δ-oxo hydrazide-hydrazone derivative compounds exhibiting anticancer activity and their synthesis methods.
Patent Information
- Authority / Receiving Office
- TR · TR
- Patent Type
- Patents
- Current Assignee / Owner
- ISTANBUL UNIVSI CERRAHPASA REKTORLUGU
- Filing Date
- 2022-12-20
- Publication Date
- 2026-06-22
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Abstract
Description
1 TARIFF δ-OXO HYDRAZIDE-HYDRAZONE DERIVATIVE EXHIBITING ANTICANCER ACTIVITY COMPOUNDS AND METHODS OF SYNTHESIS OF THESE COMPOUNDS Technical Field to Which the Invention Relates 5 The invention exhibits anticancer activity on breast (MCF-7) and prostate cancer (PC3) cells. while showing no effect on normal breast epithelial cells (ME-16C) at the same dose. δ-oxo hydrazide-hydrazone derivative compounds that do not cause toxicity and these It deals with the synthesis methods of compounds. State of the Art Cancer is caused by gene mutations and uncontrolled cell proliferation in the body. It is a disease characterized by the growth of abnormal cells. World Health Organization According to the International Agency for Cancer Research (IARC) 2020 world cancer statistics. According to the report, an estimated 19.3 million new cancer cases occur worldwide each year, and 15 Approximately 10 million cancer deaths occur annually. According to 2020 statistics, women... Breast cancer is the most commonly diagnosed type of cancer. An estimated 2.3 million new cases of breast cancer occur annually. Cancer cases were observed in 11.7% of cases, followed by lung (11.4%), colorectal (10.0%), and prostate cancer. This is followed by stomach (7.3%) and gastric (5.6%) cancers. Therefore, breast cancer is the leading cause. 20 worldwide are working to develop new drugs that may have an effect against cancer. Intensive work is being carried out. Currently, the rapidly increasing number of patients necessitates increased usage. The serious side effects caused by these drugs include toxicity to healthy cells and tumors. Several factors, such as the development of drug resistance, increase the importance of these studies. Doxorubicin, an anthracycline derivative, is the most commonly used and potent antiviral agent for breast cancer. It is one of the chemotherapeutic agents, and doxorubicin has a response rate of 25% for metastatic lesions. The success rate is approximately 25-40%. With doxorubicin use, cancer cells respond to the drug. resistance and toxicity of doxorubicin on non-cancerous cells Problems such as the development of resistance to chemotherapy drugs are observed. This is the most significant factor hindering the success of cancer chemotherapy. Continuous and monotonous chemotherapy... The use of this compound increases drug resistance in cancer cells and makes them more susceptible to the drug. 30 This leads to certain complications and reduces the response to treatment. Furthermore, chemotherapy can cause specific problems. 2 Considering that it is administered periodically at intervals, continuous use can lead to resistance to the drug. Acquired resistance limits the clinical benefit of even the most advanced drugs. At this point... New drugs need to be developed. Furthermore, doxorubicin has a low risk of... Although it appears to be very effective at killing cancer cells at certain concentrations, the same It is highly toxic even to normal cells at certain concentrations. Doxorubicin, etc., and the other 5... The most common potential side effects resulting from the use of chemotherapy drugs are: weakness, nausea, vomiting, hair loss, decreased blood counts, weakened immunity Symptoms include hair loss, mouth sores, diarrhea or constipation, darkening or peeling of the skin. It is redness. Although breast cancer is thought to most commonly affect women, breast cancer can also occur in men. 10 It can be seen that some men have abnormalities in their family that increase the risk of breast cancer. It acquires (mutated) genes, particularly those called BRCA2. A mutation in one of several genes can make a person more susceptible to breast and prostate cancers. This makes them a high-risk owner [1]. Prostate cancer is one of the most common types of cancer in men, with a frequency of 15%. In terms of incidence, it is stated as 28 per 100,000 worldwide. American Cancer According to the association's data, men's lifetime risk of encountering prostate cancer... The risk is reported to be 16.7%, and the risk of death is 2.5%. This applies to every 5-6 men. Everyone has a risk of developing prostate cancer during their lifetime. Worldwide, every... While a person is diagnosed with prostate cancer every 3 minutes, a prostate 20 disease occurs every 14 minutes. Cancer-related deaths occur. In prostate cancer, the tumor is quite large. It can exhibit aggressive behavior and attack bones and other organs. These organs include... The breast is also included. In the known state of the art, Schiff represents a hydrazide-hydrazone derivative of some category. There have been numerous studies on the synthesis of compounds and their anticancer activities. Pregnolonone-cyanoacetylhydrazone derivatives have potential anticancer properties. It has been found that they are agents. The synthesized heterocyclic compounds are used in lung cancer (NCI- High inhibitory effect on H460) and breast adenocarcinoma (MCF-7) cells. They have shown this (Mohareb and Al-Omran 2012). In the current technique, a recent 30-study study on flubiprofen ester hydrazide derivatives According to the research, these compounds show promising efficacy as anticancer agents. Conjugated furan derivatives exhibit potential anticancer activity. 