WO2024060834A1 - Use of fluoropyridoxal in preparing medicament against cancer - Google Patents
Use of fluoropyridoxal in preparing medicament against cancer Download PDFInfo
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- WO2024060834A1 WO2024060834A1 PCT/CN2023/109823 CN2023109823W WO2024060834A1 WO 2024060834 A1 WO2024060834 A1 WO 2024060834A1 CN 2023109823 W CN2023109823 W CN 2023109823W WO 2024060834 A1 WO2024060834 A1 WO 2024060834A1
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- Prior art keywords
- fluoropyridoxal
- cancer
- ovarian cancer
- present
- cells
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the invention belongs to the field of biomedical technology, and particularly relates to the application of fluoropyridoxal in the preparation of anti-cancer drugs.
- ovarian cancer is a common malignant tumor in women, and its mortality rate ranks first among all tumor-related deaths in women. Since ovarian cancer lacks obvious external symptoms in the early stage, the disease is hidden and can easily lead to misdiagnosis. Most ovarian cancer patients have metastases when diagnosed, and simple surgical treatment is difficult to completely eliminate the tumor, so postoperative recurrence is very likely to occur. More than 70% of patients are already in the advanced stage when diagnosed, and about 70% of patients relapse within two years after surgery.
- Drug therapy is an auxiliary method for surgical treatment of ovarian cancer.
- the initial treatment drugs mainly use alkylating agents, including cyclophosphamide.
- alkylating agents including cyclophosphamide.
- platinum, gemcitabine, docetabine, etoposide, paclitaxel, etc. are gradually being used for the treatment of ovarian cancer.
- clinical practice has proven that a single chemotherapy drug is not effective in ovarian cancer, so combined administration has become the main treatment plan for clinical ovarian cancer.
- Anti-ovarian cancer drugs currently under development are mainly targeted small molecule drugs.
- the present invention provides an application of fluoropyridoxal in the preparation of anti-cancer drugs.
- fluoropyridoxal in the preparation of a medicament for preventing and/or alleviating and/or treating cancer.
- the effective dose of the fluoropyridoxal is: the in vitro killing IC50 is 20-100 ⁇ M.
- the chemical structural formula of the fluoropyridoxal is as follows:
- the cancer is ovarian cancer.
- the drug for preventing and/or alleviating and/or treating cancer contains fluoropyridoxal and a pharmaceutically acceptable carrier.
- the dosage form of the drug for preventing and/or alleviating and/or treating cancer is tablets, granules, capsules, suspensions, syrups, emulsions or injections.
- the fluoropyridoxal acts by inhibiting the proliferation and growth of cancer cells.
- the fluoropyridoxal acts by inducing senescence-like death, cycle arrest and apoptosis of cancer cells.
- the invention also provides the application of fluoropyridoxal in the preparation of health care products for improving and/or preventing ovarian cancer.
- the present invention also provides the use of fluoropyridoxal in the preparation of food for improving and/or preventing ovarian cancer.
- fluoropyridoxal of the present invention can effectively inhibit the proliferation and growth of human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2.
- the fluoropyridoxal of the present invention can prepare an effective drug for treating ovarian cancer.
- the expected income and commercial value after the transformation of the technical solution of the present invention are: the vitamin B6 family members themselves are cheap and easy to obtain, and have been used in clinical applications as nutritional supplements for many years. As water-soluble vitamins, their safe dosages are relatively high. Based on the previous patent, this invention designs fluorine atom substitution, and its raw materials The cost is low, the transformed product has a good killing effect on tumor cells, and has good commercial transformation prospects and social welfare value.
- the technical solution of the present invention fills the technical gap in the industry at home and abroad: the previous understanding of the vitamin B6 family has always been based on the assumption that pyridoxal phosphate is the only active form in the family, and it exerts an inhibitory effect on tumors through its anti-inflammatory and antioxidant effects.
- the present invention that is, pyridoxal itself has biological activity and can exert an inhibitory effect on ovarian cancer in a non-phosphorylated state, uses fluorine atoms to replace the hydroxyl group in the 5th hydroxymethyl group on the pyridoxal ring in pyridoxal, thereby completely limiting the possibility of conversion to pyridoxal phosphate, which not only enhances the killing effect of pyridoxal on ovarian cancer cells, but also provides guidance for the use of vitamin B6 family derivatives in clinical treatment.
- ovarian cancer is a malignant tumor with the highest mortality rate in the female reproductive system.
- HRD homologous recombination deficiency
- the present invention selects intermediate products of cell metabolism, and after modifying them, it kills cells through an action mechanism that is different from traditional chemotherapy drugs, and is expected to fill the gaps in the current treatment methods for ovarian cancer.
- Pyridoxal phosphate is a recognized active form of the vitamin B6 family.
