deuterium, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 2 -C 30 alkenyl group, a substituted or unsubstituted C 2 -C 30 alkynyl group, substituted or unsubstituted C 1 -C 30 alkoxy group, substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 1 -C 20 heterocycloalkyl group, substituted or unsubstituted A substituted C 3 -C 20 cycloalkenyl group, a substituted or unsubstituted C 1 -C 20 heterocycloalkenyl group, a substituted or unsubstituted C 6 -C 50 aryl group, a substituted or unsubstituted C 6 -C 50 aryl It may
  • the compound may be one of the following compounds 1 or 2:
  • R 3 , R 4 , and R 5 in Formula 1 are each independently selected from a group represented by Formula 2 or Formula 3, that is, a thionaph having an electron donating substituent It may be a deimide-based compound.
  • the compound represented by Formula 1 may have one group selected from the groups represented by Formula 2 or Formula 3, that is, an electron donating substituent.
  • the thionaphthalimide-based compound or a pharmaceutically acceptable salt thereof is included in the composition and can selectively act on tumor cells, and in a hypoxic state (hypoxia, 1% O 2 ), and a normal state (normoxia, 20% O 2 ), it is possible to provide a photosensitizer capable of effectively generating reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • composition according to another embodiment may include the above-described compound or a pharmaceutically acceptable salt thereof, and at least one selected from a solvent, an acid, a base, and a buffer solution.
  • the composition may be prepared by adding the above-described compound to a solvent, a buffer solution, or a mixture thereof, and then adding an acid and/or a base thereto.
  • the composition may additionally contain other additives that can be used in the art.
  • the content of the solvent, acid, base, and buffer solution contained in the composition may be appropriately adjusted according to the required performance.
  • the solvent may include water, THF, methanol, ethanol, HI aqueous solution, or a polar solvent such as N, N-dimethylformamide.
  • the composition may be mixed with a sample.
  • the sample may be a biological sample including at least one selected from microorganisms, cells, and tissues, but is not necessarily limited thereto, and any sample that can be used as a biological sample in the art may be used. Do.
  • the compound or a pharmaceutically acceptable salt thereof may be an organelle targeting agent that targets intracellular organelles.
  • the organelle targeting agent can target tumor cells. These organelle targeting agents can have superior water solubility compared to conventional untargeted compounds. Therefore, the compound or a pharmaceutically acceptable salt thereof can increase the efficiency of tumor cell removal in vivo within a shorter time and avoid dark toxicity.
  • the compound or a pharmaceutically acceptable salt thereof is chemically stable and may have excellent spectroscopic properties, for example, photoluminescence (PL)/UV/Vis absorption spectrum and quantum yield.
  • PL photoluminescence
  • FIG. 1 schematically shows a mechanism that acts during photodynamic therapy for a composition according to an embodiment.
  • the composition absorbs photons (energy) from light when exposed to light of a specific wavelength, for example, in a wavelength range of 650 nm to 1250 nm, and is excited from a ground state (singlet state) (triple State).
  • the composition can then relax to its ground state in three ways, such as via non-radioactive decay, by photon emission and/or by energy transfer.
  • the detectable result of emitting a photon can be detected with a fluorescence emission spectrum.
  • the conversion of energy generates reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • composition in accordance with one embodiment, the substrate, for example, by reaction directly with the cell membrane or molecular drag e naemeurosseo superoxide anion radical - hydroxyl radicals to form or to transfer electrons or hydrogen atoms ((O 2)
  • Type I photodynamic reactions that generate free radicals by forming OH * ) and/or peroxide radicals (OOH * ) and Type I photodynamics reactions that generate singlet oxygen ( 1 O 2 ) by transferring energy directly to the substrate are have.
  • the compound or a pharmaceutically acceptable salt thereof may generate reactive oxygen species (ROS) in normal oxygen (normoxia) and hypoxia (hypoxia) conditions, thereby treating or preventing tumors.