3 For example, the compound flubiprofen ester hydrazide targets ovarian carcinoma and leukemia cells. It inhibits its proliferation and metastasis (Cui et al., 2015). In the current state of the art, hydrazide-hydrazones of 3-hydroxy-2-naphthoic acid, They showed interesting antitumor activity against HepG2 and 769-P cell lines. It has been found. In particular, N-[(2-bromophenyl)methylidene]-3-hydroxynaphthalene-2-carbohydrazide, 5 Up to 39% increase in viability of 769-P cancer cell line and up to 67% for HepG2. It showed a time- and dose-dependent decrease (Popiołek et al., 2018). In current technology, numerous hydrazide-hydrazone derivatives containing the 5H-chromen-5-one group are used. Compounds were synthesized and these compounds were used against HCT116 (colon carcinoma cell), MGC803 10 called (gastric carcinoma cell) and Huh7 (hepatoma carcinoma cell) When the anticancer activities of the compounds were examined against three different human cell lines Some have shown greater activity than the positive control drug 5-fluorouracil. (Mohareb, EL-Sharkawy, and Al Farouk 2019). A mutation in one of several genes, including one called BRCA2, can cause a person to... the condition that makes them at high risk for breast and prostate cancers and 15 In prostate cancer seen in male individuals, the tumor can spread to other organs, including the breast. Considering the possibility of metastasis, both breast (MCF-7) and anticancer without any toxicity against prostate (PC-3) cancer cells. The need for new compounds exhibiting activity is increasing day by day. The technique... In its known form, although Schiff represents some category of hydrazide-hydrazone 20 Although the effects of derivative compounds on anticancer activity are known, both breast Healthy breast epithelial cells are effective against both (MCF-7) and prostate (PC-3) cancer cells. (ME-16C) shows anticancer activity at the same dose without any toxicity. A compound that exhibits this behavior does not yet exist. The current technique includes 25 that have an effect against cancer, especially breast cancer. There is intensive work worldwide to develop new drugs that can demonstrate this. Although measures are being taken, there are serious side effects caused by the drugs currently in use. This means that the drugs in question cause toxicity in non-cancerous cells. There are also problems such as the development of resistance to the use of these drugs. This is the issue. Drugs with anticancer efficacy used in current technology have a low efficacy rate of 30%. Although it appears to be very effective at killing cancer cells at certain concentrations, the same At that concentration, it is quite toxic even to normal cells. In addition, in men 4 due to reasons such as metastasis, genetic factors, etc. any that affects both prostate and breast cancers that can be seen It is not available in the known state of the composite technique. Consequently, the nozzle (MCF-7) and It shows anticancer activity against prostate (PC-3) cancer cells, at the same dose. 5 that showed no toxicity on healthy breast epithelial cells (ME-16C) The development of a new compound has become necessary. Brief Description and Objectives of the Invention The invention demonstrates anticancer activity on breast (MCF-7) and prostate cancer (PC3) cells. while showing, any 10 on normal mammary epithelial cells (ME-16C) at the same dose δ-oxo hydrazide-hydrazone derivative compounds that do not cause toxicity and these The synthesis methods of the compounds are described. The general structure of the compounds subject to the invention is explained. The formula is represented by X. Formula X 15 Among these compounds, N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo- The compound pentanhydrazide strongly inhibits the growth of cancer cell lines. while having no cytotoxic effect on normal cells at the same concentration It has been observed that there is no effect. All the synthesized compounds that are the subject of the invention have anticancer properties. When evaluated in terms of activity, these compounds target breast (MCF-7) and / or prostate 20 In addition to showing significant inhibitory activity against (PC-3) cancer cells these compounds show no effect against normal healthy cells. It has been proven. One aim of the invention is to target breast (MCF-7) and / or prostate (PC-3) cancer cells. It exhibits anticancer activity, and when used, it increases the resistance of cancer cells. The goal is to discover new compounds that will not be revealed otherwise. The compounds that are the subject of the discovery must be novel. This eliminates the possibility of cancerous cells developing resistance. Continuous use of a single compound increases drug resistance in cancer cells and makes them more resistant to the drug. This makes it more sensitive to the substance and reduces the treatment response. The subject of the invention... Thanks to these compounds, the problem in question has been solved. Another aim of the invention is to treat both breast (MCF-7) and prostate (PC-3) cancer. The goal is to achieve an anticancer effect against cancer cells with the use of a single drug. Specifically... In men, simultaneous metastasis occurs due to various reasons such as genetic factors. It affects both prostate and breast cancers, which can be seen as cancers that can occur simultaneously. because any compound is not available in the known state of the art The situation where two different drugs are used against breast and prostate cancer cells is 10 Male individuals who have both diseases have additional substances in their bodies This causes them to take in chemicals. The compounds subject to the invention are both in the nipple (MCF-7). and simultaneously exhibit anticancer activity against prostate (PC-3) cancer cells. The problem is eliminated thanks to the fact that they demonstrate this. The invention... The subject is the administration of δ-oxo hydrazide-hydrazone derivative compounds at the specified doses. 