- the functions of pyridoxal phosphate were status or body content as a testing standard.
- the anti-cancer effect of pyridoxal phosphate is believed to come from its anti-inflammatory and antioxidant effects, while pyridoxal is only the precursor of pyridoxal phosphate and needs to be absorbed within cells. Biological activity can only be exerted after phosphorylation.
- the present invention constructed a pyridoxal modified compound that replaced the phosphate group binding site, completely limiting the possibility of its conversion into pyridoxal phosphate, and verified that non-phosphorylation in ovarian cancer cells
- the killing effect of pyridoxal overcomes traditional technical prejudices.
- Figure 1 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line SKOV3 provided by the embodiment of the present invention
- Figure 2 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line OVCAR3 provided by the embodiment of the present invention
- Figure 3 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line 3AO provided by the embodiment of the present invention
- Figure 4 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line ES-2 provided by the embodiment of the present invention
- Figure 5 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line SKOV3 provided by the embodiment of the present invention.
- Figure 6 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line OVCAR3 provided by the embodiment of the present invention.
- Figure 7 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line 3AO provided by the embodiment of the present invention.
- Figure 8 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line ES-2 provided by the embodiment of the present invention.
- the embodiments of the present invention provide applications of fluoropyridoxal in the preparation of medicaments for preventing and/or alleviating and/or treating ovarian cancer.
- the effective dose of fluoropyridoxal provided by the embodiment of the present invention is: the IC50 of ovarian cancer cells in in vitro experiments is lower than 100 ⁇ M.
- the F atom replaces the hydroxyl group in the hydroxymethyl group on the pyridoxine ring.
- the fluoropyridoxal provided in the embodiment of the present invention is used to prepare drugs for alleviating and/or preventing and/or treating ovarian cancer.
- Figures 1 to 4 are schematic diagrams showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2 provided by embodiments of the present invention.
- the gray lines are the solvent control, that is, the growth of each ovarian cancer cell line after equal volume DMSO treatment
- the black lines are the growth of each ovarian cancer cell line after adding 0.5mM F-PL.
- the abscissa is the time after cell treatment (unit is hour), and the ordinate on the left is the cell index (Cell index), whose value is proportional to the number of cells.
- RTCA living cell label-free counting method
- DMSO so that the final concentration in each well is 0.5mM. After letting it stand for 30 minutes, set the automatic scanning interval to 15 minutes and detect the cell proliferation curve. The total scanning time is 72 hours.
- Figures 5 to 8 are IC50 fitting curves of fluoropyridoxal killing human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2 provided by the embodiments of the present invention.
- Figure 5-8 the ordinate on the left side Compared with the control group, the survival rate of cells after treatment with different concentrations of pyridoxal or fluoropyridoxal for 72 hours is compared with the control group.
- the abscissa is the drug concentration.
- the solid line is the fitting curve of the cell survival rate after treating the cells with gradient concentrations of fluoropyridoxal for 72 hours.
- the dotted line is the fitting curve of the cell survival rate after treating the cells with gradient concentrations of pyridoxal for 72 hours.
- the IC50 concentration of fluoropyridoxal F-PL against four ovarian cancer cells is much lower than that of the pyridoxal PL prototype: the IC50 of pyridoxal-treated SKOV3 cells is 0.516mM, and the IC50 of fluoropyridoxal-treated SKOV3 cells is 0.1041.
- the IC50 of pyridoxal-treated OVCAR3 cells is 0.4686mM, and the IC50 of fluoropyridoxal-treated OVCAR3 cells is 0.05714mM; the IC50 of pyridoxal-treated 3AO cells is 0.8725mM, and the IC50 of fluoropyridoxal-treated 3AO cells is 0.8725mM.
- the IC50 of ES-2 cells treated with pyridoxal is 0.3675mM, and the IC50 of ES-2 cells treated with fluoropyridoxal is 0.024mM.
- a 96-well plate and CCK-8 method were used to detect the reactivity of cells to pyridoxal PL and fluoropyridoxal F-PL.
- the gradient is 0, 0.01, 0.1, 0.5, 1, 10mM
- the final concentration gradient of fluoropyridoxal in each well is 0, 0.001, 0.01, 0.05, 0.1, 1mM.
Abstract
The present invention relates to the technical field of biopharmaceuticals, and particularly, to use of fluoropyridoxal in preparing a medicament against a cancer, comprising: use in preparing a medicament for preventing and/or relieving and/or treating a cancer. The cancer is ovarian cancer. The medicament for preventing and/or relieving and/or treating the cancer comprises fluoropyridoxal and a pharmaceutically acceptable carrier. The dosage form of the medicament for preventing and/or relieving and/or treating the cancer is a tablet, a granule, a capsule, a suspension, a syrup, an emulsion, or an injection. Fluoropyridoxal induces the senescence-like death, cycle retardation, and cell apoptosis in cancer cells. Fluoropyridoxal works by inducing the apoptosis of cancer cells. According to the present invention, fluoropyridoxal can effectively inhibit the proliferation and growth of human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2. Fluoropyridoxal of the present invention can be used as an effective therapy for treating ovarian cancer.
