SILICON PHTHALOCYANINE, A WATER-SOLUBLE PYRIDINE GROUP WITH HIGH ACTIVITY IN THE LUNG CANCER CELL LINE.

Abstract

The invention relates to silicon phthalocyanine compounds containing pyridine groups that exhibit activity in cancer cells resistant to metal-containing compounds, have a broader spectrum of activity than metal-containing compounds, have lower toxic effects, reduced side effects, and possess anti-cancer and antioxidant effects, making them potential anti-tumor drugs, and also relates to the synthesis methods of these compounds.

Description

1 TARIFF PYRIDINE HAS HIGH ACTIVITY IN THE LUNG CANCER CELL LINE. SILICON PHTHALOCYANINE, WHICH CONTAINS A GROUP OF THIS FORM AND IS SOLUBLE IN WATER. Technical Area 5 The invention explores how cancer cells exhibit resistance to metal-containing compounds. exhibiting activity, having a broader spectrum of action than metal-containing compounds, and It has a lower toxic effect and reduced side effects compared to metal-containing compounds. It could be used as a potential anti-tumor drug, an anti-cancer (cancer-treating) drug. Silicon phthalocyanine compounds containing pyridine groups with antioxidant effects, and these 10 It deals with the synthesis methods of compounds. State of the Art According to the latest report from the World Health Organization, cancer is prevalent in 183 countries. In 177 cases, it is the top three leading cause of death before the age of 30-69. (2022 data shows 15 cases) According to the report, approximately 20 million new cancer cases are reported, while about 10 million people die from it. He lost his life due to the disease. In general, cancer incidence and mortality. This trend is rapidly increasing worldwide; this is due to both the aging population and It is considered to be growth. Furthermore, many of them are associated with socioeconomic development. It appears that the prevalence of the main risk factors for cancer is increasing. 20 Lung cancer is caused by the uncontrolled multiplication and development of lung cells. It is a type of cancer characterized by the development of a neoplasm within the lung. With an estimated 2.5 million new cancer cases and 1.8 million deaths, lung cancer, In 2022, it was the third most frequently diagnosed cancer and the leading cause of cancer deaths. That is the reason. Lung cancer accounts for approximately one in eight cancers diagnosed (12.40%) in 25 years. and represents one in five deaths (18.70%). Lung cancer in men While cancer is a leading cause of morbidity and mortality in women, breast cancer is a major cause in men. It ranks second after cancer. When looking at the total numbers, lung cancer is the most common. The incidence and mortality rate of cancer in men is approximately twice as high as in women. It is higher. In North Africa and Eastern Europe, this rate is four to five times higher. 30 It has been reported. Turkey has the highest incidence of lung cancer in men. Lung Cancer has many genetic and non-genetic risk factors. DNA repair polymorphism observed in genes associated with enzymes that play a role in mechanisms 2 changes constitute an important step in terms of lung cancer risk It is known to play a role in the production of interleukin, which stimulates immune system cells. In genes, cyclooxygenase enzymes involved in inflammation are tumor suppressor genes. The p53 gene exhibits characteristics similar to those seen in many other genes, such as the oncogenes KRAS and EGFR. These deteriorations pose a threat for lung cancer. In addition, tobacco and tobacco products 5 Tobacco products are among the leading risk factors for lung cancer. polycyclic aromatic hydrocarbons and N-nitrosoamines contained in the products It is responsible for the carcinogenic effect. With the elucidation of its double helix structure... the three-dimensional structure of deoxyribonucleic acid (DNA) which becomes a molecular target It can be modified without changing the nucleotide sequence, therefore its function is 10 Studies have shown that it can be modified. DNA has anticancer properties. It is also noteworthy in the search for drug molecules. The aim is to enable molecules to interact with DNA in various ways. electrostatic, with chemical bonds (hydrophobic, ionic, hydrogen bonding and Van der Waals), This interaction occurs through intercalation or groove binding. Thus, DNA interacts with other molecules. structure, replication, transcription, repair or other 15 involving DNA By directly affecting fundamental cellular processes, it can cause cancer, genetic disorders, and infectious diseases. The clinic aims to treat various conditions, including diseases. In the clinic, cancer... Although it is known that various drugs targeting DNA are used in its treatment, DNA itself... interacting with and directly