WO2020147471A1 - 天冬氨酸的新应用 - Google Patents
天冬氨酸的新应用 Download PDFInfo
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- WO2020147471A1 WO2020147471A1 PCT/CN2019/125158 CN2019125158W WO2020147471A1 WO 2020147471 A1 WO2020147471 A1 WO 2020147471A1 CN 2019125158 W CN2019125158 W CN 2019125158W WO 2020147471 A1 WO2020147471 A1 WO 2020147471A1
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- 229960002703 undecylenic acid Drugs 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
Definitions
- the invention relates to a new application of aspartic acid.
- Purine anabolism is a ubiquitous and very important biological metabolism in organisms. Its products AMP and GMP not only provide raw materials for the biosynthesis of DNA and RNA in the organism, but also provide many key coenzymes (NAD, NADP, FAD and CoA) in the body. ), signal molecules (such as cAMP) and important energy molecule ATP provide purine bases necessary for its synthesis. It can be seen that purine anabolism is at the core of the entire metabolic network. Purine synthesis includes two synthetic pathways: de novo purine synthesis and salvage pathway.
- Adenylosuccinate lyase deficiency (adenylosuccinate lyase deficiency ADSL deficiency) is a metabolic disease that produces deletions and confusion in the de novo synthesis of adenine and the metabolic pathway of purine nucleotides.
- the cause of the disease is mainly due to the mutation or deletion of the adenylate succinate lyase in the patient's body, which leads to the excessive accumulation of the enzyme's substrate SAICAR in the cell and cannot be cleared in time [Jaeken J, Van den Berghe G. (1984). An infantile automatic syndrome characterized by the presence of succinylpurines in body fluids. Lancet 8411:1058-1061.].
- ADSL deficiency There are three consecutive main phenotypes of ADSL deficiency: neonatal lethal, severe (type I) and mild to moderate (type II). It is clinically found that even patients from the same family have different phenotypes. The incidence is generally seen from birth to infancy. The reported cases have fatal neonatal encephalopathy (manifestations of hypokinesia, refractory epilepsy, and respiratory disorders) and moderate mental retardation. All patients have mental retardation, most of them have different types of epilepsy, and about 1/3 have autism characteristics (inability to make eye contact, sensitivity to sound and light, repetitive behavior, restlessness, tantrums, self-injury and Self-harm).
- Pyruvate kinase isoform 2 (Pyruvate kinase isoform M2, PKM2), as an important enzyme in the metabolic process, is rapidly proliferated and highly expressed in most tumor cells, and has a huge impact on the metabolism and growth of tumor cells [3,4].
- various pharmacological agents for the enzyme activity of PKM2 affect cell growth and proliferation [5,6], which also suggests that by targeting the enzyme activity of PKM2 as a representative, further changing the way of tumor metabolism has become a new approach for tumor treatment [ 7].
- SAICAR ribose-50-phosphate
- PAICS is highly expressed in acute lymphocytic leukemia, lung cancer, glioma, prostate cancer, and colorectal cancer, and can be used as a prognostic marker for stage III colorectal cancer [11-13].
- SAICAR is highly accumulated under glucose-limited conditions, which changes the energy level, sugar uptake and lactate production in tumor cells, and these phenomena did not occur in adult epidermal cells and lung fibroblasts [14, 15].
- SAICAR can induce the enzymatic activity of PKM2 and promote the survival of tumor cells [14], and the combination of SAICAR-PKM2 can induce phosphorylation of Erk1/2.
- High concentrations of SAICAR can also induce the up-regulation of the oncogene myc [15]. Due to the abnormal accumulation of adenine in the de novo anabolic pathway, SAICAR promotes the proliferation and survival of tumor cells.