15 The result is anticancer against both breast (MCF-7) and prostate (PC-3) cancer cells. The fact that it shows activity, inhibition of cell proliferation within 48 hours and This is achieved by causing cell death. Another aim of the invention is to target breast (MCF-7) and prostate (PC-3) cancer cells. While exhibiting anticancer activity, the same dose of healthy breast epithelial cells (ME-16C) 20 The goal is to identify compounds that show no toxicity. Explanation of the Figures Figure 1. N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanehydrazide compound (Formula 1) IR spectrum of 25 Figure 2. N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanehydrazide compound (Formula 1) 1HNMR spectrum Figure 3. N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanehydrazide compound (Formula 1) 13CNMR spectrum Figure 4. N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide compound 30 IR spectrum of (Formula 2) 6 Figure 5. N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide compound. 1HNMR spectrum of (Formula 2) Figure 6. N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide compound. 13CNMR spectrum of (Formula 2) Figure 7. N'-(4-methoxybenzylidene)-5-oxo-5-p-tolylpentanhydrazide compound (Formula 5 3) belonging to the IR spectrum Figure 8. N'-(4-methoxybenzylidene)-5-oxo-5-p-tolylpentanhydrazide compound (Formula 3) 1HNMR spectrum Figure 9. N'-(4-methoxybenzylidene)-5-oxo-5-p-tolylpentanehydrazide compound (Formula 3) 13CNMR spectrum of 10 Figure 10. N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanhydrazide IR spectrum of compound (Formula 4) Figure 11. N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanhydrazide 1HNMR spectrum of compound (Formula 4) Figure 12. N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanhydrazide 15 13CNMR spectrum of compound (Formula 4) Figure 13. N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl) pentanhydrazide compound. (Formula 5) IR spectrum Figure 14. N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl) pentanhydrazide compound. (Formula 5) 1HNMR spectrum 20 Figure 15. N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl) pentanhydrazide compound. (Formula 5) 13CNMR spectrum Detailed Description of the Invention The invention exhibits anticancer activity on breast (MCF-7) and prostate cancer (PC3) cells. while showing no effect on normal breast epithelial cells (ME-16C) at the same dose. δ-oxo hydrazide-hydrazone derivative compounds that do not cause toxicity and these It relates to the synthesis methods of compounds. The general structure of the compounds that are the subject of the invention is the formula. It is indicated by an X. 7 Formula X The compounds that are the subject of the invention are: • N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanhydrazide, 5 • N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanehydrazide, • N'-(4-methoxybenzylidene)-5-oxo-5-p-tolylpentanhydrazide, • N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanehydrazide • N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl) pentanhydrazide These are compounds. When these compounds are evaluated in terms of anticancer activity, 10 the compounds have a significant effect against breast (MCF-7) and / or prostate (PC-3) cancer cells. In addition to exhibiting inhibitory activity, these compounds also affect healthy breast epithelium. It has been proven that it does not show any toxic effects against ME-16C cells. Formula X 15 Here, R is selected from the following formulas; 8 R: , , R1 R2 R3 , R4 R5 In the case where the group R in the said Formula X is R=R1, the obtained N'-(4-5 The compound methoxybenzylidene)-5-oxo-5-phenylpentanehydrazide is represented by Formula 1. Formula 1 It is a white solid synthesized with an 88% yield and has a melting point of 199-200ºC. It is within the range of 10. IR (ATR) υmax / cm-1: 3279 (NH), 3049 (CH, aryl), 2933 (CH, alkyl), 1663, 1604 (2C=O), 1505 (C=N), 1380 (CO), 1021 (NN), 822 (CH, aryl) 1H NMR (500 MHz, DMSO) δ: 9.87 (brs, 1H), 7.99 (d, J = 7.1 Hz, 2H), 7.78 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.90 (d, J = 9 8.8 Hz, 2H), 3.84 (s, 3H), 3.14 (t, J = 7.2 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.24- 2.18 (m, 2H). 13C NMR (126 MHz, DMSO) δ: 200.2, 200.1, 174.2, 168.4, 161.1, 160.9, 146.1, 142.9, 137.0, 133.5, 133.5, 129.1, 129.1, 128.9, 128.6, 128.3, 127.2, 114.7, 114.6, 55.6, 37.8, 37.6, 33.6, 31.3, 20.1, 19.6. 5 LC-MS (m / z): 324 (M+). In the case where the group R in the said Formula X is R=R2, N'-(4- The compound (methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide has the formula 2. It is shown. It is a white solid synthesized with an 80% yield and has a melting point of 121-122.5ºC. It is within this range. IR (ATR) υmax / cm-1: 3200 (NH), 3081 (CH, aryl), 2954 (CH, alkyl), 1665, 1607 (2C=O), 1504 (C=N), 1394 (CO), 1026 (NN), 819 (CH, aryl). 