KR20190054773A - Visible light-sensitive composition for delivering hydrogen sulfide and use thereof - Google Patents

Abstract

According to one aspect of the present invention, provided are a composition for delivering H_2S, including a compound, a stereoisomer, a derivative, or a salt thereof, and a singlet oxygen (^1O_2) photosensitizer, and to a pharmaceutical composition, and a method using the same. Accordingly, tunable photosensitivity and a very high ^1O_2 reactivity of an H_2S precursor, in particular, the ability for modifying the wavelength of light irradiation through selection of ^1O_2PS can be provided. Also, a biological utility is provided through intracellular delivery and cytoprotection of H_2S produced under visible light irradiation.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a visible light-sensitive composition for delivering hydrogen sulfide,

To a composition for transferring visible light-sensitive hydrogen sulfide containing a compound containing a fused aromatic ring and a photosensitizer, and a use thereof.

Hydrogen sulfide (H ₂ S) belongs to a gaseous transporter (gasotransmitter) and is inseparably associated with various pathophysiological applications in the human body. H ₂ S is protective against many diseases such as Parkinson's disease, Down's syndrome, Alzheimer's disease, diabetes, and cardiovascular disease. Interest has been attracted in the development of drugs or prodrugs that release H ₂ S. Inorganic salts of H ₂ S, such as NaSH and Na ₂ S, are unsuitable for applying therapeutic regimens because they increase H ₂ S levels abruptly and cause acute side effects. To avoid this problem, an organic donor that releases H ₂ S in response to biological stimuli has been developed. However, the ability to control stimulation is limited, making full use of the potential of H ₂ S delivery.

Photoresponsive H ₂ S donors are a promising alternative to existing donors. Photon flux is controllable and orthogonal to biological stimuli and enables selective H ₂ S release. In addition, the ability to transmit photons remotely and position-specifically enables very high spatio-temporal control over H ₂ S generation. Thus, the development of H ₂ S photoreceptors has been the focus of research (Devarie-Baez et al., Org. Lett., 2013, vol. 15, p. 2786-2789). Several photocage scaffolds have been used to make photocleavable H ₂ S donors, including the leuco form of o-nitrobenzyl, ketoprofenate, and malachite gree . However, these H ₂ S photoreceptors have a disadvantage in that they are biologically exploited. One major drawback is the need for ultraviolet light. Short wavelength light irradiation poses potential problems in biological applications due to phototoxicity and limited penetration depth of UV light into the tissue.

Therefore, there is a need to develop a photocatalyst capable of generating H ₂ S upon irradiation with light in the visible light region.

There is provided a composition for transferring hydrogen sulfide (H ₂ S).

The present invention provides a pharmaceutical composition for preventing or treating diseases by intracellular delivery of H ₂ S.

Lt; _{RTI ID =} 0.0 > H < / RTI _> S by intracellular delivery.

One aspect includes a compound comprising a fused aromatic ring, a stereoisomer, derivative, or salt thereof; And a singlet oxygen ( ¹ O ₂ ) photosensitizer (PS). The present invention also provides a composition for transferring hydrogen sulfide (H ₂ S).

The compound may be a compound represented by the following formula (1): < EMI ID =

[Chemical Formula 1]

.

.

In the above formula (1), the CY1 ring represents a fused aromatic ring containing S, and represents a substituted or unsubstituted C ₃ to C ₂₀ cyclic ring group, a substituted or unsubstituted C ₃ to C ₂₀ hetero A substituted or unsubstituted C ₆ to C ₂₀ aryl group, a substituted or unsubstituted C ₆ to C ₂₀ heteroaryl group, or a combination thereof.

Wherein R ₁ and R ₂ independently represent a hydrogen atom, a hydroxyl group, an ether group, an amino group, an ester group, an amide group, a carboxylic acid and a carbonyl group derivative, a substituted or unsubstituted C ₁ to C ₂₀ alkyl group, An unsubstituted C ₃ to C ₂₀ cyclic ring group, a substituted or unsubstituted C ₃ to C ₂₀ heterocyclic ring group, a substituted or unsubstituted C ₆ to C ₂₀ aryl group, a substituted or unsubstituted A C ₆ to C ₂₀ heteroaryl group, or a combination thereof.

The term " substituted " or " unsubstituted " means that one or more hydrogen atoms of the organic compound are replaced by another atomic group to form a derivative, and the substituent is introduced instead of a hydrogen atom. It says. The substituent may be a halogen atom, a C ₁ to C ₅ alkyl group (e.g., CCF ₃ , CHCF ₂ , CH ₂ F, CCl ₃ ) substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, hydrazine, hydrazone, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid or a salt thereof, or an alkyl group of C ₁ to C _5, C ₂ to C ₅ alkenyl group, C ₂ to C ₅ in the alkynyl group, C C ₃ to C ₁₀ cycloalkyl groups, C ₆ to C ₁₀ aryl groups, C ₆ to C ₁₀ heteroaryl groups, C ₆ to C ₂₀ arylalkyl groups, C ₆ to C ₂₀ heteroarylalkyl groups, or combinations thereof Lt; / RTI >

The term " alkyl group " means a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon group. The C ₁ to C ₂₀ alkyl group may be C ₁ To C ₁₅ , C ₁ To C ₁₀ , C ₁ To C ₅ , or C ₁ To C < ₃ >. The alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and n-pentyl.

The term " cyclic ring group " refers to a non-aromatic organic compound whose ring atoms are carbon and which are saturated or partially unsaturated. Wherein the cyclic ring group is C ₃ to C ₂₀ , C ₁ To C ₁₅ , C ₁ To C ₁₀ , C ₁ To C ₅ , or C ₁ To C ₃ cyclic ring groups. The cyclic ring group is, for example, cyclopentyl, cyclopentenyl, cyclohexyl, and boronyl.

The term " heterocyclic ring group " refers to a nonaromatic organic compound having a ring containing at least one heteroatom selected from N, O, P, or S and the remaining ring atoms carbon. The heterocyclic ring group may be a C ₃ to C ₂₀ , C ₁ To C ₁₅ , C ₁ To C ₁₀ , C ₁ To C ₅ , or C ₁ To C ₃ heterocyclic ring groups. The heterocyclic ring group is, for example, tetrahydropyran, and tetrahydropyridine.

The term " aryl group ", alone or in combination, refers to an aromatic system comprising one or more rings. The aryl group may be substituted with C ₆ to C ₂₀ , C ₆ To C ₁₅ , C ₆ To C ₁₀ , or C ₆ To date it may be aryl of C _8. The aryl group is, for example, phenyl, naphthyl, tetrahydronaphthyl.