- PAICS phosphoribosylaminoimidazole succinocarboxamide synthesis/phosphoribosylaminoimidazole carboxylase
- PAICS phosphoribosylaminoimidazole succinocarboxamide synthesis/phosphoribosylaminoimidazole carboxylase
- SAICAR de novo purine synthesis pathway
- a key reaction process is shown below
- Aspartic acid is an ⁇ -amino acid, and the L-isomer of aspartic acid is one of the 20 protein amino acids, the building blocks of protein. Its codons are GAU and GAC. It is the same acidic amino acid as glutamic acid. Aspartic acid is ubiquitous in biosynthesis. It is a synthetic precursor of amino acids such as lysine, threonine, isoleucine, methionine, and purine and pyrimidine bases in organisms. It can be used as a carrier of K + and Mg 2+ ions to deliver electrolytes to the myocardium, thereby improving myocardial contractility and reducing oxygen consumption. It has a protective effect on the myocardium when the coronary circulatory disorder is hypoxic.
- aspartic acid is a good nutritional supplement, added to various refreshing drinks; it is also the main raw material of sweetener (aspartame)-aspartame.
- Aspartic acid is a substrate synthesized by SAICAR.
- the traditional proxy network analysis theory believes that an increase in its intake will cause the accumulation of SAICAR and aggravate the symptoms of ADSL deficiency.
- nematodes As a good model organism, nematodes have been widely used in the research of human genetic and metabolic diseases. In nematodes, there are also genes homologous to the human gene ADSL. The deletion of the adenylate succinate lyase encoded by this gene will cause the nematodes to produce severe phenotypes such as developmental delay, slow movement, and reduced number of eggs. Through the expression of the RNA interference gene ADSL, a nematode model of ADSL deficiency can be constructed.
- Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme.J Exp Med, 2011.208(2): p.313-26.
- the purpose of the present invention is to provide new applications of aspartic acid and its derivatives.
- aspartic acid can effectively reduce the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, and further related diseases caused by accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado Has a certain relief or treatment effect.
- toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado
- Preliminary experimental data confirm that the inventor's analysis is valid.
- the first aspect of the present invention provides:
- the disease is associated with accumulation of SAICAR; or
- the disease can be alleviated or ameliorated by a decrease in the cumulative amount of SAICAR.
- the disease is selected from tumors or adenosuccinate lyase deficiency; further, the disease is related to the accumulation of SAICAR;
- the amount of SAICAR is higher than the normal level, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, high expression of Erk1/2 and high expression of PKM2 gene.
- the tumor includes lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioma, head and neck squamous cell carcinoma Cell cancer, pancreatic cancer, stomach cancer, endometrial cancer, leukemia.
- the amount of SAICAR in the tumor is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, Liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the disease is a tumor, which also includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
- the second aspect of the present invention provides:
- Aspartic acid and its derivatives used to treat, improve or prevent diseases used to treat, improve or prevent diseases
- the disease is associated with accumulation of SAICAR; or
- the disease can be alleviated or ameliorated by a decrease in the cumulative amount of SAICAR.
- the disease is selected from tumors or adenosuccinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
- the amount of SAICAR is higher than the normal level, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, high expression of Erk1/2 and high expression of PKM2 gene.
- the tumor includes lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioma, head and neck squamous cell carcinoma , Pancreatic cancer, stomach cancer, endometrial cancer, leukemia.
- the amount of SAICAR in the tumor is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, multiforming glioma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the third aspect of the present invention provides:
- a composition for treating, improving or preventing diseases, the active ingredient of the composition includes at least one of aspartic acid or its derivatives;
- the disease is associated with accumulation of SAICAR; or
- the disease can be alleviated or ameliorated by a decrease in the cumulative amount of SAICAR.
- the disease is selected from tumors or adenosuccinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
- the amount of SAICAR is higher than the normal level, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, high expression of Erk1/2 and high expression of PKM2 gene.
- the tumor includes lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioma, head and neck squamous cell carcinoma , Pancreatic cancer, stomach cancer, endometrial cancer, leukemia.