1H NMR (500 MHz, DMSO) δ: 11.09 (brs, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.89 (s, 1H), 15 7.55-7.52 (m, 4H), 6.95 (d, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.09 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.4 Hz, 2H), 1.93-1.87 (m, 2H). 13C NMR (126 MHz, DMSO) δ: 199.2, 199.1, 174.2, 168.4, 160.8, 146.18, 142.9, 138.4, 135.7, 130.2, 129.2, 128.5, 127.3, 114.5, 55.7, 33.6, 31.5, 20.0, 19.2. LC-MS (m / z): 357 (M+-1). 20 In the case where the group R in the said Formula X is R= R3, then N'-(4- The compound methoxybenzylidene)-5-oxo-5-p-tolylpentanehydrazide is represented by Formula 3. Formula 2 Formula 3 It is a white solid synthesized with a yield of 90% and has a melting point of 133-134ºC. It is within this range. IR (ATR) υmax / cm-1: 3244 (NH), 3031 (CH, aryl), 2951 (CH, alkyl), 1681, 1601 (2C=O), 5 1488 (C=N), 1391 (CO), 1029 (NN), 810 (CH, aryl). 1H NMR (500 MHz, DMSO) δ: 11.15 (brs, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.30 (t, J = 8.2 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H), 1.93-1.87 (m, 2H). 13C NMR (126 MHz, DMSO) δ: 199.7, 199.5, 174.2, 168.5, 161.0, 160.8, 146.1, 143.7, 10 142.8, 134.6, 134.6, 129.6, 129.6, 128.9, 128.5, 128.4, 127.3, 114.6, 55.6, 37.7, 37.5, 33.7, 31.7, 21.5, 20.2, 19.5. LC-MS (m / z): 337 (M+-1). In the case where the group R in the said Formula X is R=R4, then N'-(4- The compound (methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanhydrazide has formulas 4 to 15. It is shown. Formula 4 11 It is a white solid synthesized with a yield of 92% and has a melting point of 154-155ºC. It is within this range. IR (ATR) υmax / cm-1: 3238 (NH), 3061 (CH, aryl), 2959 (CH, alkyl), 1668, 1646 (2C=O), 1507 (C=N), 1245 (CO), 1023 (NN), 830 (CH, aryl). 1H NMR (500 MHz, DMSO) δ: 11.09 (brs, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.89 (s, 1H), 5 7.54 (d, J = 8.8 Hz, 2H), 7.01 (t, J = 9.2 Hz, 4H), 3.81 (s, 3H), 3.77 (s, 3H), 3.02 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H) 1.91-1.88 (m, 2H). 13C NMR (126 MHz, DMSO) δ: 198.6, 198.4, 174.2, 168.5, 163.4, 161.0, 160.8, 146.1, 142.8, 130.6, 130.0, 128.9, 128.5, 127.3, 114.6, 114.2, 55.9, 55.7, 37.3, 37.2, 33.7, 31.8, 20.3, 19.7. 10 LC-MS (m / z): 353 (M+-1). In the case where the group R in the said Formula X is R=R5, the obtained N'-(4- The compound methoxybenzylidene)-5-oxo-5-(thiophen-2-yl)pentanhydrazide has the formula 5. It is shown. Formula 5 It is a white solid synthesized with a yield of 92% and has a melting point of 130-131ºC. It is within this range. IR (ATR) υmax / cm-1: 3233 (NH), 3070 (CH, aryl), 2931 (CH, alkyl), 1651, 1604 (2C=O), 1504 (C=N), 1236 (CO), 1021 (NN), 827, 714. 20 1H NMR (500 MHz, DMSO) δ: 11.17 (brs, 1H), 7.98 (t, J = 5.7 Hz, 1H), 7.95 (d, J = 3.8 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.23-7.21 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 1.94-1.91 (m, 2H). 12 13C NMR (126 MHz, DMSO) δ: 193.4, 193.2, 174.1, 168.4, 161.1, 160.9, 146.1, 144.2, 142.8, 135.1, 135.0, 133.6, 133.5, 129.1, 129.1, 128.9, 128.6, 127.3, 127.3, 114.7, 55.7, 38.3, 38.1, 33.6, 31.7, 20.4, 19.8. LC-MS (m / z): 329 (M+-1). The invention has an anticancer effect against breast (MCF-7) and prostate (PC-3) cancer cells. while showing activity on healthy breast epithelial cells (ME-16C) at the same dose Synthesis of δ-oxo hydrazide-hydrazone derivative compounds that show no toxicity. The stages are shown below, in the order Reaction i, Reaction ii, etc. The invention has anticancer properties against breast (MCF-7) and prostate (PC-3) cancer cells. while showing activity on healthy breast epithelial cells (ME-16C) at the same dose Synthesis of δ-oxo hydrazide-hydrazone derivative compounds that show no toxicity. method; i. δ-oxo esters, in ethanol, approximately 4-6 hours, hydrazine monohydrate 15 As a result of the condensation reaction, 5-oxo-5-phenylpentanhydrazide, 5-(4- 13 chlorophenyl)-5-oxopentanhydrazide, 5-oxo-5-p-tolylpentanhydrazide, 5-(4- methoxyphenyl)-5-oxopentanhydrazide or 5-oxo-5-(thiophen-2- 1) Preparation of pentanhydrazide compounds, ii. the resulting 5-oxo-5-phenylpentanhydrazide, 5-(4-chlorophenyl)-5- oxopentanhydrazide, 5-oxo-5-p-tolylpentanehydrazide, 5-(4-methoxyphenyl)-5-5 oxopentanhydrazide or 5-oxo-5-(thiophen-2-yl)pentanhydrazide compounds Reflexology with p-anisaldehyde in dimethylformamide (DMF) medium for 6-8 hours being subjected to the reaction and N'-(4-methoxybenzylidene)-5-oxo-5- phenylpentanehydrazide (Compound 1), N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5- oxo-pentanhydrazide (Compound 2), N'-(4-methoxybenzylidene)-5-oxo-5-p-10 toylpentanhydrazide (Compound 3), N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5- oxo-pentanhydrazide (Compound 4) or N'-(4-methoxybenzylidene)-5-oxo-5- Synthesis of (thiophen-2-yl) pentanhydrazide (Compound 5) compounds It includes the processing steps. Here; 5-oxo-5-phenylpentanhydrazite dimethylformamide Reflex reaction with p-anisaldehyde in (DMF) medium for 6-8 hours 15 As a result, the compound N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanehydrazide (Compound 1), 5-(4-chlorophenyl)-5-oxopentanhydrazide in dimethylformamide (DMF) medium with p-anisaldehyde as a result of being subjected to a reflex reaction for 6-8 hours, N'-(4- methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide compound (Compound 2), 5-oxo-5- p-tolylpentanhydrazide was mixed with p-anisaldehyde in dimethylformamide (DMF) medium for 6-8 hours. as a result of being subjected to a reflex reaction