influencing various cellular processes, essential for cancer growth. By targeting molecules or pathways, it increases treatment effectiveness and minimizes side effects. The search continues for more selective and potent drug molecules that can lower blood pressure. Palchaudhuri and Hergenrother used DNA in the development of anti-cancer molecules. In addition to their interactions with other substances, it is also important to investigate drug-protein interactions. Albumin, the most abundant protein in human blood, is a good anti-cancer molecule. It is a carrier candidate. Albumin, which has a long half-life, remains in the body for 25 years. Colloidal chain fatty acids, amino acids, hormones, metal ions, and various drugs. It facilitates dissolution and transport. It also grows rapidly and is nutritious. It is taken up and metabolized in higher amounts by cancer cells that are deficient in it. Their presence provides a significant advantage in targeting these regions. Today, there are 30 different cancer treatment methods, including surgery, radiotherapy, and chemotherapy. Despite the methods used, writing areas can be extended as much as needed. The methods applied address neuronal, dermatological, gastrointestinal, and swallowing difficulties. side effects that negatively affect human life, such as hematological and cardiac problems It is known to have this. Therefore, an alternative with a safer side effect profile is preferable. 3 Treatment strategies and new molecules are needed. This alternative treatment... Photodynamic Therapy (PDT), one of the methods used, is used to diagnose and treat many types of cancer. It is used in treatment. The basis of Photodynamic Therapy (PDT) is a light-sensitive medium. Exposure of matter to light results in the photochemical depletion of molecular oxygen in the environment. It is based on the formation of reactive oxygen species as a result of reactions. The resulting reactive 5 Species cause cell death by interacting with biomolecules (DNA, proteins, etc.). Information has been reported indicating that it causes [unrelated] Photodynamic Therapy (PDT) is frequent. Low toxicity in the dark compared to preferred treatment methods, post-treatment Advantages include a low recurrence rate and minimally invasive treatment. It is located. 10 In Photodynamic Therapy (PDT), photosensitizers such as hematoporphyrin and photofrin are used. These agents are frequently preferred in clinical practice, however, the chemical structures of these agents are complex. their low tumor selectivity, and the long duration of their elimination from the body There are a number of negative effects, such as the time it takes. Therefore, the photosensitizing compounds that are planned to be synthesized are 15 the purity of their chemical structures, their solubility with commonly used solvents availability, ease of synthesis steps, low cost, high singlet oxygen It has high efficiency and achieves strong absorption between 600-800 nm. It is expected to possess a number of features such as these. In this context, the most frequently preferred One of the groups of molecules obtained is phthalocyanines. The phthalocyanine ring has 20 The metal ion at the center significantly influences the chemical and physical properties of the compound. It has an effect. Phthalocyanine compounds, which contain silicon in their central cavity. Its effects against various types of cancer have been studied and proven effective in vitro, in vivo, and Clinical studies are available in the literature. We chose to use them in this study. The pyridine analogs, which are the substituted group we have developed, have rich biological and pharmacological properties. It is known to have an effect. In addition, it is positioned axially. The aggregation of compounds containing substituted groups reduces the aggregation of these compounds, and this situation It is thought that it will enhance the effect of Photodynamic Therapy (PDT). Additionally, pyridine... by converting the quaternary ammonium structures in its composition into pyridinium groups It increases the water solubility of compounds. Water-soluble photosensitizer 30 Compounds are also preferred in Photodynamic Therapy (PDT) due to their ease of application. is being done. 4 In the known state of the art, DNA is used in patent number 201814010. Interactive silicon exhibiting topoisomerase inhibition and having anti-cancer effects. Phthalocyanine compounds have been mentioned. Patent number 201814012 describes water-soluble silicon phthalocyanine. compounds with anti-5 efficacy against lung, liver, breast, and melanoma cancer types. Cancer characteristics have been examined. The patent with registration number 201923135 describes an acetylcholinesterase inhibitor in water. Soluble cobalt (II) phthalocyanine compounds have been investigated. Considering the studies in the current state of the art, the synthesized In order for compounds to be used as medicine, they need to be injected directly into the body. It is important that it provides the necessary solubility in water. Considering the explanations and studies above, the impact Its spectrum is broader than that of metal-containing compounds, and its toxic effect is similar to that of metal-containing compounds. It has reduced side effects compared to other compounds and is water-soluble. Thanks to this, 15 potential anti-tumor drugs can be injected directly into the body. silicon containing a pyridine side group that can be used for anti-cancer (cancer-treating) purposes. Phthalocyanine compounds have been synthesized. Problems that the invention aims to solve. Silicon (IV) phthalocyanine (DT-2,3-20) containing a water-soluble pyridine side group. The effects of the compound SiQ on DNA / BSA interactions and the efficacy of in vitro photodynamic therapy (PDT). It is an examination. Lung cancer, one of the most common types of cancer, is genetic and It can be caused by many non-genetic factors. According to the World Health Organization... According to reports published in 2024, there were approximately 2.5 million new cases of lung cancer. While 25 cases are reported, approximately 1.8 million people have lost their lives due to this disease. It has lost many lives. The incidence and mortality of this disease are rapidly increasing worldwide. In the clinic, the most commonly used drugs for lung cancer treatment are carboplatin and doxorubicin. Given that chemotherapeutic drugs like cisplatin have serious side effects When these are in place, new strategies and molecules can be developed against this disease. It is among the priorities of scientists. Photodynamic Therapy (PDT) 30 Photosensitizer, selectively destroys tumor tissue in the presence of oxygen and light. Its effectiveness and low side effect profile have made it an attractive option in recent years. It has started to become a field. Pyridines are known in the literature to contain groups rich in biological activity. Photodynamics of combining group and silicon phthalocyanine compounds These are quite remarkable in that they are new agents with potential for use in DDT (Dialectical Behavioral Therapy). It is considered valuable. In the literature, silicon compounds are mentioned in relation to lung cancer. A limited number of studies have investigated the effect of Photodynamic Therapy (PDT) on cell lines. There is a study available. Because of the high incidence and mortality rates of lung cancer. Photodynamic Therapy (PDT) effects of the compounds subject to the invention on the A549 cell line Their potential and relationship to apoptotic processes constitute the technical impact of the invention. The compounds in question, which are the subject of this discovery and are being introduced to the literature for the first time, have DNA 10 resistance against the A549 cell line. The interaction and efficacy of photodynamic therapy (PDT) in vitro have been investigated for the first time. Shapes Figure 1a: Hydrolytic and photonuclease activities of DT-2,3-SiPcQ compound (dark) Figure 1b: Hydrolytic and photonuclease activities of DT-2,3-SiPcQ compound (5 min light) 15 Figure 1c: Hydrolytic and photonuclease activities of DT-2,3-SiPcQ compound (15 min light) Figure 1d: Hydrolytic and photonuclease activities of DT-2,3-SiPcQ compound (30 min light) Figure 1e: Hydrolytic and photonuclease activities of DT-2,3-SiPcQ compound (60 min light) Detailed Description of the Invention 20 STAGE 1 The first stage of the discovery is the synthesis of the compound 2,3-bis(pyridin-4-ylthio)propan-1-ol. The structure of the synthesis is given in Formula 2 below. FORMULA 2 30 6 STAGE 2 In the second stage of the invention, 2,3-bis(pyridin-4-) synthesized in the first stage Using the compound ylthio)propan-1-ol, 2,3-bis(pyridin-4- Synthesis of the compound ylthio)propoxy)phthalocyanine silicon (IV) occurs It is derived from this synthesis. This synthesis is given in Formula 3 below. 5 15 FORMULA 3 20 STAGE 3 In the third stage of the discovery, 2,3-bis(pyridin-4-) synthesized in the second stage 2,3-bis(pyridin- by using the compound ylthio)propoxy) phthalocyanine silicon (IV) 4-ylthio)propoxy)phthalocyanine silicon (IV) iodide compound is obtained. The diagram in Formula 1 is given below. 25 FORMULA 1 30 7 The invention relates to silicon containing water-soluble 2,3-bis(pyridine-4-thio)propoxy groups. This is related to the phthalocyanine compound and its synthesis method. The synthesized 2,3- bis(pyridin-4-ylthio)propoxy)phthalocyanine silicon (IV) iodide is the molecular name silicon phthalocyanine compound containing 2,3-bis(pyridine-4-thio)propoxy groups This is shown with formula 1. 