- the amount of SAICAR in the tumor is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, multiforming glioma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the disease is a tumor, which also includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
- the fourth aspect of the present invention provides:
- a method for treating, ameliorating or preventing diseases comprising administering at least one of aspartic acid or its derivatives in a therapeutic or preventive amount to a patient,
- the disease is associated with accumulation of SAICAR; or
- the disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR;
- the modes of administration include oral administration, injection, transdermal absorption, and respiratory tract inhalation.
- the disease is selected from tumors or adenosuccinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
- the amount of SAICAR is higher than the normal level, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, high expression of Erk1/2 and high expression of PKM2 gene.
- the tumor includes lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioma, head and neck squamous cell carcinoma , Pancreatic cancer, stomach cancer, endometrial cancer, leukemia.
- the amount of SAICAR in the tumor is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, multiforming glioma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the disease is a tumor, which also includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
- the compounds and/or reagents that have therapeutic effects on the tumor are compounds and reagents known in the art, including but not limited to various chemotherapeutic drugs, targeted drugs and the like.
- the therapeutic or preventive amount of the drug can be determined by methods known in the art, or determined by a doctor based on his experience. Generally speaking, its dosage should be below the safe dosage.
- Figure 1 shows the results of the toxicological test of nematodes
- Figure 2 shows the effect of aspartic acid on the development of ADSL RNAi nematodes.
- a pharmaceutically acceptable derivative of the compound especially one of pharmaceutically acceptable salts and lower amides, that is, a condensation of a carboxylic acid, alcohol, or amine with a carbon number of 1 to 6, preferably 2 to 6, and 2 to 4 with the parent compound Derivatives obtained.
- the pharmaceutically acceptable salt of the compound can be synthesized from the parent compound by conventional chemical methods, such as in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: The method described in 3-90639-026-8, Hardcover, 388 pages, August 2002.
- these salts can be prepared by reacting the free base of the compound with an acid in water or an organic solvent or a mixture of the two; usually, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used. .
- Acid addition salts can be prepared by various acids (inorganic acids and organic acids).
- acid addition salts include salts made from acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (such as L-ascorbic acid), L-aspartic acid , Benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, Caprylic acid, cinnamic acid, citric acid, cyclamic acid, laurylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glucoheptonic
- Nematode strain NL2099 (Bristol strain) was purchased from the Caenorhabditis Genetics Center/CGC at the University of Minnesota, USA.
- Nematodes are cultured on NGM (nematode growth medim) medium coated with OP50 at a temperature of 16°C and a humidity of 40-60%.
- Aspartic acid was prepared into solutions of different concentrations, and 200 uL was added to a 3.5 cm petri dish containing NGM medium.
- the survival rate of nematodes treated with different concentrations of aspartic acid solution for 6 days was calculated, and the results are shown in Figure 1.
- the results showed that when the concentration of aspartic acid was 0.064 ⁇ g/mL, 0.32 ⁇ g/mL, 1.6 ⁇ g/mL 8 ⁇ g/mL, 40 ⁇ g/mL, 0.2mg/mL, 1mg/mL, 5mg/mL, the survival rate of nematodes All are above 90%, indicating that aspartic acid has good safety.
- RNAi ADSL genes were synchronized on a plate containing RNAi ADSL genes with different concentrations of aspartic acid.
- aspartic acid concentrations were 40 mg/mL, 0.2 mg/mL, 1 mg/ml, and 5 mg/mL
- Negative control only includes RNAi control bacteria
- RNAi ADSL only includes R06C7.5a interference bacteria
- Negative control-L3 includes control bacteria and different concentrations of aspartic acid
- RNAi ADSL-L3 includes R06C7.5a interference Bacteria and different concentrations of aspartic acid.
- RNAi ADSL deficiency model
- the length of the nematodes treated with aspartic acid was significantly increased, and the length of the nematodes was not significantly different from the length of normal nematodes. It shows that aspartic acid can effectively improve the symptoms of ADSL deficiency, and has a good treatment or improvement effect.