throughout, N'-(4-methoxybenzylidene)-5-oxo- 5-p-tolylpentanhydrazide compound (Compound 3), 5-(4-methoxyphenyl)-5-oxopentanhydrazide Reflexology with p-anisaldehyde in dimethylformamide (DMF) medium for 6-8 hours as a result of being subjected to the reaction N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5- oxo-pentanhydrazide compound (Compound 4) and 5-oxo-5-(thiophen-2-yl)pentanhydrazide 25 Reflexology with p-anisaldehyde in dimethylformamide (DMF) medium for 6-8 hours as a result of being subjected to the reaction N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl) Pentanhydrazide compound (Compound 5) is being synthesized. The compounds Formula 1, 2, 3, 4 and 5, which are the subject of this invention, were synthesized with a yield of 80-92%. The cytotoxic activity tests of the compounds subject to the invention (Formula 1, 2, 3, 4 and 5) were carried out in 30 days. To achieve this, from the American Type Culture Collection (ATCC Distributor: LGC) Standards, Wessel, Germany) breast cancer (MCF-7; ATCC Number: HTB-22), 14 prostate cancer (PC-3; ATCC Number: CRL-1435) and breast epithelial tissue (ME- 16C; ATCC) human cell lines were purchased and these cells were treated with 0.25% Trypsin / EDTA After separation with the solution, the cells were placed in DMEM with 10% FBS and 0.1 mg / ml primosin. The cells were inoculated into a new culture dish containing LG. Subsequently, the aforementioned cells... Incubated at 37°C in a 5% CO2 incubator. The incubated cell media are 48 5 The cells were renewed every hour and passaged every 5-6 days. The newly synthesized compounds are 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Cancer (MCF-7 and PC-3) and normal (ME-16C) cell lines were identified using the (MTT) test. It has been tested for its cytotoxic activities. MTT test, yellow tetrazolium Based on their ability to reduce salt MTT to purple formazan crystals, living cells can 10 To assess cell viability by determining mitochondrial activity. The MTT test (Thermo, Category No: M6494) is used according to the manufacturer's instructions. This was carried out. The cells were placed in 96-well plates at a density of 1x10⁴ cells / well. They were seeded and incubated in a 5% CO2 incubator at 37°C. The cells were then 48 It was treated with compounds of different concentrations (1-1000 µM) for 15 hours. After incubation, 10 µl of MTT solution was added to the cells, and the cells were left for 4 hours. It was incubated throughout. After incubation, 100 µl of dissolution solution was added. The samples were prepared and incubated overnight. Absorbance was measured using a microplate reader. Measurements were taken at 570 nm using Synergy H1 (Biotek). In all tests, the positive control was... cells were treated with doxorubicin and untreated cells were treated with the compound as a negative control. 20 was used. As a solvent for the compounds, the final concentration was 0.5% v / v. Dimethyl sulfoxide was used in a way that would not exceed [a certain threshold]. All tests were performed three times, and each One of them was made in triplicate. The compounds subject to the invention (Formulas 1, 2, 3, 4 and 5) at concentrations of 1-1000 µM Their cytotoxic activities have been investigated. These synthesized compounds were used in prostate (PC-3) and breast cancer 25 (MCF-7) cancer and in vitro cytotoxicity in normal breast epithelial cell (ME-16C) lines To evaluate the effects, cells were exposed to varying concentrations for 48 hours. The compounds that are the subject of the invention (Formulas 1, 2, 3, 4 and 5) were treated with (1-1000 µM). In the trials, various cancer cells known in the current technique were used as positive controls. The commonly preferred chemotherapy drug for treatment is doxorubicin 30 It has been used. When the obtained results are evaluated, it is understood that the compounds Formulas 1, 2, 3, 4, and 5, which are the subject of the invention, With IC50 values ranging from 7.52 ± 0.32 to 57.33 ± 0.92 µM, to cancer cells It has been found to have cytotoxic activity against the virus. However, this dose No antiproliferative effect was observed in healthy cells within this range. This also applies to the invention. This shows that all synthesized compounds have selective cytotoxic properties. 5 Among the selected cancer cell lines were breast cancer (MCF-7) cells, a new type of cell line. synthesized δ-oxo hydrazide-hydrazones are more susceptible to antiproliferative effects. It has been observed that this is the case. Doxorubicin, used as a positive control in cytotoxicity tests, respectively breast cancer (MCF-7), prostate cancer (PC-3), and normal breast epithelial cells (ME-16C) 10 Significantly higher concentrations of 0.83 ± 0.07, 0.75 ± 0.04 and 0.80 ± 0.09 µM were observed in the lines. It has shown low IC50 values. Doxorubicin, at low concentrations, is cancer-causing. Although it appears to be very effective at killing these cells, at the same concentration it can kill normal cells. It is also highly toxic. When cytotoxic activity data were examined, N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-15 5-oxo-pentanhydrazide (Compound 4) is used in breast cancer (MCF-7) and prostate cancer (PC-3). The most active against the cells were with IC50 values of 7.52 ± 0.32 μM and 10.19 ± 0.52 μM, respectively. It was determined to be a compound, and the results are shown in Table 1. Also, The IC50 value of compound Formula 4 in normal breast epithelial tissue (ME-16C) cells is 250.43. It has been determined as ± 1.88. 