Description
本申请要求于2022年09月19日提交中国专利局、申请号为CN202211136057.5、发明名称为“一种氟代吡哆醛在制备用于抗癌症的药物中的用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application is required to be submitted to the China Patent Office on September 19, 2022. The application number is CN202211136057.5 and the invention name is "Use of fluoropyridoxal in the preparation of anti-cancer drugs". priority, the entire contents of which are incorporated into this application by reference.
本发明属于生物医学技术领域，尤其涉及一种氟代吡哆醛在制备用于抗癌症的药物中的应用。The invention belongs to the field of biomedical technology, and particularly relates to the application of fluoropyridoxal in the preparation of anti-cancer drugs.
目前，卵巢癌是女性常见的恶性肿瘤，其死亡率居女性肿瘤所致死亡率之首。由于卵巢癌早期缺乏明显的外显症状，病情隐匿，极易导致漏诊。大多数卵巢癌患者确诊时已出现转移，单纯的手术治疗难以彻底清除瘤灶，因此极易发生术后复发。超过70％的患者确诊时已属晚期，约70％的患者在术后两年内复发。Currently, ovarian cancer is a common malignant tumor in women, and its mortality rate ranks first among all tumor-related deaths in women. Since ovarian cancer lacks obvious external symptoms in the early stage, the disease is hidden and can easily lead to misdiagnosis. Most ovarian cancer patients have metastases when diagnosed, and simple surgical treatment is difficult to completely eliminate the tumor, so postoperative recurrence is very likely to occur. More than 70% of patients are already in the advanced stage when diagnosed, and about 70% of patients relapse within two years after surgery.
药物治疗是卵巢癌手术治疗的辅助手段，最初的治疗药物主要应用烷化剂类药物，包括环磷酰胺。随着新药研发的不断发展，铂类、吉西他滨、多西他滨、依托泊苷、紫杉醇等也逐渐被用于卵巢癌的治疗。但临床实践证明，单一化疗药物对卵巢癌的疗效不理想，因此联合给药方案成为临床卵巢癌的主要治疗方案。如环磷酰胺、顺铂联合用药以及紫杉醇与顺铂联合用药等等。目前在研的抗卵巢癌药物主要以靶向小分子药物为主。Drug therapy is an auxiliary method for surgical treatment of ovarian cancer. The initial treatment drugs mainly use alkylating agents, including cyclophosphamide. With the continuous development of new drug research and development, platinum, gemcitabine, docetabine, etoposide, paclitaxel, etc. are gradually being used for the treatment of ovarian cancer. However, clinical practice has proven that a single chemotherapy drug is not effective in ovarian cancer, so combined administration has become the main treatment plan for clinical ovarian cancer. Such as the combination of cyclophosphamide and cisplatin, the combination of paclitaxel and cisplatin, etc. Anti-ovarian cancer drugs currently under development are mainly targeted small molecule drugs.
现有技术尚没有关于氟代吡哆醛在制备治疗卵巢癌的药物的相关报道。There are no relevant reports on the use of fluoropyridoxal in the preparation of drugs for treating ovarian cancer in the prior art.
通过上述分析，现有技术存在的问题及缺陷为：Through the above analysis, the problems and defects of the prior art are as follows:
(1)现有技术尚没有关于氟代吡哆醛在制备治疗卵巢癌的药物的相关报道。(1) There are no relevant reports on the use of fluoropyridoxal in the preparation of drugs for the treatment of ovarian cancer in the prior art.
(2)尚未见维生素B6家族成员的修饰产物用作卵巢癌治疗的药物。(2) Modified products of vitamin B6 family members have not yet been used as drugs for the treatment of ovarian cancer.
发明内容Contents of the invention
针对现有技术存在的问题，本发明提供了一种氟代吡哆醛在制备用于抗癌症的药物中的应用。In view of the problems existing in the prior art, the present invention provides an application of fluoropyridoxal in the preparation of anti-cancer drugs.
为了实现上述发明目的，本发明提供以下技术方案：
In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:
一种氟代吡哆醛在制备用于预防和/或缓解和/或治疗癌症的药物中的应用。Use of fluoropyridoxal in the preparation of a medicament for preventing and/or alleviating and/or treating cancer.