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Abstract
公开了天冬氨酸的新应用。天冬氨酸可以改善ADSL缺陷症的症状,同时天冬氨酸可以有效减少SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积,对SAICAR、SAICAr、S-Ado等有毒中间代谢产物过度累积相关的部分肿瘤也具有一定的治疗、改善或预防作用。
Description
本发明涉及天冬氨酸的新应用。
嘌呤合成代谢是生物体普遍存在而又十分重要的生物代谢,其产物AMP和GMP不仅为生物体内DNA和RNA的生物合成提供原料,而且也为体内许多关键的辅酶(NAD、NADP、FAD和CoA)、信号分子(如cAMP)和重要的能量分子ATP提供其合成所必需的嘌呤碱基。可见,嘌呤合成代谢在整个代谢网络中处于核心位置。嘌呤合成包括从头合成(de novo purine synthesis)和补救途径(salvage pathway)两个合成途径。
腺苷酸琥珀酸裂解酶缺陷症(adenylosuccinate lyase deficiency ADSL缺陷症)是一种在腺嘌呤从头合成以及嘌呤核苷酸代谢途径中产生缺失、混乱的代谢疾病。该疾病产生的原因主要是由于患者体内的腺苷酸琥珀酸裂解酶发生了突变或者缺失,从而导致细胞中该酶的底物SAICAR过度地积累而得不到及时的清除[Jaeken J,Van den Berghe G.(1984).An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids.Lancet 8411:1058-1061.]。1984年Jaeken以及Van den Berghe首次在几个患有运动迟缓症和自闭症的患者体液中检测到该代谢物的积累。患有腺苷酸琥珀酸裂解酶缺陷症的患者通常会出现严重的发育不良、运动迟缓、目光呆滞、癫痫、自闭等症状[Spiegel,E.K.,Colman,R.F.,and Patterson,D.(2006).Adenylosuccinate lyase deficiency.Mol Genet Metab 89,19-31.Clamadieu,C.,Cottin,X.,Rousselle,C.,and Claris,O.(2008).Adenylosuccinate lyase deficiency:an unusual cause of neonatal seizure.Arch Pediatr 15,135-138.Castro,M.,Perez-Cerda,C.,Merinero,B.,Garcia,M.J.,Bernar,J.,Gil Nagel,A.,Torres,J.,Bermudez,M.,Garavito,P.,Marie,S.,et al.(2002).Screening for adenylosuccinate lyase deficiency:clinical,biochemical and molecular findings in four patients.Neuropediatrics 33,186-189.Jurecka,A.,Zikanova,M.,Tylki-Szymanska,A.,Krijt,J.,Bogdanska,A.,Gradowska,W.,Mullerova,K.,Sykut-Cegielska,J.,Kmoch,S.,and Pronicka,E.(2008b).Clinical,biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency.Mol Genet Metab 94,435-442.]。
ADSL缺陷症有3种连续的主要表型:新生儿致死型、重度(Ⅰ型)和轻到中度(Ⅱ型)。临床上发现即便是来自同一家族的患者也具有不同的表型。发病一般见于出生至婴幼儿期。 已报导的病例有致死的新生脑病变(表现有运动功能减退、难治性癫痫、呼吸障碍),中度智力缺陷。所有的患者均存在智力缺陷,大多数存在不同类型的癫痫,约1/3的存在自闭症特征(无法进行眼神交流、对声光敏感、重复性行为、躁动、乱发脾气、自伤和自残)。其他不常见的临床表现包括心理运动延迟、过度活跃、语言障碍、肌肉张力减退、肌肉萎缩和痉挛。重度患者通常小头畸形。产前临床表现报导的有:宫内生长受损、小头畸形、胎儿运动功能减退以及胎儿心率变化缺失。