20 Table 1. In vitro cytotoxic activity of the δ-oxo hydrazide-hydrazone compounds subject to the invention. IC50 (µM) Compound MCF-7 PC-3 ME-16C Compound 1 25.41 ± 0.82 57.33 ± 0.92 545.32 ± 0.75 Compound 2 10.27 ± 0.63 15.00 ± 0.40 158.37 ± 1.90 Compound 3 9.25 ± 0.54 12.57 ± 0.67 227.65 ± 1.76 Compound 4 7.52 ± 0.32 10.19 ± 0.52 250.43 ± 1.88 Compound 5 12.54 ± 0.84 10.81 ± 0.71 672.18 ± 2.69 16 Doxorubicin 0.83 ± 0.07 0.75 ± 0.04 0.80 ± 0.09 As clearly shown in Table 1, N'-(4-methoxybenzylidene)- is represented by Formula 4. The compound 5-(4-methoxyphenyl)-5-oxo-pentanhydrazide inhibits the growth of cancer cell lines. While strongly inhibiting, compound Formula 4 at the same concentration is normal. It has been observed that it has no cytotoxic effects on cells. Furthermore, Formula 5 The compound N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl)pentanhydrazide, represented by , while characterized by high cytotoxic effects on both cancer cells At the same dose, it does not show antiproliferative activity in normal cells. Consequently, the subject of the invention is N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanhydrazide (Compound 1), N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide (Compound 2), 10 N'-(4-methoxybenzylidene)-5-oxo-5-p-tolylpentanhydrazide (Compound 3), N'-(4- methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanhydrazide (Compound 4) and N'-(4- methoxybenzylidene)-5-oxo-5-(thiophen-2-yl)pentanhydrazide (Compound 5) compounds When evaluated in terms of anticancer activity, these compounds are found in breast cancer (MCF-7). and / or significant inhibitory activity against prostate (PC-3) cancer cells 15 In addition to demonstrating this, these compounds, at the same dose, affect normal breast epithelial cells (ME- It has been proven that it does not show any toxic effects against 16C). 25 17 REFERENCES [1] Male Breast Cancer. Male Breast Cancer - Neolife Medical Center. (nd). Retrieved November 15, 2022, from https: / / www.neolife.com.tr / elektrikdeki- breast cancer / 10 20
Claims
18 REQUESTS 1. δ-oxo hydrazide-hydrazone, denoted by formula X, possesses anticancer activity. It is a derivative compound, Formula X Here, R is selected from the following formulas; 2. Which of the following forms is a compound with respect to Claim 1, having any of the following formulas? feature; • N'-(4-methoxybenzylidene)-5-oxo-5-phenylpentanehydrazide (Compound 1) 19 • N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide (Compound) 2) • N'-(4-methoxybenzylidene)-5-oxo-5-p-tolylpentanehydrazide (Compound 3) • N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanehydrazide (Compound 4) or 5 • N'-(4-methoxybenzylidene)-5-oxo-5-(thiophen-2-yl) pentanhydrazide (Compound 5) It is the fact that.
3. If R = R1, then according to Claim 1 or 2, shown by Formula 1, one compound 4. It is a compound according to claim 3 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5- The melting point of phenylpentanehydrazide (Formula 1) is 199-200 ºC. that is. 15 5. It is a compound according to claim 3 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5- IR spectrum of phenylpentanehydrazide (Formula 1), IR (ATR) υmax / cm-1: 3279 (NH), 3049 (CH, aryl), 2933 (CH, alkyl), 1663, 1604 (2C=O), 1505 (C=N), It contains peaks of 1380 (CO), 1021 (NN), and 822 (CH, aryl).
6. It is a compound according to claim 3 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5-20 The 1H-NMR spectrum of phenylpentanehydrazide (Formula 1) is shown in 1H-NMR (500 MHz, DMSO) δ: 9.87 (brs, 1H), 7.99 (d, J = 7.1 Hz, 2H), 7.78 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.14 (t, J = 7.2 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.24- 2.18 It includes the peaks (m, 2H). 25 7. It is a compound according to claim 3 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5- The 13C-NMR spectrum of phenylpentanehydrazide (Formula 1) is shown in 13C-NMR (126 MHz, DMSO) δ: 200.2, 200.1, 174.2, 168.4, 161.1, 160.9, 146.1, 142.9, 137.0, 133.5, 133.5, 129.1, 129.1, 128.9, 128.6, 128.3, 127.2, 114.7, 114.6, 55.6, 37.8, It includes peaks of 37.6, 33.6, 31.3, 20.1, and 19.
6.
8. It is a compound according to claim 3 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5- Liquid chromatography-mass spectrum of phenylpentanhydrazide (Formula 1) (LC-MS (m / z)), LC-MS (m / z): 357 (M+-1).324 (M+) peak included. 5 9. If R = R², then according to Claim 1 or 2, shown by Formula 2, one of the following is true. compound 10. It is a compound according to claim 9 and its property is; N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-10 The melting point of 5-oxo-pentanhydrazide (Formula 2) is 121-122.5ºC. It is the fact that.
11. It is a compound according to claim 9 and its property is; N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)- IR spectrum of 5-oxo-pentanhydrazide compound (Formula 2), IR (ATR) υmax / cm- 1: 3200 (NH), 3081 (CH, aryl), 2954 (CH, alkyl), 1665, 1607 (2C=O), 1504 (C=N), 15 It contains peaks of 1394 (CO), 1026 (NN), and 819 (CH, aryl).
12. It is a compound according to claim 9 and its property is; N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)- The 1H-NMR spectrum of 5-oxo-pentanhydrazide (Formula 2) is shown in the 1H-NMR diagram. (500 MHz, DMSO) δ: 11.09 (brs, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.89 (s, 1H), 7.55- 7.52 (m, 4H), 6.95 (d, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.09 (t, J=7.2 Hz, 2H), 2.67 20 (t, J=7.4 Hz, 2H), includes peaks of 1.93-1.87 (m, 2H).