优选的，所述氟代吡哆醛的有效剂量为：体外杀伤的IC50为20-100μM。Preferably, the effective dose of the fluoropyridoxal is: the in vitro killing IC50 is 20-100 μM.
优选的，所述氟代吡哆醛化学结构式如下：
Preferably, the chemical structural formula of the fluoropyridoxal is as follows:
Preferably, the chemical structural formula of the fluoropyridoxal is as follows:
优选的，所述癌症为卵巢癌。Preferably, the cancer is ovarian cancer.
优选的，所述用于预防和/或缓解和/或治疗癌症的药物包含氟代吡哆醛及药学上可接受的载体。Preferably, the drug for preventing and/or alleviating and/or treating cancer contains fluoropyridoxal and a pharmaceutically acceptable carrier.
优选的，所述用于预防和/或缓解和/或治疗癌症的药物的剂型为片剂、颗粒剂、胶囊剂、悬浮剂、糖浆剂、乳剂或注射剂。Preferably, the dosage form of the drug for preventing and/or alleviating and/or treating cancer is tablets, granules, capsules, suspensions, syrups, emulsions or injections.
优选的，所述氟代吡哆醛通过抑制癌细胞的增殖和生长起作用。Preferably, the fluoropyridoxal acts by inhibiting the proliferation and growth of cancer cells.
优选的，所述氟代吡哆醛通过诱导癌细胞衰老样死亡、周期阻滞和细胞凋亡起作用。Preferably, the fluoropyridoxal acts by inducing senescence-like death, cycle arrest and apoptosis of cancer cells.
本发明还提供了一种氟代吡哆醛在制备用于改善和/或预防卵巢癌的保健品中的应用。The invention also provides the application of fluoropyridoxal in the preparation of health care products for improving and/or preventing ovarian cancer.
本发明还提供了一种氟代吡哆醛在制备用于改善和/或预防卵巢癌的食品中的应用。The present invention also provides the use of fluoropyridoxal in the preparation of food for improving and/or preventing ovarian cancer.
与现有技术相比，本发明的优点和有益效果在于：Compared with the prior art, the advantages and beneficial effects of the present invention are:
第一、本发明氟代吡哆醛能够有效抑制人卵巢癌细胞系SKOV3、OVCAR3、3AO、ES-2的增殖和生长。First, fluoropyridoxal of the present invention can effectively inhibit the proliferation and growth of human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2.
第二，本发明的氟代吡哆醛能够制备治疗卵巢癌的有效药物。Secondly, the fluoropyridoxal of the present invention can prepare an effective drug for treating ovarian cancer.
第三，本发明的技术方案转化后的预期收益和商业价值为：维生素B6家族成员本身廉价易得，且作为营养补剂在临床应用多年，作为水溶性维生素其安全剂量较高。本发明在前期专利基础上，设计了氟原子取代，其原料
成本低，转化后的产物对肿瘤细胞杀伤效果好，具有良好的商业转化前景和社会福利价值。Third, the expected income and commercial value after the transformation of the technical solution of the present invention are: the vitamin B6 family members themselves are cheap and easy to obtain, and have been used in clinical applications as nutritional supplements for many years. As water-soluble vitamins, their safe dosages are relatively high. Based on the previous patent, this invention designs fluorine atom substitution, and its raw materials The cost is low, the transformed product has a good killing effect on tumor cells, and has good commercial transformation prospects and social welfare value.
第四，本发明的技术方案填补了国内外业内技术空白：既往对于维生素B6家族的理解一直立足于磷酸吡哆醛作为家族中唯一活性形式的假设，且通过其抗炎、抗氧化效应发挥对肿瘤的抑制效应。但本发明在前期研究基础上，即吡哆醛本身即具有生物学活性，可通过非磷酸化状态发挥对卵巢癌的抑制效应，使用氟原子取代了吡哆醛中吡哆环上的第5位羟甲基中羟基，从而完全限制了转化为磷酸吡哆醛的可能，不仅增强了吡哆醛对卵巢癌细胞的杀伤效应，也为维生素B6家族衍生物使用于临床治疗提供了思路上的指导。Fourth, the technical solution of the present invention fills the technical gap in the industry at home and abroad: the previous understanding of the vitamin B6 family has always been based on the assumption that pyridoxal phosphate is the only active form in the family, and it exerts an inhibitory effect on tumors through its anti-inflammatory and antioxidant effects. However, based on previous research, the present invention, that is, pyridoxal itself has biological activity and can exert an inhibitory effect on ovarian cancer in a non-phosphorylated state, uses fluorine atoms to replace the hydroxyl group in the 5th hydroxymethyl group on the pyridoxal ring in pyridoxal, thereby completely limiting the possibility of conversion to pyridoxal phosphate, which not only enhances the killing effect of pyridoxal on ovarian cancer cells, but also provides guidance for the use of vitamin B6 family derivatives in clinical treatment.