癌细胞的一个重要的标志是代谢重编程,包括提高葡萄糖摄取和非氧依赖的乳酸发酵,也常被称为沃伯格效应(Warburg effect)[1,2]。这种重新编程对于肿瘤的生长和存活是必要,特别是外界低氧等压力条件下。然而,对于肿瘤细胞代谢重整与肿瘤快速增殖、分化、迁移等相关性的重要分子机制以及作用方式仍然不清楚。
丙酮酸激酶同工酶2(Pyruvate kinase isoform M2,PKM2)作为一个代谢过程中重要的酶在快速增殖和多数肿瘤细胞中高表达,且对肿瘤细胞的代谢和生长影响巨大[3,4]。此外,针对PKM2酶活性的各种药理试剂影响细胞生长和增殖[5,6],这也提示通过靶向PKM2的酶活性为代表,进一步改变肿瘤代谢的方式成为肿瘤治疗的一种新途径[7]。
在人体中腺嘌呤从头合成代谢途径中代谢酶的异常,往往导致中间有害的代谢产物5-氨基-4-琥珀酸甲酰胺咪唑核糖核苷酸(succinyl-5-aminoimidazole-4-carboxamide-1-ribose-50-phosphate,SAICAR)的累积,在临床上表现为自闭、癫痫、张力减退、发育不良等症状[8-10]。SAICAR合成酶由基因PAICS(phosphoribosylaminoimidazolesuccinocarboxamide synthase)编码,在体内负责SAICAR的合成。相关的研究报道,PAICS高表达于急性淋巴细胞性白血病,肺癌,神经胶质瘤、前列腺癌以及结直癌中,并可以作为Ⅲ期结直肠癌的一个预后标记[11-13]。近期研究发现,在葡萄糖受限的条件下高度积累SAICAR,从而改变了肿瘤细胞中能量水平、糖摄取和乳酸的产生,而这些现象并未发生在成人表皮细胞以及肺成纤维细胞中[14,15]。SAICAR能够诱导PKM2的酶活性,促进肿瘤细胞的存活[14],而且SAICAR-PKM2的结合能够诱导Erk1/2的磷酸化,高浓度的SAICAR也可诱导癌基因myc的上调表达[15],这些由于腺嘌呤从头合成代谢途径中异常积累的SAICAR促进肿瘤细胞的增殖和存活。
氨基咪唑琥珀基氨甲酰核苷酸合成酶/氨基咪唑核苷酸羧化酶,即PAICS(phosphoribosylaminoimidazole succinocarboxamide synthetase/phosphoribosylaminoimidazole carboxylase)是一种嘌呤从头合成途径中重要的双功能酶,它具有SAICAR合成酶(4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase,SAICARs)和AIR羧化 酶(5-aminoimidazole ribonucleotide carboxylase,AIRc)的功能,催化嘌呤从头合成代谢第六步、第七步反应,其中的一个关键反应过程如下所示
所以,对于异常高表达PAICS的肿瘤常常会伴随着有害代谢产物SAICAR、SAICAr或S-Ado的过度积累,而针对抑制PAICS的表达或其酶活性的研究将成为肿瘤治疗的新手段。开发或筛选出可以有效抑制PAICS活性的化合物,具有非常重要的意义。
天冬氨酸是一种α-氨基酸,天冬氨酸的L-异构物是20种蛋白胺基酸之一,即蛋白质的构造单位。它的密码子是GAU和GAC。它与谷氨酸同为酸性氨基酸。天冬氨酸普遍存在于生物合成作用中。它是生物体内赖氨酸、苏氨酸、异亮氨酸、蛋氨酸等氨基酸及嘌呤、嘧啶碱基的合成前体。它可作为K
+、Mg
2+离子的载体向心肌输送电解质,从而改善心肌收缩功能,同时降低氧消耗,在冠状动脉循环障碍缺氧时,对心肌有保护作用。它参与鸟氨酸循环,促进氧和二氧化碳生成尿素,降低血液中氮和二氧化碳的量,增强肝脏功能,消除疲劳。在食品工业方面,天冬氨酸是一种良好的营养增补剂,添加于各种清凉饮料;也是甜味素(阿斯巴甜)-天冬酰苯丙氨酸甲酯的主要原料。
天冬氨酸是SAICAR合成的一种底物,传统代理网络分析理论认为其摄取量增加会引起SAICAR的累积,加重ADSL缺陷症的症状。
线虫作为一种很好的模式生物,已被广泛用于人类遗传、代谢疾病的研究。在线虫中,也存在与人类基因ADSL同源的基因,该基因编码的腺苷酸琥珀酸裂解酶缺失后,将会使线虫产生严重的发育延缓、运动迟钝、产卵数减少等表型。通过RNA干扰基因ADSL的表达,可以构建得到ADSL缺陷症的线虫模型。
参考文献:
1.Hanahan,D.and R.A.Weinberg,Hallmarks of cancer:the next generation.Cell,2011.144(5):p.646-74.