5 The hydrolytic and photonuclease activities of the DT-2,3-SiPcQ compound are shown in Figure 1; a) a) Darkness. b) 5 min light c) 15 min light d) 30 min light e) 60 min light. (Light: white, dose: 17.5) mW / cm2). Band 1: DNA control; bands 2-4: DNA + 1.3 (0.5 µM – 1 µM – 10 µM); Bands 5-7: DNA + 2,3 (0.5 µM – 1 µM – 10 µM); Bands 8-10: DNA + Methylene blue (0.5 µM – 1 µM – 10 µM). 10 In in vitro studies conducted after the synthesis of the compound shown in Formula 1 It damages DNA in the presence of light and is phototoxic in lung cancer cell lines. It has been observed to have activity (Figure 1a-1e). Anti in the known state of the technique Gastrointestinal problems, hematological, neuronal, observed with tumor drugs 15 has a safer side effect profile due to its dermatological and cardiac side effects. Alternative treatment strategies and targeted Formula 1 water-soluble new silicon Phthalocyanines have been identified. Table 1. IC50 values ​​of DT-2,3-SiPcQ compound in cell line A549. Dark (µM) Light (30 min) (µM) DT-2,3-SiQ 39.82 ± 2.27 0.39 ± 0.08 Methylene blue 8.69 ± 1.44 6.47 ± 1.49 Table 1 shows the results of in vitro studies conducted with the compound designated as Formula 1. The compound did not damage DNA in the dark, but it did damage DNA when light was applied. It has been observed to cause damage. Furthermore, its effects on lung cancer cell lines have been noted. Studies have shown that it exhibits a strong phototoxic effect. The synthesis method for the compound given in Formula 1 is described below in steps: • Pyridine-4-thiol and potassium tert-butylate are added to a single-necked flask and dried. Mixing in DMSO until homogeneous, 8 • Add 2,3-dibromopropanol to the dissolved mixture using a dropper. by dripping and removing dissolved oxygen several times, • The reaction mixture is stirred in a nitrogen atmosphere at 70 ℃ for two days. • Obtained by completely vaporizing the mixture after it has been cooled to room temperature, • The crude product remaining after evaporation has a 5% concentration in 100 ml of chloroform. Dissolving and extracting three times with 100 ml of pure water each time, • The organic phase after extraction is dried with MgSO4 to remove chloroform. evaporation, • The resulting crude product is passed through an aluminum oxide-loaded column in 2 fractions. The fraction was taken with 10 ml MeOH and 10 ml chloroform, purified, and 2,3-10 Preparation of the compound bis(pyridin-4-ylthio)propan-1-ol, • 165 mg (0.267 mmol) silicon phthalocyanine dichloride and a single-necked balloon were added. 150 mg (0.534 mmol) of 2,3-bis(pyridin-4-ylthio)propan-1-ol is added to 20 ml dissolution in toluene, • Stirring for 10 minutes in a nitrogen atmosphere at room temperature, 15 • Quickly add a spatula tip of NaH to the resulting mixture and removal of dissolved oxygen from the nitrogen atmosphere several times, • Reflexology in a nitrogen atmosphere at 110 ℃ for 24 hours, • Complete evaporation of the solvent from the mixture after it has cooled to room temperature, • The resulting raw product is passed through the column using a neutral silica packing material for 20 seconds. Obtained with dichloromethane and ethanol, purified to produce 2,3-bis(pyridin-4- Preparation of the ylthio)propoxy)phthalocyanine silicon (IV) compound, • 2,3-bis(pyridin-4-ylthio)propoxy)phthalocyanine silicon was added to a 50 ml flask. (IV) compound is taken and dissolved in 3 ml of chloroform, • Add 2.5 ml of methyl iodide CH3I and wrap in aluminum foil at room temperature for 25 minutes. It should be covered, kept in a sealed container, and stirred for 3 days. • The product that settles in the medium is filtered and then washed first with chloroform and hexane. Water-soluble 2,3-bis(pyridin-4-) is obtained by drying in a vacuum oven. Preparation of the compound ylthio)propoxy)phthalocyanine silicon (IV) iodide (1a). Industrial Application of the Invention According to WHO reports, cancer is among the leading causes of death worldwide. It is included. The methods currently used in lung cancer treatment are serious. 9 It is known to have side effects. Therefore, a safer side effect profile is preferred. There is a need for alternative treatment strategies and new molecules. The successful completion of the proposed project would address the high incidence and treatment requirements of this condition. Photodynamic therapy is an alternative method in the treatment of difficult-to-treat lung cancer. This will lead to the emergence of new agents that have the potential to be used in (FDT). 5 The fact that these compounds will be used for the first time also means the results are expected to be impactful. It is believed that there is patent potential in this case. 15 25