The term " heteroaryl group " refers to a monocyclic or bicyclic organic compound having at least one heteroatom selected from the group consisting of N, O, P and S, and the remaining ring atoms carbon. The heteroaryl group may include, for example, 1 to 5 heteroatoms and may include 5 to 10 ring members. The S or N may be oxidized to have various oxidation states. The heteroaryl group is optionally substituted with one or more groups selected from the group consisting of C ₆ to C ₂₀ , C ₆ To C ₁₅ , C ₆ To C ₁₀ , or C ₆ To C ₈ heteroaryl groups. The heteroaryl is, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, and isothiazolyl.

The compound represented by Formula 1 may be a compound represented by Formula 2 below.

[Compound 2]

.

.

In Formula 2, CY2 ring is thiophene (thiophene) indicates that form a ring fused to the ring, a substituted or unsubstituted C ₆ to C ₂₀ aryl group, a substituted or unsubstituted C ₆ to C ₂₀ ring A heteroaryl group, or a combination thereof.

In Formula 2, R ₁ and R ₂ independently represent a hydrogen atom, a hydroxy group, a substituted or unsubstituted C ₁ to C ₅ alkyl group, a substituted or unsubstituted C ₆ to C ₂₀ aryl group, C ₆ to C ₂₀ heteroaryl groups, or combinations thereof.

The alkyl group, aryl group, and heteroaryl group are as described above.

The compound represented by the formula 1 may be a compound represented by the following formula 3:

[Compound 3]

.

.

The compound of Formula 3 is 1,3-diphenylisobenzothiophene (DPBT).

The term " stereoisomer " refers to compounds that have the same molecular formula and method of linking members but differ in the spatial arrangement between atoms. The stereoisomer may be a diasteromer or an enantiomer. An enantiomer is an isomer that does not overlap with its mirror image, such as the relationship between the left and right hands, and is also referred to as an optical isomer. Enantiomers are divided into R (Rectus) and S (sinister) counterclockwise when four or more substituents are different on the chiral center carbon. Diastereoisomers refer to stereoisomers that are not mirror images and can be divided into cis-trans isomers where the spatial arrangement of atoms is different.

The term " derivative " refers to a compound obtained by replacing part of the structure of the above compound with another atom or atomic group.

The term " salt " refers to an addition salt of an inorganic acid salt, an organic acid salt, or a metal salt of a compound. The salt may be a salt that is administered to a cell to not cause toxicity or serious irritation to the cell and does not impair the biological activity and properties of the compound. The inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfide. The organic acid salt may be at least one selected from the group consisting of a formate, a acetate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a beateate, a camphateate, an edisleite, trichloroacetic acid, There may be mentioned acetic acid salts, benzoic acid salts, gluconic acid salts, methanesulfonic acid salts, glycolic acid salts, succinic acid salts, 4-toluenesulfonic acid salts, Or aspartate. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

The term " singlet oxygen ( ¹ O ₂ ) " refers to an O ₂ molecule in the singlet state. The bottom state of O ₂ molecules is triplet oxygen ( ³ O ₂ ), while the singlet state of O ₂ molecules is excited.

The term " photosensitizer (PS) " refers to a substance that exhibits a light-sensitive response and is also referred to as a photosensitizer. The photo-sensitizer absorbs light by photoirradiation to become an excited state, and excites the substrate molecule by the movement of excited energy or generates radical ion species by electron transfer with the substrate molecule, Lt; / RTI > The photosensitizer can catalyze triplet oxygen with singlet oxygen by light (e.g., visible light). The above photosensitizer is a biscyclometalated iridium (III) complex ([iridium bis (2- (3-methoxyphenyl) pyridinate (1,10-phenanthroline)] PF6: IrOMe) , Platinum (II) octaethylporphine (PtOEP), hematoporphyrin derivatives (photofrin), amino laevulinic acid (ALA), benzo Benzoporphyrin derivative monoacid ring A (BPD-MA), chlorin photosensitizer tin etiopurpurin, tetra (m-hydroxyphenyl) chlorine, chlorin: mTHPC), lutetium texaphyrin, 9-acetoxy-2,7,12,17-tetrakis- (beta -methoxyethyl) -phosphine (9-Acetoxy-2,7,12 , 17-tetrakis- (β-methoxyethyl) -porphycene, zinc phthalocyanine, naphthalocyanine, metallo-porphyrin, It is also possible to use metallo-phthalocyanine, metallo-naphthocyaninesulfobenzo-porphyrazine (M-NSBP), and metallo-naphthalocyanine Lt; / RTI >

Said compound, its isomer, derivative or salt; The photosensitizer, or a combination thereof, may be encapsulated in a vesicle.

The term " vesicle " or " vesicle " refers to a membrane structure surrounded by a lipid bilayer. The vesicle may be a polymerome or a liposome. Polymerases are artificial vesicles containing block copolymers. The liposomes are artificially produced vesicles composed of a lipid bilayer containing natural lipids. Liposomes can be unilamellar vesicles or multivesicular vesicles. The vesicles are composed of poly (ethylene glycol) (PEG), poly (2-methyloxazoline), polydimethylsiloxane (PDMS), poly (caprolactone) may comprise a block selected from the group consisting of poly (caprolactone: PCL), poly (lactide): PLA, and poly (methyl methacrylate: PMMA) Poloxamer is a hydrophilic non-ionic surfactant that is a triblock copolymer of polyethylene glycol (two blocks) and polypropylene glycol (one block) The poloxamer may be pluronic F-127 or pluronic F-68.

The diameter of the vesicles may be, for example, from about 5 nm to about 100 nm, from about 10 nm to about 90 nm, from about 10 nm to about 80 nm, from about 10 nm to about 70 nm, from about 10 nm to about 60 nm, From about 10 nm to about 50 nm, from about 10 nm to about 40 nm, or from about 10 nm to about 20 nm. The diameter of the vesicle may increase after light irradiation compared to before light irradiation. The average diameter of the vesicles prior to light irradiation may be from about 10 nm to about 30 nm, from about 10 nm to about 25 nm, from about 10 nm to about 20 nm, or about 17 nm. After irradiation, the average diameter of the vesicles may be from about 10 nm to about 40 nm, from about 10 nm to about 30 nm, from about 10 nm to about 25 nm, from about 15 nm to about 25 nm, or about 19 nm.