2.Hsu,P.P.and D.M.Sabatini,Cancer cell metabolism:Warburg and beyond.Cell,2008.134(5):p.703-7.
3.Christofk,H.R.,et al.,The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.Nature,2008.452(7184):p.230-3.
4.Wolf,A.,et al.,Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme.J Exp Med,2011.208(2):p.313-26.
5.Chen,J.,et al.,Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2.Oncogene,2011.30(42):p.4297-306.
6.Anastasiou,D.,et al.,Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.Nat Chem Biol,2012.8(10):p.839-47.
7.Vander Heiden,M.G.,Exploiting tumor metabolism:challenges for clinical translation.J Clin Invest,2013.123(9):p.3648-51.
8.Ciardo,F.,C.Salerno,and P.Curatolo,Neurologic aspects of adenylosuccinate lyase deficiency.J Child Neurol,2001.16(5):p.301-8.
9.Gitiaux,C.,et al.,Misleading behavioural phenotype with adenylosuccinate lyase deficiency.Eur J Hum Genet,2009.17(1):p.133-6.
10.Mierzewska,H.,et al.,Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI,clinical,biochemical and neuropathological findings of Polish patients.Folia Neuropathol,2009.47(4):p.314-20.
11.Eissmann,M.,et al.,A functional yeast survival screen of tumor-derived cDNA libraries designed to identify anti-apoptotic mammalian oncogenes.PLoS One,2013.8(5):p.e64873.
12.Goswami,M.T.,et al.,Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer.Oncotarget,2015.6(27):p.23445-61.
13.Chakravarthi,B.V.,et al.,Expression and Role of PAICS,a De Novo Purine Biosynthetic Gene in Prostate Cancer.Prostate,2017.77(1):p.10-21.
14.Keller,K.E.,I.S.Tan,and Y.S.Lee,SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions.Science,2012.338(6110):p.1069-72.
15.Keller,K.E.,et al.,SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells.Mol Cell,2014.53(5):p.700-9。
16、Chen P,Wang D,Chen H,et al.The non-essentiality of essential genes in yeast provides therapeutic insights into a human disease[J].Genome research,2016:gr.205955.116。
发明内容
本发明的目的在于提供天冬氨酸及其衍生物的新应用。
发明人通过自有软件分析,发现天冬氨酸可以有效减少SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积,进而对SAICAR、SAICAr、S-Ado等有毒中间代谢产物累积造成的相关病症具有一定的缓解或治疗作用。初步的实验数据证实发明人的这一分析是成立的。
本发明所采取的技术方案是:
本发明的第一个方面,提供:
天冬氨酸及其衍生物在制备治疗、改善或预防疾病药物中的应用,
所述疾病与SAICAR累积相关;或
所述疾病可因SAICAR累积量的减少而减轻或改善。
在一些应用的实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;
所述肿瘤具有如下任一种特性:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
在一些应用的实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些应用的实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些应用的实例中,所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。
本发明的第二个方面,提供:
用于治疗、改善或预防疾病的天冬氨酸及其衍生物,
所述疾病与SAICAR累积相关;或
所述疾病可因SAICAR累积量的减少而减轻或改善。
在一些实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;