第五：本发明的技术方案解决了人们一直渴望解决、但始终未能获得成功的技术难题：卵巢癌是女性生殖系统死亡率最高的恶性肿瘤，尽管当前化疗药物的迭代使部分患者的预后得到了显著改善，但是化疗药物耐药始终是患者最终将面对的困境。以PARPi为首的靶向药物的开发使存在同源重组缺陷(HRD)的患者显著得到了获益，但在临床中，这类患者仅占总人群的50％，且由于HRD的存在，对传统化疗药物的反应性本就更好。而另外一半并未携带同源重组缺陷的患者，目前还没有针对性的治疗方案来改善预后。本发明选择细胞代谢的中间产物入手，在对其进行修饰后，通过有别于传统化疗药物的作用机制对细胞产生杀伤，有望补充当前卵巢癌治疗手段中的空白。Fifth: The technical solution of the present invention solves a technical problem that people have been eager to solve but have never been successful: ovarian cancer is a malignant tumor with the highest mortality rate in the female reproductive system. Although the current iteration of chemotherapy drugs has improved the prognosis of some patients, Significant improvement has been achieved, but resistance to chemotherapy drugs is always a dilemma that patients will eventually face. The development of targeted drugs led by PARPi has significantly benefited patients with homologous recombination deficiency (HRD). However, in clinical practice, such patients only account for 50% of the total population, and due to the existence of HRD, traditional drugs Chemotherapy drugs are inherently more responsive. The other half of patients who do not carry homologous recombination defects currently have no targeted treatment options to improve their prognosis. The present invention selects intermediate products of cell metabolism, and after modifying them, it kills cells through an action mechanism that is different from traditional chemotherapy drugs, and is expected to fill the gaps in the current treatment methods for ovarian cancer.
第六：本发明的技术方案克服了技术偏见：磷酸吡哆醛是公认的维生素B6家族活性形式，既往无论是营养学研究还是肿瘤相关的临床干预性研究，都是以磷酸吡哆醛的功能状态或体内含量作为检测标准进行的。且近年来的肿瘤学研究中，磷酸吡哆醛的抗癌效应被认为来自于其抗炎和抗氧化效应，而吡哆醛则仅仅是磷酸吡哆醛的前体物质，需要在细胞内被磷酸酯化后才能发挥生物学活性。本发明在前期研究基础上，构建了取代了磷酸酯基团结合位点的吡哆醛修饰化合物，完全限制了其转化为磷酸吡哆醛的可能，并验证了在卵巢癌细胞中非磷酸化的吡哆醛具有杀伤效应，克服了传统的技术偏见。Sixth: The technical solution of the present invention overcomes technical prejudice: Pyridoxal phosphate is a recognized active form of the vitamin B6 family. In the past, whether it was nutritional research or tumor-related clinical intervention research, the functions of pyridoxal phosphate were status or body content as a testing standard. In recent oncology research, the anti-cancer effect of pyridoxal phosphate is believed to come from its anti-inflammatory and antioxidant effects, while pyridoxal is only the precursor of pyridoxal phosphate and needs to be absorbed within cells. Biological activity can only be exerted after phosphorylation. Based on previous research, the present invention constructed a pyridoxal modified compound that replaced the phosphate group binding site, completely limiting the possibility of its conversion into pyridoxal phosphate, and verified that non-phosphorylation in ovarian cancer cells The killing effect of pyridoxal overcomes traditional technical prejudices.
图1是本发明实施例提供的氟代吡哆醛抑制人卵巢癌细胞系SKOV3生长的示意图；Figure 1 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line SKOV3 provided by the embodiment of the present invention;
图2是本发明实施例提供的氟代吡哆醛抑制人卵巢癌细胞系OVCAR3生长的示意图；Figure 2 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line OVCAR3 provided by the embodiment of the present invention;
图3是本发明实施例提供的氟代吡哆醛抑制人卵巢癌细胞系3AO生长的示意图；Figure 3 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line 3AO provided by the embodiment of the present invention;
图4是本发明实施例提供的氟代吡哆醛抑制人卵巢癌细胞系ES-2生长的示意图；Figure 4 is a schematic diagram showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell line ES-2 provided by the embodiment of the present invention;
图5是本发明实施例提供的氟代吡哆醛杀伤人卵巢癌细胞系SKOV3的IC50拟合曲线；Figure 5 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line SKOV3 provided by the embodiment of the present invention;
图6是本发明实施例提供的氟代吡哆醛杀伤人卵巢癌细胞系OVCAR3的IC50拟合曲线；Figure 6 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line OVCAR3 provided by the embodiment of the present invention;
图7是本发明实施例提供的氟代吡哆醛杀伤人卵巢癌细胞系3AO的IC50拟合曲线；Figure 7 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line 3AO provided by the embodiment of the present invention;
图8是本发明实施例提供的氟代吡哆醛杀伤人卵巢癌细胞系ES-2的IC50拟合曲线。Figure 8 is an IC50 fitting curve of fluoropyridoxal killing human ovarian cancer cell line ES-2 provided by the embodiment of the present invention.