The composition for transferring H ₂ S may be visible light-sensitive. The term "visible light" refers to the area of light that the human eye can perceive. The wavelength of the visible light is from about 380 to about 700 nm, from about 380 to about 650 nm, from about 380 to about 600 nm, from about 380 to about 550 nm, from about 380 to about 500 nm, from about 400 to about 550 nm, About 550 nm, or about 500 to about 550 nm.

The composition may deliver H ₂ S intracellularly. The composition may be delivered into a cell to transfer H ₂ S photosensitively within the cell. The term " transmission " includes generation or generation.

The composition may provide cytoprotective activity, apoptosis inhibitory activity, or a combination thereof against oxidative stress. The oxidative stress may be a stimulation by reactive oxygen species (ROS). The active oxygen species refers to a chemically reactive molecule containing an oxygen atom. Reactive oxygen species, for example _{H 2 O 2, · OH,} O 2 · -, OCl -, t-BuOOH, t-BuO ·, GSNO, NO, HNO, and ONOO ^- is. The term " apoptosis " refers to a form of the manner in which a cell is regulated by a gene and dies. The cell suicide can be killed by intracellular stress or an external signal. The composition may provide an inhibitory activity against acute cellular suicide.

Another aspect relates to a compound of formula I, an isomer, derivative or pharmaceutically acceptable salt thereof according to one aspect; And a singlet oxygen ( ¹ O ₂ ) photosensitizer, for the prevention or treatment of diseases selected from Parkinson's disease, Down's syndrome, Alzheimer's disease, diabetes, and cardiovascular disease.

The compounds, isomers, derivatives, singlet oxygen and photosensitizers represented by the above formula (1) are as described above.

The term " pharmaceutically acceptable salts " refers to inorganic and organic acid addition salts of compounds. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfide. The organic acid salt may be at least one selected from the group consisting of a formate, a acetate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a beateate, a camphateate, an edisleite, trichloroacetic acid, There may be mentioned acetic acid salts, benzoic acid salts, gluconic acid salts, methanesulfonic acid salts, glycolic acid salts, succinic acid salts, 4-toluenesulfonic acid salts, Or aspartate.

The term " prevention " includes inhibiting the occurrence of a disease. The term " treatment " includes inhibiting, alleviating, or eliminating the development of the disease. Such diseases include diseases that can be prevented or treated by the cytoprotective effect of H ₂ S or the cell suicide inhibitory effect. The disease may be selected from Parkinson's disease, Down's syndrome, Alzheimer's disease, diabetes, and cardiovascular disease. The cardiovascular disease may be myocardial infarction, cardiac ischemia, angina pectoris, cardiomyopathy, endocarditis, or a combination thereof.

The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or diluent. Pharmaceutically acceptable carriers or diluents may be those known in the art. The carrier or diluent may be selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, Saline, or sterile water), syrups, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, Ringer's solution, buffer, maltodextrin solution, glycerol, ethanol, Lt; / RTI > The pharmaceutical composition may further comprise a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, or a combination thereof.

The pharmaceutical composition may be prepared in unit dose form by formulating it with a pharmaceutically acceptable carrier and / or excipient according to methods known to those skilled in the art, or may be prepared by inserting it into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents. The aqueous medium may be physiological saline or PBS.

Another aspect includes the step of simultaneously or sequentially administering to a subject a compound represented by formula (1), an isomer, a derivative, or a pharmaceutically acceptable salt thereof, and a singlet oxygen ( ¹ O ₂ ) photosensitizer according to an aspect Parkinson's disease, Down's syndrome, Alzheimer's disease, diabetes, and cardiovascular disease.

The compound, isomer, derivative, singlet oxygen, photosensitizer, disease, prevention, and treatment represented by Formula 1 are as described above.

The compound represented by Formula 1, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof and a monooxygen ( ¹ O ₂ ) photo-sensitizer may be administered simultaneously or sequentially. For example, the compound may be administered to a subject after administering a compound represented by the formula (1), an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof. The compound of formula 1, its isomer, derivative or pharmaceutically acceptable salt thereof and the photosensitizer may be administered by different routes of administration.

The subject may be a mammal, including a mouse, a mouse, a dog, a rabbit, a horse, and a human.

The administration may be oral or parenteral administration. The parenteral administration can be administered, for example, by intravenous administration, subcutaneous, intramuscular, intrathecal (abdominal cavity, joint, or facial), or by direct injection. Direct injection may be the site of the pathology, for example, direct injection into the tumor site. The liposome may be administered into the blood, such as the vein, and delivered to the target site, such as the tumor site, by the bloodstream. The target site may be one having a leaky property. The dose may be variously prescribed by such factors as formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate and responsiveness of the patient. The dose may be, for example, 0.001 mg / kg to 100 mg / kg.

The term " comprising " is used herein to indicate that it is possible to add and / or intervene other elements, not to exclude other elements unless specifically stated otherwise.

Figure 1 A is a schematic diagram of an H ₂ S delivery system comprising a monooxygen ( ¹ O ₂ ) photosensitizer (PS) and a 1,3-diphenylisobenzothiophene (DPBT) Fig. In this system, under visible light irradiation, ¹ O ₂ PS converts the molecular dioxygen present everywhere to ¹ O ₂ , DPBT then reacts with ¹ O ₂ to form an unstable endoperoxide, . Endoperoxid immediately undergoes subsequent fragmentation to produce 2-benzoylbenzophenone and H ₂ S.

A compound according to one aspect, a stereoisomer, derivative, or salt thereof; And singlet oxygen ⁽¹ O ₂₎ According to the method using the compositions, pharmaceutical compositions, and this, for the H ₂ S transmission including a light-sensitive agent, a variable (tunable) a very high optical sensitivity and H ₂ S precursor ¹ O ₂ It is possible to provide the ability to modify the light irradiation wavelength through the choice of reactivity, especially ¹ O ₂ PS. In addition, there is biological utility through intracellular delivery and cytoprotective action of H ₂ S produced under visible light irradiation.