所述肿瘤具有如下任一种特性:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
在一些实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
本发明的第三个方面,提供:
一种治疗、改善或预防疾病的组合物,组合物的活性成分包括天冬氨酸或其衍生物中的至少一种;
所述疾病与SAICAR累积相关;或
所述疾病可因SAICAR累积量的减少而减轻或改善。
在一些实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;
所述肿瘤具有如下任一种特性:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
在一些实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些实例中,所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。
本发明的第四个方面,提供:
一种治疗、改善或预防疾病的方法,包括给予病人治疗量或预防量的天冬氨酸或其衍生物中的至少一种,
所述疾病与SAICAR累积相关;或
所述疾病可因SAICAR累积量的减少而减轻或改善;
进一步的,给药方式包括口服、注射、透皮吸收、呼吸道吸入。
在一些实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;
所述肿瘤具有如下任一种特性:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
在一些实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
在一些实例中,所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。
所述肿瘤有治疗作用的化合物和/或试剂为本领域已知的化合物和试剂,包括但不限于各种化疗药物、靶向药物等。
药物的治疗量或预防量可以通过本领域的公知方法确定,或由医生基于其经验确定。一般而言,其用量应当在安全剂量之下。
本发明的有益效果是:
发明人通过ADSL缺陷症的线虫模型实验意外发现,天冬氨酸可以恢复ADSL缺陷症线虫的体长,证明天冬氨酸可以改善ADSL缺陷症的症状。
图1是线虫的毒理实验结果;
图2是天冬氨酸对ADSL RNAi线虫发育的影响。
化合物药学上可接受的衍生物,尤其药用盐、低级酰胺中的一种,即碳原子数在1~6,优选为2~6,2~4的羧酸、醇、胺与母化合物缩合得到的衍生物。
化合物药学上可接受的药用盐可以通过常规的化学方法从母体化合物合成,如在Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(Editor),Camille G.Wermuth(Editor),ISBN:3-90639-026-8,Hardcover,388 pages,August 2002中描述的方法。一般 来说,这些盐可以由化合物的游离碱和酸在水或有机溶剂或二者的混合液中反应制得;通常,使用非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。
酸加成盐可以通过各种酸(无机酸和有机酸)制得。酸加成盐的实例包括由酸制成的盐,所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸(如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸(如D-葡萄糖醛酸)、谷氨酸(如L-谷氨酸)、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸,以及酰化氨基酸和阳离子交换树脂组成的组。
下面结合实验,进一步说明本发明的技术方案。
材料与方法
材料与试剂
线虫
线虫株系NL2099(Bristol strain)为从美国明尼苏达大学秀丽线虫遗传中心(Caenorhabditis Genetics Center/CGC)购买。
线虫培养
线虫培养在涂有OP50的NGM(nematode growth medim)培养基上,培养温度为16℃,湿度40-60%。
药物毒理评价
将天冬氨酸配置成不同浓度的溶液,以200uL的量加到包含NGM培养基的3.5cm的培养皿中。
毒理结果
统计线虫使用不同浓度天冬氨酸溶液处理6天的存活率,结果如图1所示。结果显示,在天冬氨酸浓度为0.064μg/mL、0.32μg/mL、1.6μg/mL 8μg/mL、40μg/mL、0.2mg/mL、1mg/mL、5mg/mL时,线虫的存活率均在90%以上,说明天冬氨酸具有很好的安全性。
天冬氨酸对ADSL RNAi线虫发育的影响
将线虫同步化在含有不同浓度天冬氨酸的RNAi ADSL基因的平板上,天冬氨酸浓度为40mg/mL、0.2mg/mL、1mg/m L、5mg/mL时,结果如图2A~D所示。图2中,Negative control为只包含RNAi对照菌;RNAi ADSL为只包含R06C7.5a干扰菌;Negative control-L3为包含对照菌及不同浓度天冬氨酸;RNAi ADSL-L3为包含R06C7.5a干扰菌及不同浓度天冬氨酸。与不加天冬氨酸的RNAi(ADSL缺陷症模型)平板相比,天冬氨酸处理的线虫长度显著增长,线虫的长度与正常的线虫长度无显著区别。说明天冬氨酸可以有效改善ADSL缺陷症的症状,具有很好的治疗或改善效果。
在培养的乳腺癌细胞MD231中加入天冬氨酸,发现SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降,抗癌效果显著。
在培养的肺癌细胞H1299中加入天冬氨酸,SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降,抗癌效果显著。
ADSL缺陷转基因小鼠在给予天冬氨酸后,实验证明SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降,ADSL得到显著改善。由此可说明其对SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积相关的肿瘤具有显著的治疗作用、改善或预防。