  • ROS reactive oxygen species
  • the compound or a pharmaceutically acceptable salt thereof can treat or prevent a tumor by a Type I photodynamic reaction that generates free radicals and a Type I photodynamic reaction that generates singlet oxygen ( 1 O 2 ) . .
  • the tumor is selected from breast cancer, kidney cancer, testicular cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, fallopian tube cancer, rectal cancer, lung cancer, gastric cancer, liver cancer, esophageal cancer, small intestine cancer, pancreatic cancer, oral cancer, melanoma, or sarcoma. It can be.
  • FIG. 2 schematically shows the progress of an intersystem crossing (ISC) process from a singlet excited state to a triplet excited state for the MANI-S compound prepared in Synthesis Example 2 I did it.
  • ISC intersystem crossing
  • the LUMO-HOMO energy gap of the compound according to an embodiment, that is, the MANI-S compound prepared in Synthesis Example 2 is reduced, so that the triplet excited state is in a singlet excited state. state) shows that the intersystem crossing (ISC) process is promoted.
  • ISC intersystem crossing
  • the compound or a pharmaceutically acceptable salt thereof may form a self-assembled nanostructure in a solvent, acid, base, or buffer solution, and may be decomposed upon contact with a target protein.
  • FIG. 3 schematically shows a process in which the MANI-S compound prepared in Synthesis Example 2 is dissolved in water to form a self-assembled nanostructure, and is decomposed upon contact with a target protein.
  • the compound according to an embodiment that is, the MANI-S compound prepared in Synthesis Example 2
  • the self-assembled nanostructures may have a mean size of about 50 nm to 200 nm.
  • the self-assembled nanostructure and the target protein are contacted at a molar ratio of 1:5 or higher, the self-assembled nanostructure may be decomposed.
  • the composition may be a composition for photodynamic treatment or prevention comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the photodynamic treatment or prevention is possible by the mechanism of the Type I photodynamic reaction that generates free radicals as shown in FIG. 1 and the Type I photodynamic reaction that generates singlet oxygen ( 1 O 2 ) .
  • Photodynamic therapy comprises the steps of contacting the above-described composition with living cells or living tissues; Allowing time for the compound in the composition or a pharmaceutically acceptable salt thereof to be dispensed into biological tumor cells; And irradiating the biological tumor cells to which the compound or a pharmaceutically acceptable salt thereof is distributed with excitation light having an absorbable wavelength; including, wherein the composition generates reactive oxygen species (ROS) by generating a reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • Tumor cells can be inactivated or killed.
  • the photodynamic treatment method according to the embodiment can be usefully applied as a photodynamic treatment method because the above-described composition can be easily synthesized in a single process in both small and large scale.
  • a substituent group is derived by exchanging one or more hydrogens from another atom or functional group in an unsubstituted mother group.
  • a functional group is considered to be “substituted”, it is understood that the functional group is an alkyl group having 1 to 40 carbon atoms, an alkenyl group having 2 to 40 carbon atoms, an alkynyl group having 2 to 40 carbon atoms, a cyclo It means substituted with one or more substituents selected from an alkyl group, a cycloalkenyl group having 3 to 40 carbon atoms, and an aryl group having 7 to 40 carbon atoms.
  • a functional group is described as being “optionally substituted”, it means that the functional group may be substituted with the aforementioned substituent.
  • a and b of "carbon number a to b" mean the number of carbon atoms in a specific functional group. That is, the functional group may include carbon atoms from a to b.
  • an alkyl group having 1 to 4 carbon atoms is an alkyl group having 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, It means CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • alkyl refers to a branched or unbranched aliphatic hydrocarbon.
  • the alkyl group may or may not be substituted.
  • the alkyl group includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc. It is not necessarily limited to these, and each of them may be optionally substituted or unsubstituted.
  • the alkyl group may have 1 to 6 carbon atoms.
  • the alkyl group having 1 to 6 carbon atoms may be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, etc., but is not limited thereto.
  • alkoxy refers to an alkyl or aryl each bonded to an oxygen atom.