Figure 1a is a schematic view showing that the schematic diagram and, ₂ S donor Figure 1b is H represents the H ₂ S generation process also mineral oil inhibited the oxidative stress in the cells.
2B and 2C show 1 H NMR (300 MHz, CDCl ₃ ) spectrum and ¹³ C { ¹ H} NMR (126 MHz, CD ₂ Cl ₂ ) spectrum of DPBT, respectively .
3 is a graph comparing the ¹ O ₂ reactivity of DPBF and DPBT.
Figure 4a shows the results of HPLC determination that DPBT is fragmented by H ₂ S and 2-benzoylbenzophenone by ¹ O ₂ (*: peak of IrOMe).
FIG. 5A is a graph showing the distribution of the diameters of the polymerases before and after the light irradiation in the light scattering experiment ((a): before light irradiation, (b): after light irradiation) ((A): before light irradiation, and (b): after light irradiation).
Figure 6a is different from ¹ O ₂ a graph showing the change in the fluorescence spectrum of the H ₂ S- selective probe with the photo sensitive ((a) and (b)) and the light emission intensity of an integrated H ₂ S according to the condition of the photo-generated (au: arbitrary unit), and FIG. 6B is a graph (c) showing the concentration of H ₂ in the presence or absence of the conditions of 0.2 wt% DPBT, 0.01 wt% IrOMe, O ₂ and light irradiation (λ _irr = 380 nm, (Au) of the light-emitting layer (S).
7A is a graph showing the result of colorimetric results showing the concentration of total sulfides using lead acetate analysis and FIG. 7B is a graph showing the concentration (μM) of H ₂ S with light irradiation time (minute) using methylene blue analysis .
8 is a graph showing the change (nA) of the current (nA) with the irradiation time (hour) depending on the presence or absence of the DPBT (dotted line: DPBT excluded, solid line: DPBT included).
Figure 9 is a graph of the concentration (μM) of H ₂ S according to the active oxygen species.
10 is a fluorescence image of intracellular H ₂ S light-generated from the polymerase before and after light irradiation ((a): before light irradiation, (b): after light irradiation, bar scale: 50 μm).
11 is an image showing the cytoprotective effect of H ₂ S produced by light irradiation ((a): no H ₂ S is generated, (b): photo-generated H ₂ S, bar scale: 100 μm).

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these embodiments are intended to illustrate one or more embodiments, and the scope of the present invention is not limited to these embodiments.

Example  One. Mineral oil H ₂ S Creation of

One. ^One O ₂ For DPBT  Evaluation of reactivity

(1) 1,3- Of diphenyl isobenzothiophene  Ready

1,3-diphenylisobenzothiophene (DPBT) has been modified by a method reported by Lin et al. (Hsu et al., J. Org. Chem. 2009, 74, p.9180-91871) , And 3-diphenylisobenzofuran (DPBF) (TCI) (Fig. 2a).

Specifically, 1,3-diphenylisobenzofuran (3.70 g, 13.7 mmol) and Irppy (11.3 mg, 13.7 μmol) (Woo et al., J. Am. Chem. Soc. 2013, , p. 4777-4787) was added to a 250 mL 1-neck round bottom flask. To the flask was added CH ₂ Cl ₂ (150 mL) and the solution was stirred at 365 nm for 2 days under continuous light irradiation and aerobic conditions. The mixture was concentrated in vacuo. Column purification was performed with silica gel using hexane: EtOAc = 3: 1 (v / v) as an eluent to obtain a white powder of 2-benzoylbenzophenone in 64% yield.

_Rf = 0.5 (hexane: EtOAc = 3: 1, v / v). ^{1 H NMR (300 MHz, CDCl} 3) δ (ppm): 7.38 (t, J = 7.8 Hz, 4H), 7.52 (t, J = 7.5 Hz, 2H), 7.62 (s, 4H), 7.70 (m, 4H). ¹³ C { ¹ H} NMR (126 MHz, CD ₂ Cl ₂ )? (Ppm): 128.47, 129.81, 129.97, 130.50, 133.14, 137.32, 140.16, 196.72 (Fig. 2b and Fig. 2c).

2-benzoylbenzophenone (0.500 g, 1.75 mmol) and P ₂ S ₅ (0.389 g, 1.75 mmol) were added to a 50 mL 2-neck round bottom flask. Pyridine anhydride (20 mL) was added to the flask under argon gas and then the reaction mixture was heated at 115 < 0 > C for 24 h. After cooling to room temperature, the solution was concentrated under reduced pressure. Column purification was carried out on silica gel using hexane: EtOAc = 19: 1 (v / v) as eluent to give a yellowish white powder of DPBT in 76% yield. _Rf = 0.6 (hexane: EtOAc = 4: 1, v / v). ^{1 H NMR (300 MHz, CDCl} 3) δ (ppm): 7.10 (m, 2H), 7.39 (t, J = 3.9 Hz, 2H), 7.48 (t, J = 8.1 Hz, 4H), 7.70 (m, 4H), < / RTI > 7.84 (m, 2H). ¹³ C { ¹ H} NMR (126 MHz, CD ₂ Cl ₂ ) 隆 (ppm): 121.61, 124.83, 128.06, 129.61, 129.70, 134.66, 134.78, 135.75. HR MS (FAB, cation, m-NBA): C ₂₀ H ₁₄ S ([M + H] ⁺ ) predicted value: 287.0894; Actual value: 287.0848.

(2) ^One O ₂ For DPBT Reaction of

(i) Identification of UV-visible light absorption spectrum

To compare the reactivity of DPBF and DPBT to singlet oxygen, an O ₂ -saturated DMSO solution containing 100 μM IrOMe, and 10 μM DPBF or 10 μM DPBT was added at 350 nm (350 nm band pass filter Xenon lamp). The decrease in absorbance (Abs) at 420 nm (DPBF and DPBT) was monitored during continuous light exposure. A graph of? Abs was made as a function of light exposure time and the initial four data points were fitted in a straight line. The ratio of the slope value in the DPBF linear graph for DPBT was 13. The rate constants for the DPBT and singlet oxygen reactions were calculated based on their ratios and the literature values of the DPBF and singlet oxygen reactions (9.6 × 10 ⁸ M ^-1 s ^-1 ) .

DPBT exhibits an apparent absorption band at 398 nm due to the transfer of π-π * in isobenzothiophene units. The decrease in absorbance of this band was observed during continuous light irradiation of an O ₂ -saturated acetonitrile solution containing 10 μM DPBT and 100 μM IrOMe due to reaction with ¹ O ₂ (FIG. 3).

FIG. 3 (a) shows the change in UV-visible light absorption spectrum of an O ₂ -saturated acetonitrile solution containing 10 μM DPBF and 100 μM IrOMe at 350 nm with continuous light irradiation, and (b) Visible light absorption spectra of an O ₂ -saturated acetonitrile solution containing 10 μM DPBT and 100 μM IrOMe according to continuous light irradiation, and (c) showing the change in absorbance with respect to light irradiation time, A graph of DPBF (square) and DPBT (circle) at 420 nm is shown. In (c) of FIG. 3, the lines connecting the squares and the solid lines are obtained by connecting the initial four data points with lines. The ratio of the slope of the two lines (DPBF / DPBT) was 13.