初步的细胞生物学实验和动物实验证明天冬氨酸可以有效减少SAICAR的累积,对SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积相关的肿瘤具有显著的治疗、改善或预防作用。
Claims (15)
- 天冬氨酸及其衍生物在制备治疗、改善或预防疾病药物中的应用,其特征在于:所述疾病与SAICAR累积相关;或所述疾病可因SAICAR累积量的减少而减轻或改善。
- 根据权利要求1所述的应用,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;所述肿瘤具有如下任一种特性:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
- 根据权利要求2所述的应用,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
- 根据权利要求2或3所述的应用,其特征在于:所述疾病为肿瘤,所述药物还包括至少一种对肿瘤有治疗作用的化合物和/或试剂。
- 用于治疗、改善或预防疾病的天冬氨酸及其衍生物,其特征在于:所述疾病与SAICAR累积相关;或所述疾病可因SAICAR累积量的减少而减轻或改善。
- 根据权利要求5所述的天冬氨酸及其衍生物,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;所述肿瘤具有如下任一种特性:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
- 根据权利要求6所述的天冬氨酸及其衍生物,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
- 一种治疗、改善或预防疾病的组合物,其特征在于:组合物的活性成分包括天冬氨酸或其衍生物中的至少一种;所述疾病与SAICAR累积相关;或所述疾病可因SAICAR累积量的减少而减轻或改善。
- 根据权利要求8所述的组合物,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;所述肿瘤具有如下任一种特性:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
- 根据权利要求9所述的组合物,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
- 根据权利要求8~10所述的组合物,其特征在于:所述疾病为肿瘤,所述药物还包括至少一种对肿瘤有治疗作用的化合物和/或试剂。
- 一种治疗、改善或预防疾病的方法,包括给予病人治疗量或预防量的天冬氨酸或其衍生物中的至少一种,其特征在于:所述疾病与SAICAR累积相关;或所述疾病可因SAICAR累积量的减少而减轻或改善;进一步的,给药方式包括口服、注射、透皮吸收、呼吸道吸入。
- 根据权利要求12所述的方法,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;所述肿瘤具有如下任一种特性:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。
- 根据权利要求13所述的方法,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。
- 根据权利要求12~14所述的方法,其特征在于:所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014077289A1 (ja) * | 2012-11-15 | 2014-05-22 | 株式会社日本生物製剤 | 抗癌剤 |
WO2018192323A1 (zh) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | 亚精胺及其衍生物的应用 |
WO2018192293A1 (zh) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | 精胺及其衍生物在制备抗肿瘤药物中的应用 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014077289A1 (ja) * | 2012-11-15 | 2014-05-22 | 株式会社日本生物製剤 | 抗癌剤 |
WO2018192323A1 (zh) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | 亚精胺及其衍生物的应用 |
WO2018192293A1 (zh) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | 精胺及其衍生物在制备抗肿瘤药物中的应用 |
Non-Patent Citations (2)
Title |
---|
LI, BAOKUN: "The Effect of Aspartic Acid and Glutamic Acid on Telomerase Activity of Hela Cells", THESIS MASTER DEGREE:SUPERVISOR: CHINA MEDICAL UNIVERSITY GRADUATE SCHOOL, 15 October 2005 (2005-10-15), CN, pages 1 - 35, XP009522068 * |
TYAGI, ANIL K. ET AL.: "Prospects for the Chemotherapy of Cancer Using Analogs of L-Aspartic Acid", TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 4, no. 7, 31 July 1983 (1983-07-31), pages 299 - 304, XP025996919, ISSN: 0165-6147 * |
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