下面将对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本申请的一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of this application.
本发明实施例提供的氟代吡哆醛在制备用于预防和/或缓解和/或治疗卵巢癌的药物中的应用。The embodiments of the present invention provide applications of fluoropyridoxal in the preparation of medicaments for preventing and/or alleviating and/or treating ovarian cancer.
本发明实施例提供的氟代吡哆醛的有效剂量为：体外实验对卵巢癌细胞的IC50均低于100μM。The effective dose of fluoropyridoxal provided by the embodiment of the present invention is: the IC50 of ovarian cancer cells in in vitro experiments is lower than 100 μM.
本发明实施例提供的吡哆醛(PL)化学结构式如下：
The chemical structural formula of pyridoxal (PL) provided by the embodiment of the present invention is as follows:
The chemical structural formula of pyridoxal (PL) provided by the embodiment of the present invention is as follows:
本发明实施例提供的氟代吡哆醛化学结构式如下：
The chemical structural formula of fluoropyridoxal provided by the embodiment of the present invention is as follows:
The chemical structural formula of fluoropyridoxal provided by the embodiment of the present invention is as follows:
本发明实施例提供的氟代吡哆醛(F-PL)：F原子取代了吡哆环上羟甲基中的羟基。In the fluoropyridoxal (F-PL) provided in the embodiment of the present invention, the F atom replaces the hydroxyl group in the hydroxymethyl group on the pyridoxine ring.
将本发明实施例提供的氟代吡哆醛用于制备缓解和/或预防和/或治疗卵巢癌的药物。The fluoropyridoxal provided in the embodiment of the present invention is used to prepare drugs for alleviating and/or preventing and/or treating ovarian cancer.
图1至图4为本发明实施例提供的氟代吡哆醛抑制人卵巢癌细胞系SKOV3、OVCAR3、3AO、ES-2生长的示意图。图1-图4中，灰色线条为溶剂对照，即等体积DMSO处理后各卵巢癌细胞系的生长情况，黑色线条为加入0.5mM F-PL后各卵巢癌细胞系生长情况。横坐标为细胞处理后的时间(单位为小时)，左侧纵坐标为细胞指数(Cell index)，其数值与细胞数目成正比。可见0.5mM F-PL处理后，卵巢癌细胞数目显著低于溶剂对照组，表示氟代吡哆醛F-PL对四种卵巢癌细胞均具有显著的抑制效应。Figures 1 to 4 are schematic diagrams showing that fluoropyridoxal inhibits the growth of human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2 provided by embodiments of the present invention. In Figures 1-4, the gray lines are the solvent control, that is, the growth of each ovarian cancer cell line after equal volume DMSO treatment, and the black lines are the growth of each ovarian cancer cell line after adding 0.5mM F-PL. The abscissa is the time after cell treatment (unit is hour), and the ordinate on the left is the cell index (Cell index), whose value is proportional to the number of cells. It can be seen that after treatment with 0.5mM F-PL, the number of ovarian cancer cells was significantly lower than that in the solvent control group, indicating that fluoropyridoxal F-PL has a significant inhibitory effect on all four types of ovarian cancer cells.
本发明实施例采用RTCA(活细胞无标记计数法)检测细胞生长情况。构建氟代吡哆醛，并利用DMSO配制为500mM无菌工作液；利用xCELLigence工作站及对应的培养板进行活细胞无标记计数检测。向E-Plate板中每孔加入50μl完全培养基用于基线校正，再加入100μl细胞悬液，使每孔细胞数为1×104，最后加入50μl完全培养基稀释的F-PL或等体积DMSO，使每孔终浓度为0.5mM，静置30min后，设置自动扫描间隙为15min，检测细胞增殖曲线，总扫描时间为72小时。In the embodiment of the present invention, RTCA (living cell label-free counting method) is used to detect cell growth. Construct fluoropyridoxal and use DMSO to prepare a 500mM sterile working solution; use xCELLigence workstation and corresponding culture plates to perform label-free counting detection of viable cells. Add 50 μl of complete medium to each well of the E-Plate plate for baseline correction, then add 100 μl of cell suspension to make the number of cells in each well 1 × 10 4 , and finally add 50 μl of F-PL diluted in complete medium or an equal volume. DMSO, so that the final concentration in each well is 0.5mM. After letting it stand for 30 minutes, set the automatic scanning interval to 15 minutes and detect the cell proliferation curve. The total scanning time is 72 hours.