Since the rate constant for a two-molecule reaction between DPBF and ¹ O ₂ is known to be 9.6 × 10 ⁸ M ^-1 s ^-1 , the rate constant for a two-molecule reaction between DPBT and ¹ O ₂ is 7.4 × 10 ⁷ M ^-1 s ^-1 , respectively. Therefore, the DPBT reaction rate was compared with the DPBF reaction rate, and the rate constant for the two-molecule reaction between DPBT and ¹ O ₂ was smaller at 7.4 × 10 ⁷ M ^-1 s ^-1 .

(ii) HPLC  Technique monitoring

The reaction of DPBT with photosensitized ¹ O ₂ was further monitored using HPLC. An O ₂ -saturated CH ₃ CN solution (10 mL) containing 1.0 mM DPBT and 100 μM IrOMe was irradiated with a xenon lamp at 380 nm. A 1.0 mL aliquot was obtained in the solution at 5 minute intervals and analyzed by HPLC-6120 DW LC with Electrospray ionization (ESI) -MS method (EC-C18 (2.1 x 100 mm, 2.7 m) (Poroshell) / MSD (Agilent) eluting conditions: H ₂ O: CH ₃ CN = 50:50 to 100% CH ₃ CN). The ¹ O ₂ - oxidation products of DPBT, IrOMe, and DPBT were observed at elution times of 14.67, 1.67, and 4.00 min, respectively. The results of the HPLC analysis are shown in FIG. 4A (*: peak of IrOMe) and mass spectrometry (ESI MS, cation mode) results are shown in FIG. In FIG. 4b, the formula is 2-benzoylbenzophenone, and the embedded graph is a graph showing a comparison of calculated values with measured values of the protonated form of 2-benzoylbenzophenone.

As shown in Figure 4a, the liquid chromatogram obtained at 5 minute intervals showed complete depletion of DPBT within about 30 minutes, with a new band increase at short elution times.

As shown in Figure 4b, mass spectral analysis of the band showed an m / z value of 287.2 amu, which corresponds to the protonated class of 2-benzoylbenzophenone. The formation of 2-benzoylbenzophenone is consistent with the H ₂ S-emission mechanism. Taken together, these results demonstrate a very high reactivity of DPBT to ¹ O ₂ .

2. H ₂ S For optical transmission  Making donors

(One) Polymeric  Ready

Photogeneration of H ₂ S in aqueous media was achieved using polymeric polymers of biocompatible Pluronic F-127.

To prepare a little polymer, 736 mg of Pluronic F-127 (Sigma-Aldrich) , 500 μL 10 mM DPBT solution (CH ₂ Cl ₂ in), and 10 μL of 10 mM ¹ O ₂ PS solution (CH ₂ Cl ₂ ) was added to a 20 mL glass vial and completely dissolved in 10 mL of CH ₂ Cl ₂ . The proportions of DPBT and ¹ O ₂ PS in the pluronic F-127 polymer were 0.2 wt% and 0.01 wt%, respectively. 20 μL of a 10 mM SF4 solution (0.01 wt% in DMSO) was added to detect the fluorescence of H ₂ S. The CH ₂ Cl ₂ was slowly evaporated using a rotary evaporator to obtain a firm solution of the polymer in the thin film. Then, 10 mL of buffer solution (pH 7.4; 10 mM PBS (Sigma-Aldrich) + 1.0 mM cetrimonium bromide (CTAB, Sigma-Aldrich) was added to the vial. Vigorous vortexing, and a cloudy suspension was used for the H ₂ S light generation experiment.

(2) Irradiated Polymeric  size

As described in Example 1.2 (1), a polymeric bezle was prepared by molecularly dispersing 0.2 wt% DPBT and 0.01 wt% ¹ O ₂ PS in a Pluronic F-127 polymer. To get prepared polymer, 74 mg · buffered aqueous solution of a mL ^-1 (pH 7.4; 10 mM phosphate buffered saline (phosphate buffered saline: PBS, Sigma -Aldrich) + 1.0 mM cetyltrimethylammonium bromide (cetyltrimethylammonium bromide: CTAB, Sigma- Aldrich ) Was added and the solid solution vortexed vigorously.

In a dynamic light scattering (DLS) experiment, the distribution of the diameter of the 10 μM polymer jam before and after light irradiation (λ _irr = 350 nm; 24 min) was measured using an ELS-Z1000 instrument (Photal Otsuka Electronics, Japan) The measurement was carried out at room temperature. Data analysis was performed using software provided by the manufacturer. The distribution of the diameter of the polymeric resin before and after the light irradiation is shown in Fig. 5A ((a): before light irradiation, and (b): after light irradiation). As shown in FIG. 5A, the average diameter of the polymerase before light irradiation was about 17 nm, and the average diameter of polymerase after irradiation was about 19 nm.

Also, for Field-Emission Scanning Electron Microscopy (FE SEM) experiments, the fraction of the polymer mousse suspension was dropped onto a 1 cm x 1 cm glass substrate and dried in the dark. Polymerization was confirmed by FE SEM (100 k × 2.00 kV) before and after light irradiation (λ _irr = 350 nm; 24 min). The FE SEM photographs of the polymer were obtained by platinum coating (120 seconds) using EM ACE200 (Leica, Austria) and then using a SUPRA 55VP device (Carl Zeiss, Germany). An image of the polymeric film before and after the light irradiation is shown in FIG. 5B ((a): before light irradiation, (b): after light irradiation).

As shown in Figures 5a and 5b, the vesicle suspension exhibited the formation of spherical particles of ~ 10 nm diameter. The vesicle suspension was stable and no aggregation or precipitation was observed for 3 months.

(3) Photogenerated H ₂ S of monitoring

For temporal monitoring of the light generated H ₂ S, phosphor turned on (turn-on) probe (SF4) for the _{H 2 S (Lin et al.} , Proc. Natl. Acad. Sci. USA 2013, vol.110, p , 7131-7135) was incorporated into the polymer (0.01 wt%).

A graph showing the optical generation of H ₂ S using different ¹ O ₂ photosensitizers is shown in FIGS. 6A and 6B ((a): the use of IrOMe as a ¹ O ₂ photosensitizer, and b) the use of PtOEP as a ¹ O ₂ photosensitizer. In Figure 6a, (a) and (b) is 0.2 wt% DPBT, 0.01 wt% SF4, and _{0.01 wt% IrOMe (λ irr =} 380-500 nm) , or 0.01 wt% PtOEP (Sigma-Aldrich ) (λ irr = Upon continuous light irradiation of an O ₂ -saturated buffer (pH 7.4; 10 mM PBS + 1.0 mM CTAB) containing a Pluronic F-127 polymeric bead with added 500-550 nm, the H ₂ S- Lt; RTI ID = 0.0 > SF4. ≪ / RTI > In Figures 6 (a) and 6 (b), the peaks indicated by * and ** are due to excitation light and PtOEP emission, respectively.