  • alkenyl refers to a branched or unbranched hydrocarbon having at least one carbon-carbon double bond.
  • alkenyl groups include vinyl, allyl, butenyl, isopropenyl, or isobutenyl.
  • alkynyl refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond.
  • Non-limiting examples of the alkynyl group include ethynyl, butynyl, isobutynyl, isopropynyl, and the like.
  • cycloalkyl group refers to a hydrocarbon having a general formula of C n H 2n (n is an integer) and lacking two hydrogens as terminal carbon atoms of the alkyl group are connected to each other.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl group refers to a non-aromatic monocyclic or polycyclic ring in which at least one of carbon is substituted with a heteroatom such as nitrogen, oxygen, or sulfur.
  • Non-limiting examples of the heterocycloalkyl group include aziridinyl, pyrrolidinyl, pyrrolidino, or piperidinyl.
  • cycloalkenyl group has the general formula of C n H 2n-2 (n is an integer) and is a hydrocarbon in which several carbon atoms are bonded in a ring and hydrogen is bonded to each carbon atom. It refers to a hydrocarbon that is located in the ring but is not aromatic.
  • Non-limiting examples of the cycloalkenyl group include cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • heterocycloalkenyl group refers to the term “heterocycloalkyl group”. At least one of carbons is substituted with a heteroatom such as nitrogen, oxygen, or sulfur, and several carbon atoms are bonded to each other in a ring, and each carbon It is a hydrocarbon in which hydrogen is bonded to an atom. It refers to a hydrocarbon whose double bond is located in a ring but is not aromatic
  • each ring in the system is aromatic.
  • the aryl group includes, but is not limited to, a phenyl group, a biphenyl group, a naphthyl group, a phenanthrenyl group, a naphthacenyl group, and the like.
  • the aryl group may be substituted or unsubstituted.
  • aryloxy has the general formula of -O-aryl, and aryl is the same as described above.
  • arylthio has the general formula of -S-aryl, and aryl is the same as described above.
  • heteroaryl refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from N, O, P, or S, and the remaining ring atoms are carbon. do.
  • the heteroaryl group may include, for example, 1-5 heteroatoms, and may include 5-10 ring members.
  • the S or N may be oxidized to have various oxidation states.
  • heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxa Diazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl group, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- Thiadiazolyl, 1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4- Yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4-triazol-3-yl, 1,2, 4-triazol-5-yl, 1,2,
  • hydroxy group is -OH.
  • amino group is -NH 2 .
  • cyano group is -CN.
  • nitro group is -NO 2 .
  • hydrazino group is -NHNH 2 .
  • Dynamic light scattering was measured using Nano-ZS (manufactured by Malvern).
  • the SEM image was obtained using a JSM-6700F field emission scanning electron microscope (manufactured by JEOL).
  • UV/Vis absorption and photoluminescence (PL) spectra were recorded with a Thermo Scientifiic Evolution 201 UV/VIS spectrophotometer and FS-2 spectrophotometer (manufactured by Scinco), respectively.
  • a sample solution diluted to a concentration of about 1.0 ⁇ 10 -5 M was prepared from a stock solution having a concentration of 1.0 ⁇ 10 -3 M under atmospheric conditions.
  • UV/Vis absorption and photoluminescence (PL) spectrum solutions were obtained from an organic solution of 1.0 ⁇ 10 -5 M using a 1 cm quartz cuvette.
  • the MONI-S compound of Synthesis Example 1 and the MANI-S compound of Synthesis Example 2 were synthesized according to Reaction Scheme 1 below.
  • MONI-S compound powder 0.07 g (42) using 0.14 g (0.50 mmol) of MONI-O compound and 0.61 g (Lawesson reagent, 1.5 mmol) of the MONI-O compound in a similar manner to the'(1) Synthesis of NI-S compound' % Yield) was obtained.
  • the average diameter (mean size) of the self-assembled nanostructure formed by the composition including the MANI-S compound prepared in Synthesis Example 2 exhibits almost the same distribution over time.