13. It is a compound according to claim 9 and its property is; N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)- The 13C-NMR spectrum of 5-oxo-pentanhydrazide (Formula 2) is shown in the 13C-NMR diagram. (126 MHz, DMSO) δ: 199.2, 199.1, 174.2, 168.4, 160.8, 146.18, 142.9, 138.4, 21 135.7, 130.2, 129.2, 128.5, 127.3, 114.5, 55.7, 33.6, 31.5, 20.0, 19.2 peaks It includes.
14. It is a compound according to claim 9 and its property is; N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)- Liquid chromatography-mass analysis of 5-oxo-pentanhydrazide compound (Formula 2) The spectrum (LC-MS (m / z)) contains LC-MS (m / z): 357 (M+-1) peaks. 5 15. If R = R3, then according to Claim 1 or 2, shown by Formula 3, one compound 16. A compound according to claim 15, with the property of; N'-(4-methoxybenzylidene)-5-oxo-5-p- The melting point of toylpentanhydrazide (Formula 3) is 133-134ºC. 10 17. It is a compound according to claim 15 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5-p- IR spectrum of toylpentanhydrazide (Formula 3), IR (ATR) υmax / cm-1: 3244 (NH), 3031 (CH, aryl), 2951 (CH, alkyl), 1681, 1601 (2C=O), 1488 (C=N), It contains peaks 1391 (CO), 1029 (NN), and 810 (CH, aryl).
18. It is a compound according to claim 15 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5-p-15 The 1H-NMR spectrum of toylpentanhydrazide (Formula 3), 1H-NMR (500 MHz, DMSO) δ: 11.15 (brs, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.30 (t, J = 8.2 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H), 1.93-1.87 (m, 2H) It includes its peaks. 20 19. It is a compound according to claim 15 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5-p- The 13C-NMR spectrum of toylpentanhydrazide (Formula 3), 13C-NMR (126 MHz, DMSO) δ: 199.7, 199.5, 174.2, 168.5, 161.0, 160.8, 146.1, 143.7, 142.8, 134.6, 134.6, 129.6, 129.6, 128.9, 128.5, 128.4, 127.3, 114.6, 55.6, 37.7, 37.5, It includes peaks of 33.7, 31.7, 21.5, 20.2, and 19.
5. 25 22 20. It is a compound according to claim 15 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5-p- Liquid chromatography-mass spectrum of toylpentanhydrazide (Formula 3) (LC-MS (m / z)), LC-MS (m / z): contains 337 (M+-1) peaks.
21. If R=R4, then a compound is formed according to Claim 1 or 2, represented by Formula 4.
23. It is a compound according to claim 21 and its property is; N'-(4-methoxybenzylidene)-5-(4- The melting temperature of the compound methoxyphenyl)-5-oxo-pentanhydrazide (Formula 4) The temperature should be 154-155ºC.
24. It is a compound according to claim 21 and its property is; N'-(4-methoxybenzylidene)-5-(4- The IR spectrum of the compound methoxyphenyl)-5-oxo-pentanhydrazide (Formula 4), IR 10 (ATR) υmax / cm-1: 3238 (NH), 3061 (CH, aryl), 2959 (CH, alkyl), 1668, 1646 (2C=O), 1507 (C=N), 1245 (CO), 1023 (NN), 830 (CH, aryl) peaks It includes.
25. It is a compound according to claim 21 and its property is; N'-(4-methoxybenzylidene)-5-(4- The 1H-NMR of the compound methoxyphenyl)-5-oxo-pentanhydrazide (Formula 4) is 15 spectrum, 1H-NMR (500 MHz, DMSO) δ: 11.09 (brs, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.89 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.01 (t, J = 9.2 Hz, 4H), 3.81 (s, 3H), 3.77 (s, 3H), 3.02 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H) 1.91-1.88 (m, It includes 2H) peaks.
26. It is a compound according to claim 21 and its property is; N'-(4-methoxybenzylidene)-5-(4-20 13C-NMR of methoxyphenyl)-5-oxo-pentanhydrazide (Formula 4) spectrum, 13C-NMR (126 MHz, DMSO) δ: 198.6, 198.4, 174.2, 168.5, 163.4, 161.0, 160.8, 146.1, 142.8, 130.6, 130.0, 128.9, 128.5, 127.3, 114.6, It includes peaks of 114.2, 55.9, 55.7, 37.3, 37.2, 33.7, 31.8, 20.3, and 19.
7.
27. It is a compound according to claim 21 and its property is; N'-(4-methoxybenzylidene)-5-(4-25 Liquid chromatography of the compound methoxyphenyl)-5-oxo-pentanhydrazide (Formula 4) The mass spectrum (LC-MS (m / z)) contains LC-MS (m / z): 353 (M+-1) peaks. 23 28. If R=R5, then according to Claim 1 or 2, shown by Formula 5, one compound 29. It is a compound according to claim 28 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5-5 The melting point of (thiophen-2-yl) pentanhydrazide (Formula 5) is 130-131ºC. It is the fact that.
30. A compound according to claim 28, with the property of; N'-(4-methoxybenzylidene)-5-oxo-5- IR spectrum (ATR) of (thiophen-2-yl) pentanhydrazide (Formula 5) υmax / cm-1: 3233 (NH), 3070 (CH, aryl), 2931 (CH, alkyl), 1651, 1604 (2C=O), 10 It includes peaks 1504 (C=N), 1236 (CO), 1021 (NN), 827, and 714.