图5至图8为本发明实施例提供的氟代吡哆醛杀伤人卵巢癌细胞系SKOV3、OVCAR3、3AO、ES-2的IC50拟合曲线。图5-图8中，左侧纵坐标
为相较于对照组，细胞在不同浓度吡哆醛或氟代吡哆醛处理72小时后以对照组作为参照的存活率，横坐标为药物浓度。实线为梯度浓度的氟代吡哆醛处理细胞72小时后，细胞存活率的拟合曲线，虚线为梯度浓度的吡哆醛处理细胞72小时后，细胞存活率的拟合曲线，更低的半数致死率(IC50)表示药物对细胞更好的杀伤效果。氟代吡哆醛F-PL对四种卵巢癌细胞的IC50浓度远低于吡哆醛PL原型：吡哆醛处理SKOV3细胞的IC50为0.516mM，氟代吡哆醛处理SKOV3细胞的IC50为0.1041mM；吡哆醛处理OVCAR3细胞的IC50为0.4686mM，氟代吡哆醛处理OVCAR3细胞的IC50为0.05714mM；吡哆醛处理3AO细胞的IC50为0.8725mM，氟代吡哆醛处理3AO细胞的IC50为0.06044mM；吡哆醛处理ES-2细胞的IC50为0.3675mM，氟代吡哆醛处理ES-2细胞的IC50为0.024mM。以上结果显示，对卵巢癌细胞来说，氟代吡哆醛F-PL具有比吡哆醛PL原型更强的杀伤效果。Figures 5 to 8 are IC50 fitting curves of fluoropyridoxal killing human ovarian cancer cell lines SKOV3, OVCAR3, 3AO, and ES-2 provided by the embodiments of the present invention. In Figure 5-8, the ordinate on the left side Compared with the control group, the survival rate of cells after treatment with different concentrations of pyridoxal or fluoropyridoxal for 72 hours is compared with the control group. The abscissa is the drug concentration. The solid line is the fitting curve of the cell survival rate after treating the cells with gradient concentrations of fluoropyridoxal for 72 hours. The dotted line is the fitting curve of the cell survival rate after treating the cells with gradient concentrations of pyridoxal for 72 hours. The lower The half lethality rate (IC50) indicates the drug's better killing effect on cells. The IC50 concentration of fluoropyridoxal F-PL against four ovarian cancer cells is much lower than that of the pyridoxal PL prototype: the IC50 of pyridoxal-treated SKOV3 cells is 0.516mM, and the IC50 of fluoropyridoxal-treated SKOV3 cells is 0.1041. mM; the IC50 of pyridoxal-treated OVCAR3 cells is 0.4686mM, and the IC50 of fluoropyridoxal-treated OVCAR3 cells is 0.05714mM; the IC50 of pyridoxal-treated 3AO cells is 0.8725mM, and the IC50 of fluoropyridoxal-treated 3AO cells is 0.8725mM. The IC50 of ES-2 cells treated with pyridoxal is 0.3675mM, and the IC50 of ES-2 cells treated with fluoropyridoxal is 0.024mM. The above results show that fluoropyridoxal F-PL has a stronger killing effect on ovarian cancer cells than the prototype pyridoxal PL.
本发明实施例采用96孔板及CCK-8法检测细胞对吡哆醛PL及氟代吡哆醛F-PL的反应性。向96孔板中铺入100μl细胞悬液，使每孔细胞总数为1×104，并向其中加入10μl吡哆醛或氟代吡哆醛工作液，吡哆醛在每孔中的最终浓度梯度为0、0.01、0.1、0.5、1、10mM，氟代吡哆醛在每孔中的最终浓度梯度为0、0.001、0.01、0.05、0.1、1mM。置于37℃孵育箱中培养72小时后，吸净上清，向孔中加入100μl完全培养基及10μl CCK-8试剂，37℃孵育30min后测定波长450nm处吸光度(OD值)，并计算各浓度处理下细胞的存活率，使用Graphpad 8.0软件绘制拟合曲线，并计算两种药物对不同细胞的半数致死率(IC50)。In the embodiment of the present invention, a 96-well plate and CCK-8 method were used to detect the reactivity of cells to pyridoxal PL and fluoropyridoxal F-PL. Pour 100 μl of cell suspension into the 96-well plate so that the total number of cells in each well is 1×10 4 , and add 10 μl of pyridoxal or fluoropyridoxal working solution to the final concentration of pyridoxal in each well. The gradient is 0, 0.01, 0.1, 0.5, 1, 10mM, and the final concentration gradient of fluoropyridoxal in each well is 0, 0.001, 0.01, 0.05, 0.1, 1mM. After culturing for 72 hours in an incubator at 37°C, aspirate the supernatant, add 100 μl of complete culture medium and 10 μl of CCK-8 reagent to the well, incubate at 37°C for 30 minutes, measure the absorbance (OD value) at a wavelength of 450 nm, and calculate each To determine the survival rate of cells under concentration treatment, use Graphpad 8.0 software to draw a fitting curve and calculate the half-lethality rate (IC50) of the two drugs on different cells.