  • the NI-S compound, the MONI-S compound, and the MANI-S compound (“RNI-S (thionaphthalimide) compound”) prepared in Synthesis Example 2 are synthesized.
  • the maximum absorption peak is about 100 nm redshift (red- shift), and it can be seen that the molar absorption coefficient is increased.
  • DCFH-DA 2′,7′-dichlorofluorescein diacetate
  • MB 10 ⁇ M methylene blue aqueous solution sample
  • the MANI-S compound prepared in Synthesis Example 2 was DCFH-DA 10 ⁇ M MANI-S self-assembled nanostructure-containing aqueous solution sample (NanoMANI-S) dissolved in water and diluted with water, and albumin (NanoMANI) in the 10 ⁇ M MANI-S self-assembled nanostructure-containing aqueous solution sample (NanoMANI-S).
  • the samples were irradiated for 0 seconds, 30 seconds, 60 seconds, 90 seconds, and 120 seconds with a white light source (0.1 W/cm 2 halogen lamp). After irradiation with the white light source, light emission spectra were recorded with an FS-2 spectrophotometer at ⁇ ex of 504 nm and ⁇ em of 522 nm for the samples.
  • a white light source 0.1 W/cm 2 halogen lamp
  • the MANI-S self-assembled nanostructure-decomposed aqueous solution sample (Disrupted NanoMANI-S) is compared with the methylene blue aqueous solution sample (MB) and the MANI-S self-assembled nanostructure-containing aqueous solution sample (NanoMANI-S). At this time, it can be seen that the generation of reactive oxygen species (ROS) is approximately 2.4 times higher.
  • ROS reactive oxygen species
  • the MANI-S compound prepared in Synthesis Example 2 has excellent photoactivity that can be converted into a photosensitizer used for photodynamic therapy.
  • the samples were irradiated for 0 seconds, 30 seconds, 60 seconds, 90 seconds, and 120 seconds with a white light source (0.1 W/cm 2 halogen lamp). After irradiation with the white light source, light emission spectra were recorded with an FS-2 spectrophotometer at ⁇ ex of 510 nm and ⁇ em of 590 nm for the samples.
  • a white light source 0.1 W/cm 2 halogen lamp
  • the MANI-S self-assembled nanostructure is decomposed aqueous solution sample (Disrupted NanoMANI-S), when compared to the methylene blue aqueous solution sample (MB), about 3.0 times higher active oxygen ( ) It can be confirmed that it indicates that it occurs.
  • the MANI-S self-assembled nanostructure-containing aqueous solution sample (NanoMANI-S) rarely generated active oxygen.
  • DMSO dimethyl sulfoxide
  • albumin albumin
  • a sample of the decomposed aqueous solution (Disrupted NanoMANI-S, absorbance: 0.2) was prepared.
  • UV/Vis absorption spectrum analysis of 1 and 3 diphenylisobenzofuran (DPBF) was performed in the presence of the MANI-S self-assembled nanostructure-decomposed aqueous solution (Disrupted NanoMANI-S) sample. The results are shown in Fig. 6c.
  • the sample was irradiated with a white light source (0.1 W/cm 2 halogen lamp) for 0 seconds, 20 seconds, 40 seconds, 60 seconds, 100 seconds, and 120 seconds.
  • a white light source 0.1 W/cm 2 halogen lamp
  • the UV/Vis absorption spectrum of the sample was recorded with a Thermo Scientifiic Evolution 201 UV/VIS spectrometer.
  • the MANI-S compound prepared in Synthesis Example 2 from the photoluminescence (PL) spectrum and UV/Vis absorption spectrum analysis of the above (2) to (4) is excellent that can be converted into a photosensitizer used for photodynamic therapy. It has photoactivity, and active oxygen (O 2 ⁇ - ) of Type I of FIG. 1 and It can be seen that it generates Type II singlet oxygen ( 1 O 2 ) .