31. A compound according to claim 28, with the property of; N'-(4-methoxybenzylidene)-5-oxo-5- The 1H-NMR spectrum of (thiophen-2-yl) pentanhydrazide (Formula 5), 1H- NMR (500 MHz, DMSO) δ: 11.17 (brs, 1H), 7.98 (t, J = 5.7 Hz, 1H), 7.95 (d, J = 3.8 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.23-7.21 (m, 1H), 6.96 (d, 15 J = 8.8 Hz, 2H), 3.78 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), It includes peaks of 1.94-1.91 (m, 2H).
32. It is a compound according to claim 28 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5- The 13C-NMR spectrum of (thiophen-2-yl) pentanhydrazide (Formula 5) shows the 13C- NMR (126 MHz, DMSO) δ: 193.4, 193.2, 174.1, 168.4, 161.1, 160.9, 146.1, 20 144.2, 142.8, 135.1, 135.0, 133.6, 133.5, 129.1, 129.1, 128.9, 128.6, 127.3, It includes the peaks of 127.3, 114.7, 55.7, 38.3, 38.1, 33.6, 31.7, 20.4, and 19.
8.
33. It is a compound according to claim 28 and its property is; N'-(4-methoxybenzylidene)-5-oxo-5- Liquid chromatography-mass analysis of (thiophen-2-yl) pentanhydrazide compound (Formula 5) The spectrum (LC-MS (m / z)) contains LC-MS (m / z): 329 (M+-1) peaks. 25 24 34. Which is a method of synthesis of a compound according to any of the previous requirements? feature; i. δ-oxo esters, hydrazine monohydrate in ethanol for 4-6 hours As a result of the condensation reaction, 5-oxo-5-phenylpentanhydrazide, 5-(4- chlorophenyl)-5-oxopentanhydrazide, 5-oxo-5-p-tolylpentanhydrazide, 5-(4-5 methoxyphenyl)-5-oxopentanhydrazide or 5-oxo-5-(thiophen-2- 1) Preparation of pentanhydrazide compounds, ii. the resulting 5-oxo-5-phenylpentanhydrazide, 5-(4-chlorophenyl)-5- oxopentanhydrazide, 5-oxo-5-p-tolylpentanehydrazide, 5-(4-methoxyphenyl)-5- 10 of the compounds oxopentanhydrazide or 5-oxo-5-(thiophen-2-yl)pentanhydrazide Reflexology with p-anisaldehyde in dimethylformamide (DMF) medium for 6-8 hours being subjected to the reaction and N'-(4-methoxybenzylidene)-5-oxo-5- phenylpentanehydrazide (Compound 1), N'-(4-methoxybenzylidene)-5-(4-chlorophenyl)-5- oxo-pentanhydrazide (Compound 2), N'-(4-methoxybenzylidene)-5-oxo-5-p- toylpentanhydrazide (Compound 3), N'-(4-methoxybenzylidene)-5-(4-methoxyphenyl)-5-15 oxo-pentanhydrazide (Compound 4) or N'-(4-methoxybenzylidene)-5-oxo-5- Synthesis of (thiophen-2-yl) pentanhydrazide (Compound 5) compounds It includes the steps of the process.
35. A method according to claim 34, and its characteristic is; in step (ii) of the process 5-oxo-5- In the case of using phenylpentanhydrazide, N'-(4-methoxybenzylidene)-5-oxo-5-20 This is the synthesis of the compound phenylpentanehydrazide (Compound 1).
36. It is a method according to claim 34 and its feature is; in step (ii) of the process 5-(4- In the case of using chlorophenyl)-5-oxopentanhydrazide, N'-(4- methoxybenzylidene)-5-(4-chlorophenyl)-5-oxo-pentanhydrazide compound (Compound 2) It is the synthesis. 25 37. A method according to claim 34, and its characteristic is; in step (ii) of the process 5-oxo-5- In the case of using p-tolylpentanhydrazide, N'-(4-methoxybenzylidene)-5- This is the synthesis of the compound oxo-5-p-tolylpentanhydrazide (Compound 3).
38. It is a method according to claim 34 and its feature is; in step (ii) of the process 5-(4- In the case of using methoxyphenyl)-5-oxopentanhydrazide, N'-(4-30 methoxybenzylidene)-5-(4-methoxyphenyl)-5-oxo-pentanhydrazide compound (Compound 4) synthesis.
39. A method according to claim 34, and its characteristic is; in step (ii) of the process 5-oxo-5- In the case of using (thiophen-2-yl)pentanhydrazide, N'-(4-methoxybenzylidene)- This is the synthesis of the compound 5-oxo-5-(thiophen-2-yl)pentanhydrazide (Compound 5).
40. For use in cancer treatment, according to any of Claims 1-33. compound. 5 41. For use in the treatment of breast cancer, according to any of 1-33. a compound.
42. For use in the treatment of prostate cancer, according to any of 1-33. a compound.
43. A pharmaceutical containing a compound according to any of claims 1-33. composition.
44. A pharmaceutical according to Claim 43 for use in cancer treatment. composition.
45. A pharmaceutical according to Claim 44 for use in the treatment of breast cancer. composition. 15 46. A pharmaceutical according to Claim 44 for use in the treatment of prostate cancer. composition.
47. Containing a pharmaceutical composition according to any of claims 43-46. It is an anti-cancer drug.
48. A 20-year-old containing a compound as an active ingredient according to any of claims 1-33. medicine.
49. A compound obtained by a synthesis method according to claim 34. 30 35