The photoluminescence spectrum was measured at room temperature (organic solution) or 37 ° C (buffered aqueous solution) using a Quanta Master 400 scanning spectral pumping system (Photon Technology International, Edison, NJ, USA). The temperature was maintained using a circulating water bath. The excitation wavelength for recording SF4 fluorescence was 496 nm. The photoluminescence spectra of the measured irradiated solutions were recorded in the SF4 emission range (lambda _ems = 500-650 nm). The UV-visible light absorption spectra were collected on a Cary 300 spectrophotometer (Agilent) at room temperature. Unless otherwise noted, 2 μM or 10 μM solutions were used for the measurements.

As shown in Fig. 6a (a), the irradiation of the polymer jam suspension containing IrOMe (λ _irr = 380-500 nm) caused a giant fluorescence increase reaction in SF4. This reaction is due to photon absorption by IrOMe, which is the photochemical action spectrum of the quantum yield for the photochemical H ₂ S production plotted as a function of the irradiation wavelength, perfectly overlapping the UV-visible absorption spectrum of IrOMe . In the light generation of the H ₂ S in order to determine the necessary conditions, the removal of one of the conditions of 0.2 wt% DPBT, 0.01 wt% IrOMe, O 2 and irradiated with light (λ _irr = 380 nm, 60 minutes) results, H ₂ S generation (Fig. 6B). Thus, DPBT, IrOMe, O _2, and photon sources are conditions necessary for H ₂ S light generation, and this provides strong evidence that the optical response of ¹ O ₂ is responsible for H ₂ S generation.

The great advantage of this donor is the variability of the light irradiation wavelength obtained by selecting ¹ O ₂ PS. The versatility of this system has been demonstrated by the production of polymerases with PtOEP instead of IrOMe. The strong visible light absorption of PtOEP makes it possible to generate H ₂ S using green light irradiation (λ _irr = 500-550 nm). As shown in Fig. 6 (a), a large fluorescence increase due to the photo-generated H ₂ S was observed. The extent and speed of the reaction was greater than that obtained using IrOMe.

The photogenerated H ₂ S was quantified by converting the integrated fluorescence intensity to H ₂ S concentration ([H ₂ S]) using a standard curve.

The photoluminescence spectra of 20 μM SF4 (buffer containing 10 mM PBS and 1.0 mM CTAB; pH 7.4) to prepare a calibration curve to convert the integrated photoluminescence intensity curves to H ₂ S concentrations were run on Na ₂ S (TCI) concentration and then integrated at λ _ems = 500-650 nm. H ₂ S concentration ([H ₂ S]) of was calculated to considering the protonation equilibrium:

H ₂ S (aq) ↔ HS ^- (aq) + H ⁺ (aq) pK _a1 = 7.0

HS ^- (aq) ^- S ^{2 -} (aq) + H ⁺ (aq) pK _a2 > 14.0

Since pK _a2 of S ^{2 -} was significantly larger than pK _a1 , the production of S ^{2 -} was neglected.

The combination of the equilibrium constant for the first protonation and the mass balance equation for the total sulphide (ie, [Na ₂ S] addition = [H ₂ S] + [HS ^- ] + [S ^{2 -} ]) The following equation for [H ₂ S] was calculated from 7.4.

[H ₂ S] = [Na ₂ S] addition / (1 + 10 ^0.4 )

The integrated fluorescence intensity was converted to [H ₂ S] using a calibration curve and the concentration of H ₂ S photo generated by PtOEP (triangle) or IrOMe (circle) was expressed as a function of irradiation time, (C) of Fig. 6A.

As shown in Figure 6 (c), the value of [H ₂ S] showed a light dose-dependent increase. [H ₂ S] reached 24 μM after 2 hours of light irradiation of polymeric material containing PtOEP (triangle). The formation of H ₂ S from IrOMe was considerably slower than that obtained with PtOEP (circle). Compared to IrOMe rapid production by PtOEP it is more may be considered a result of the larger photon absorption (i. E., At 532 nm for PtOEP at 432 nm for ε = 6600 M ^-1 cm ^-1 for IrOMe ε = 1900 M ^{- 1} cm ^-1 ).

(4) H ₂ S Of the estimated level of

The estimated level of effectiveness of H ₂ S (several micromoles in concentration) can be determined by either the lead acetate (Pb (OAc) ₂ ) assay or the methylene blue assay using N, N-dimethylaniline and FeCl ₃ And confirmed by using chemical analysis.

In the Pb (OAc) ₂ assay, the filter paper (Whatman) was immersed in 3.0 mL Milli-Q grade water saturated with Pb (OAc) ₂ (Sigma-Aldrich). The filter paper was dried in a convection oven. Colorimetric reactions to sulfides were visualized by immersing filter paper in Milli-Q grade water with different concentrations of Na ₂ S (0, 250, 500, and 1000 μM) (FIG. 7 a). As shown in FIG. 7a, a visual inspection of the treated filter paper indicated that the reaction was visible at> 250 μM [Na ₂ S] addition. Pb (OAc) ₂ -treated filter paper was used to estimate the concentration of sulphide in aqueous solution containing irradiated (λ _irr = 380 nm; 630 min) with 0.2 wt% DPBT and 0.01 wt% Respectively.

In the methylene blue assay, an aqueous buffer solution (pH 7.4, 10 mM PBS + 1.0 mM CTAB) containing a polymerase added with 0.2 wt% DPBT and 0.01 wt% IrOMe was irradiated at 380 nm for 60 min. 500 μL of the solution was taken during light irradiation and incubated with 150 μL of 20 mM N, N-dimethylaniline (7.2 M HCl) and 150 μL of 30 mM FeCl ₃ (1.2 M HCl) for 20 minutes. Absorbance change at 670 nm was recorded, and the value was converted to the concentration of H ₂ S. A graph of the concentration (μM) of H ₂ S with respect to the light irradiation time (minute) is shown in FIG. As shown in FIG. 7B, it was confirmed that the concentration of H ₂ S increases with the light irradiation time.