Claims

9 REQUESTS 1. It is a formula 1 compound that is soluble in water, 10 20 FORMULA 1 2. 2,3-bis(pyridin-4-ylthio)propoxy)phthalocyanine silicon (IV) iodide (1a) formula silicon phthalocyanine containing 2,3-bis(pyridin-4-ylthio)propoxy) groups It is a compound. 25 3. Formula 1, which is water-soluble and has the property of being found in human lung (A549) It is characterized by having phototoxic activity in cancer cell lines.

4. This is the synthesis method for the water-soluble compound mentioned in Claim 1, and its properties are: • Pyridine-4-thiol and potassium tert-butylate are added to a single-necked flask. Mixing in dry DMSO until homogeneous, 30 • Add 2,3-dibromopropanol to the dissolved mixture using a dropper. by dripping and removing dissolved oxygen several times, • The reaction mixture is stirred in a nitrogen atmosphere at 70 ℃ for two days. 9 • By completely vaporizing the mixture after it has cooled to room temperature. being done, • The crude product remaining after evaporation is mixed with 100 ml of chloroform. Dissolving and extracting three times with 100 ml of pure water each time, • The organic phase after extraction is dried with MgSO4 to obtain 5% chloroform. evaporation, • The resulting crude product is passed through an aluminum oxide-loaded column in 2 fractions.

2. Fraction is taken with 10 ml MeOH and 10 ml chloroform, and purified. and the preparation of the compound 2,3-bis(pyridin-4-ylthio)propan-1-ol, • 165 mg (0.267 mmol) of silicon phthalocyanine di 10 was placed in a single-necked balloon. chloride and 150 mg (0.534 mmol) of 2,3-bis(pyridin-4-ylthio)propan-1-ol added dissolved in 20 ml of toluene, • Stirring for 10 minutes in a nitrogen atmosphere at room temperature, • Quickly add a spatula tip of NaH to the resulting mixture and several removals of dissolved oxygen from the nitrogen atmosphere, 15 • Reflexology in a nitrogen atmosphere at 110 ℃ for 24 hours, • The solvent of the mixture is completely removed when it has cooled to room temperature. evaporation, • The obtained raw product is processed through the column using a neutral silica packing material. Obtained with dichloromethane and ethanol, purified to produce 2,3-bis(pyridin-20 Preparation of the compound 4-ylthio)propoxy)phthalocyanine silicon (IV), • Add 2,3-bis(pyridin-4-ylthio)propoxy)phthalocyaninato to a 50 ml flask. Taking silicon (IV) compound and dissolving it in 3 ml of chloroform, • Add 2.5 ml of methyl iodide CH3I and store in aluminum foil at room temperature. It is coated and mixed in a sealed container for 3 days, 25 • The product that settles in the medium is filtered and then washed first with chloroform and hexane. Water-soluble 2,3-bis(pyridin-4-) is obtained by drying in a vacuum oven. obtained from the compound ylthio)propoxy)phthalocyanine silicon (IV) iodide (1a). The process includes the following steps.

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