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，都应涵盖在本发明的保护范围之内。
The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person familiar with the technical field shall, within the technical scope disclosed in the present invention, be within the spirit and principles of the present invention. Any modifications, equivalent substitutions and improvements made within the above shall be included in the protection scope of the present invention.
Claims (9)
- 一种氟代吡哆醛在制备用于预防和/或缓解和/或治疗癌症的药物中的应用。Use of fluoropyridoxal in the preparation of a medicament for preventing and/or alleviating and/or treating cancer.
- 根据权利要求1所述的应用，其特征在于，所述氟代吡哆醛的有效剂量为：体外实验对卵巢癌细胞的IC50均低于100μM。The application according to claim 1, characterized in that the effective dose of fluoropyridoxal is: the IC50 of ovarian cancer cells in in vitro experiments is lower than 100 μM.
- 根据权利要求1所述的应用，其特征在于，所述氟代吡哆醛化学结构式如下：
The use according to claim 1, characterized in that the chemical structure of the fluoropyridoxal is as follows:
- 根据权利要求1所述的应用，其特征在于，所述癌症为卵巢癌。The application according to claim 1, wherein the cancer is ovarian cancer.
- 根据权利要求1-3任意一项所述的应用，其特征在于，所述药物包含氟代吡哆醛及药学上可接受的载体。The application according to any one of claims 1 to 3, characterized in that the drug contains fluoropyridoxal and a pharmaceutically acceptable carrier.
- 根据权利要求1-3任意一项所述的应用，其特征在于，所述药物的剂型为片剂、颗粒剂、胶囊剂、悬浮剂、糖浆剂、乳剂或注射剂。The use according to any one of claims 1 to 3 is characterized in that the dosage form of the drug is tablets, granules, capsules, suspensions, syrups, emulsions or injections.
- 根据权利要求1-3任意一项所述的应用，其特征在于，所述氟代吡哆醛通过抑制癌细胞的增殖和生长起作用。The application according to any one of claims 1 to 3, characterized in that the fluoropyridoxal acts by inhibiting the proliferation and growth of cancer cells.
- 根据权利要求1-3任意一项所述的应用，其特征在于，所述氟代吡哆醛通过诱导癌细胞衰老样死亡、周期阻滞和细胞凋亡起作用。The application according to any one of claims 1 to 3, characterized in that the fluoropyridoxal acts by inducing senescence-like death, cycle arrest and apoptosis of cancer cells.
- 一种氟代吡哆醛在制备用于改善和/或预防卵巢癌的保健品中的应用。 Application of fluoropyridoxal in the preparation of health care products for improving and/or preventing ovarian cancer.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090215727A1 (en) * | 2005-05-05 | 2009-08-27 | Medicure International Inc. | Inhibition of atp-mediated, p2x7 dependent pathways by pyridoxal-5-phosphate and vitamin b6 related compounds |
| CN106727620A (en) * | 2016-12-01 | 2017-05-31 | 复旦大学附属金山医院 | Application of the phosphopyridoxal pyridoxal phosphate in the medicine for preparing treatment oophoroma |
| CN112691103A (en) * | 2020-12-28 | 2021-04-23 | 重庆医科大学附属第一医院 | Application of pyridoxal in preparation of medicine for treating ovarian cancer |
| CN115531380A (en) * | 2022-09-19 | 2022-12-30 | 重庆医科大学附属第一医院 | Application of fluoropyridoxine in preparation of anti-cancer drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090215727A1 (en) * | 2005-05-05 | 2009-08-27 | Medicure International Inc. | Inhibition of atp-mediated, p2x7 dependent pathways by pyridoxal-5-phosphate and vitamin b6 related compounds |
| CN106727620A (en) * | 2016-12-01 | 2017-05-31 | 复旦大学附属金山医院 | Application of the phosphopyridoxal pyridoxal phosphate in the medicine for preparing treatment oophoroma |
| CN112691103A (en) * | 2020-12-28 | 2021-04-23 | 重庆医科大学附属第一医院 | Application of pyridoxal in preparation of medicine for treating ovarian cancer |
| CN115531380A (en) * | 2022-09-19 | 2022-12-30 | 重庆医科大学附属第一医院 | Application of fluoropyridoxine in preparation of anti-cancer drugs |
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