3. H ₂ S Of visible light-parametric generation of

The visible light-mediated generation of H ₂ S was further evaluated through current measurements.

Current measurements were measured using an ISO-H ₂ S-100 microsensor (World Precision Instruments). Prior to measurement, an amperometer was assayed with increasing concentration of Na ₂ S using a PBS buffered aqueous solution (pH 7.2; 10 mL).

An O ₂ -saturated polymeric suspension (5 mL) containing 0.2 wt% DPBT and 0.01 wt% IrOMe was added to the 20 mL vials covered with rubber mats. The micro sensor was inserted through the needle hole of the vial stopper to prevent gas exchange with the outside. The polymer jam suspension was irradiated while recording the current measurement response to H ₂ S with Lab-Trax-4/16 (World Precision Instruments). O ₂ -saturated buffer (pH 7.4; 10 mM PBS + 1.0 mM CTAB) containing pluronic F-127 polymerase with 0.2 wt% DPBT and 0.01 wt% IrOMe was irradiated under a blue light beam during current measurement . In addition, a control solution of the polymerase without DPBT was treated identically. The change (nA) of the current with the light irradiation time (hour) is shown in Fig. 8 (dotted line: DPBT excluded, solid line: DPBT included). In FIG. 8, the inset photo shows a H ₂ S-selective electrode immersed in a light irradiated polymeric bezel solution.

As shown in FIG. 8, light irradiation of an O ₂ -saturated buffer containing polymeric bezle (0.2 wt% DPBT and 0.01 wt% IrOMe) caused an increase in current through the H ₂ S-selective electrode. This increase was not observed in the non-DPBT-containing bejes, and it was confirmed that H ₂ S was derived from DPBT.

4. H ₂ S  Production ^One O ₂ Selectively by Be mediated  Investigation of whether

To confirm the production of H ₂ S according to the active oxygen species, active oxygen species were prepared as follows.

1) H ₂ O ₂ : An aqueous solution of 30 wt% H ₂ O ₂ (Sigma-Aldrich) was diluted in Milli-Q grade water to a concentration of 500 μM. The concentration was determined by using a ^1-molar absorbance of _{H 2 O 2 ε = 44 M} -1 cm.

2) · OH: H ₂ O ₂ was a solution of 500 μM mixed with 2.5 mM FeSO ₄ (aq), and the mixture was incubated for 10 minutes. The incubated solution was used without further treatment.

3) O ₂ ^{· -:} by dissolving KO ₂ in mm -Q-grade water was prepared at a concentration of 500 μM.

4) OCI ^- : NaOCl solution (Sigma-Aldrich) was diluted to a concentration of 500 μM using Milli-Q grade water. Concentration was determined using molar absorbance ε = 360 M ^-1 cm ^{- 1} .

5) t- BuOOH: Luperox® TBH70X, t- BuOOH solution (Sigma-Aldrich) was diluted to a concentration of 500 μM using Milli-Q grade water.

6) t -BuO ·: it was a 500 μM solution of t -BuOOH mixed with 2.5 mM FeSO ₄ (aq), and the mixture was incubated for 10 minutes. The incubated solution was used without further treatment.

7) GSNO: GSNO (Sigma-Aldrich) was dissolved in millie-Q water to prepare a concentration of 500 μM.

8) NO: Diethylamine NONOate sodium salt hydrate (Sigma-Aldrich) was dissolved in millie-Q water to prepare a concentration of 500 μM.

9) HNO: Angeli's salt (Calbiochem) was dissolved in Milli-Q grade water and prepared at a concentration of 500 μM.

10) ONOO ^- : 0.6 M NaNO ₂ ( aq ) was acidified with 0.6 M HCl and then 1.5 M KOH ( aq ) was added. After addition of excess MnO ₂ , the solution was used without further treatment.

A polymer solution containing 0.2 wt% DPBT was incubated with the prepared active oxygen species for 30 minutes. Thereafter, the concentration of H ₂ S was measured to confirm the production of ¹ O ₂ - selective H ₂ S. A graph of the concentration (μM) of H ₂ S according to the active oxygen species is shown in FIG.

As shown in Figure 9, the fluorescence H ₂ S assay applied to each incubated sample indicated that H ₂ S production was due to only ¹ O ₂ . This result was consistent with the operating mechanism shown in Figures 1A and 1B. ¹ O ₂ selectivity is advantageous in suppressing dark state H ₂ S release because ¹ O ₂ does not produce an endogenously significant amount through oxygen metabolism.

Example  2. H ₂ S For optical transmission  Biological availability of donors

One. H ₂ S For optical transmission  Donor's Intracellular H ₂ S  produce

After confirming the H ₂ S-light performance, we attempted to demonstrate the biological utility of the donor. Polymeric suspensions (containing 0.2 wt% DPBT and 0.01 wt% PtOEP) were diluted in serum-free RPMI (Gibco) at a 1:10 ratio (v / v). A 10 mM SF4 solution in DMSO (Sigma-Aldrich, Biotechnology grade) was prepared. On the day before imaging, HeLa cells were transferred to glass bottom culture dishes (SPL Life Sciences, Korea). Cells were washed and supplemented with PBS (Welgene, Korea). Diluted polymerase in serum-free RPMI was added to the culture dish and the cells were incubated for 15 minutes at 37 ° C. The cells were washed twice with PBS to remove the remaining polymerase.

HeLa cells cultured in this medium were confirmed to be viable using MTT assay, indicating that the donor has low cytotoxicity.

The cells were further treated with 10 [mu] M SF4 for 15 min at 37 [deg.] C and washed with PBS. Confocal laser-scanning microscopy was performed before and after green-LED illumination (λ _irr ~ 500 nm, 1 W, 20 min). Fluorescence images were obtained using an LSM 510 META confocal laser scanning microscope (Carl Zeiss). The excitation beam (488 nm) was fitted to the dish and the signal was obtained through a 30 emission channel covering the range of 410-691 nm (λ _ex = 488 nm, λ _obs = 503-546 nm). Fluorescence images and mean intensity were analyzed using LSM 510 version 4.0 software. Fluorescence images of cells before and after light irradiation are shown in Fig.

As shown in Fig. 10, bright spot fluorescence was generated in the cytoplasm. Fluorescent H ₂ S visualization has provided strong evidence to support that our H ₂ S donors are cell-permeable and can generate H ₂ S in the cellular environment under visible light illumination.

2. For oxidative stress Photogenerated H ₂ S Cytoprotective effect of

As a final proof of biological utility, the cytoprotective effect of photogenerated H ₂ S on oxidative stress was evaluated.