  • HeLa cells were incubated for 16 hours in the dark, hypoxic (hypoxia, 1% O 2 ), and steady state (normoxia, 20% O 2 ), then 0 ⁇ M, 0.125 ⁇ M, 0.25 ⁇ M, 0.50 ⁇ M
  • the concentration of methylene blue (MB) and the MANI-S compound prepared in Synthesis Example 2 were each cultured for 2 hours.
  • the cultured HeLa cells were washed with Dulbecco's phosphate-buffered saline (DPBS, manufactured by Gibco).
  • DPBS Dulbecco's phosphate-buffered saline
  • the HeLa cells cultured in the hypoxia (hypoxia) state (1% O 2 ) environment, and the steady state (20% O 2 ) environment were irradiated for 10 minutes with a white light source (0.1 W/cm 2 halogen lamp). After further incubation for 24 hours.
  • the survival rate of the HeLa cells was analyzed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay method. The results are shown in Fig. 7(a) (cultivated with MB) and Fig. 7(b) (cultivated with MANI-S compound), respectively.
  • FIG. 7(a) and 7(b) when compared to FIG. 7(b) (cultured with MANI-S compound) HeLa cells of FIG. 7(a) (cultured with MB) HeLa cells , Cell proliferation was remarkably suppressed, although it was concentration-dependent. From this, when the HeLa cells of FIG. 7 (b) (cultured with the MANI-S compound) were compared with the HeLa cells of FIG. 7 (a) (cultured with MB), the photodynamic treatment efficacy was remarkably excellent. In addition, Figure 7 (b) (cultivated with a MANI-S compound) HeLa cells were very excellent at half maximal inhibitory concentration (IC50) of 0.15 ⁇ M.
  • IC50 half maximal inhibitory concentration
  • HeLa cells were incubated for 2 hours with the MANI-S compound prepared in Synthesis Example 2 of 500 nM in hypoxia (hypoxia, 1% O 2 ) and irradiated for 10 minutes with a white light source (0.1 W/cm 2 halogen lamp). Thereafter, the cultured and white light source-irradiated HeLa cells were stained simultaneously with 2 ⁇ M of Calcein AM (viable cell marker) and 4 ⁇ M of propidium iodide (dead cell marker) for 30 minutes and Fluorescence images were obtained with a focal microscope (confocal microscopy, Olympus Fluoview FV1200). The results are shown in Fig. 7(c) and Fig. 7(d), respectively.
  • HeLa cells cultured with the MANI-S compound prepared in Synthesis Example 2 and irradiated with a white light source were calcein AM (survival cell marker). / It can be seen that the viable cell/dead cell simultaneous staining survival assay was clearly visualized by propidium iodide (dead cell marker).
  • HeLa cells cultured with the MANI-S compound prepared in Synthesis Example 2 and irradiated with a white light source were 2',7'-dichlorofluorescein di Total ROS/ from green/bright red fluorescence with acetate (DCFH-DA)/dihydroethidium (DHE) Occurrence can be confirmed.

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Abstract

L'invention concerne : un composé ; une composition comprenant le composé ; et un procédé de thérapie photodynamique pour inactiver ou tuer des cellules tumorales à l'aide de la composition.
PCT/KR2020/005090 2019-05-24 2020-04-16 Composé, composition comprenant un composé et procédé de thérapie photodynamique pour inactiver ou tuer des cellules tumorales à l'aide de la composition WO2020242051A1 (fr)

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KR102536815B1 (ko) * 2021-02-04 2023-05-26 부경대학교 산학협력단 광역학 암치료를 위한 신규한 화합물, 이를 포함하는 조성물 및 광역학 암치료 방법
KR102640178B1 (ko) * 2021-02-24 2024-02-23 이화여자대학교 산학협력단 화합물, 이를 포함하는 조성물, 상기 조성물을 포함하는 광감각제 및 미토콘드리아를 표적으로 하는 종양 진단 또는 치료용 조성물, 및 상기 종양 진단 또는 치료용 조성물을 이용한 광역학 치료방법

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