Annexin V-FITC, a fluorescent cell suicide marker, and propidium iodide (PI), a fluorescent necrosis marker, were purchased from Sigma-Aldrich. HeLa cells were treated with polymerases and the same procedure as in the fluorescence H ₂ S visualization experiment described above was performed. After washing twice with PBS, 1.0 mL serum-free RPMI and 102 μL binding buffer (Sigma-Aldrich) were added. The cells were then irradiated with green LED (1 W) for 5 min at λ _irr to 500 nm. 5 μL (7 nM) annexin V-FITC and 10 μL (2 μM) PI were added to the culture dish and the cells were further incubated for 10 min in the dark. 0.2 wt% H ₂ O ₂ (Sigma-Aldrich, 30 wt%) was added to the plate to induce acute apoptosis. Control cells were prepared identically except for the treatment of polymerases. Fluorescence microscopy photographs were obtained using a LSM 510 META confocal laser scanning microscope (Carl Zeiss Carl Zeiss) (Fig. 11). Fluorescence emission was obtained at λ _ex = 485 nm and λ _obs = 538-546 nm for Annexin V-FITC and at λ _ex = 493 nm and λ _obs = 625-634 nm for PI. Fluorescence images were analyzed using LSM 510 version 4.0 software.

As shown in FIG. 11, control cells (i.e., H ₂ S not photogenerated) showed strong green fluorescent signals due to apoptosis markers (7 nM annexin V-FITC) (Propidium iodide)), with a weak red fluorescence. In contrast, irradiated cells (i.e., H ₂ S was photo-generated) exhibited a significant decrease in fluorescence signal from both cell suicide and cell necrosis markers. These results indicated that H ₂ S induced by visible light could inhibit acute apoptosis induced by oxidative stress. Overall, these experiments have successfully demonstrated the biological utility of H ₂ S donors.

Claims (12)

A compound represented by the following formula (1), a stereoisomer, a derivative or a salt thereof:
[Chemical Formula 1]

In Formula 1,
The CY1 ring represents a fused aromatic ring containing S and is a substituted or unsubstituted C ₃ to C ₂₀ cyclic ring group, a substituted or unsubstituted C ₃ to C ₂₀ heterocyclic ring group, A substituted or unsubstituted C ₆ to C ₂₀ aryl group, a substituted or unsubstituted C ₆ to C ₂₀ heteroaryl group, or a combination thereof,
R ₁ and R ₂ independently represent a hydrogen atom, a hydroxyl group, an ether group, an amino group, an ester group, an amide group, a carboxylic acid and a carbonyl group derivative, a substituted or unsubstituted C ₁ to C ₂₀ alkyl group, a substituted or unsubstituted C ₃ to C ₂₀ cyclic ring group, a substituted or unsubstituted C ₃ to C ₂₀ heterocyclic ring group, a substituted or unsubstituted C ₆ to an aryl group, a substituted or unsubstituted C ₆ to C ₂₀ ring C ₂₀ ring of ring A heteroaryl group, or a combination thereof; And
A composition for transferring hydrogen sulfide (H ₂ S) comprising a singlet oxygen ( ¹ O ₂ ) photosensitizer (PS). The composition according to claim 1, wherein the compound represented by Formula 1 is represented by the following Formula 2:
[Compound 2]

In Formula 2,
CY2 ring is thiophene (thiophene) indicates that form a ring fused to the ring, a substituted or unsubstituted C ₆ to C ₂₀ aryl group, a heteroaryl group, a substituted or unsubstituted C ₆ to C _20, or A combination thereof,
R ₁ and R ₂ are each independently a hydrogen atom, a hydroxy group, a substituted or unsubstituted C ₁ to C ₅ alkyl group, a substituted or unsubstituted C ₆ to C ₂₀ aryl group, a substituted or unsubstituted C ₆ to C ₂₀ heteroaryl group, or a combination thereof. The composition according to claim 1, wherein the compound represented by Formula 1 is represented by the following Formula 3:
[Compound 3]

. The method of claim 1, wherein the photosensitive agent is selected from the group consisting of biscyclometallated iridium (III) complexes ([iridium bis (2- (3-methoxyphenyl) pyridinate (1,10-phenanthroline) ] PF6: IrOMe), platinum (II) octaethylporphine (PtOEP), haematoporphyrin derivatives (photofrin), amino laevulinic acid : ALA), benzoporphyrin derivative monoacid ring A (BPD-MA), chlorin photosensitizer tin etiopurpurin, tetra (m-hydroxyphenyl) chlorine (m-hydroxyphenyl) chlorin: mTHPC), lutetium texaphyrin, 9-acetoxy-2,7,12,17-tetrakis- (p- methoxyethyl) 2,7,12,17-tetrakis- (? -Methoxyethyl) -porphycene, zinc phthalocyanine, naphthalocyanine, methyl-porphyrin allo-porphyrin, metallochlorins, metallo-phthalocyanine, metallo-naphthocyaninesulfobenzo-porphyrazine (M-NSBP), and metallo- Wherein the composition is selected from the group consisting of metallo-naphthalocyanine. The compound according to claim 1, wherein said compound, a stereoisomer, derivative or salt thereof; The photosensitizer, or a combination thereof, is encapsulated in a vesicle. 6. The composition of claim 5, wherein the vesicle is a polymerome or a liposome. [5] The method of claim 5, wherein the vesicle is selected from the group consisting of poly (ethylene glycol): PEG, poly (2-methyloxazoline), polydimethylsiloxane (PDMS) A block selected from the group consisting of poly (caprolactone: PCL), poly (lactide): PLA, and poly (methyl methacrylate: PMMA) ). ≪ / RTI > The composition of claim 1, wherein the composition for H ₂ S delivery is visible light sensitive. The composition of claim 1, wherein the composition is capable of delivering H ₂ S intracellularly. The composition of claim 1, wherein the composition provides cytoprotective, apoptosis inhibiting, or a combination thereof against oxidative stress. A compound represented by the general formula (1) of claim 1, a stereoisomer, a derivative, or a pharmaceutically acceptable salt thereof; And Down's syndrome, Alzheimer's disease, diabetes, and cardiovascular disease, comprising a singlet oxygen ( ¹ O ₂ ) photosensitizer. A method of treating Parkinson's disease, comprising administering to a subject, simultaneously or sequentially, a compound of formula (1), an isomer, derivative or pharmaceutically acceptable salt thereof and a singlet oxygen ( ¹ O ₂ ) , Down's syndrome, Alzheimer's disease, diabetes, and cardiovascular disease.

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