WO2021204018A1 - 具有ptp1b抑制活性的化合物及其应用 - Google Patents
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- WO2021204018A1 WO2021204018A1 PCT/CN2021/083890 CN2021083890W WO2021204018A1 WO 2021204018 A1 WO2021204018 A1 WO 2021204018A1 CN 2021083890 W CN2021083890 W CN 2021083890W WO 2021204018 A1 WO2021204018 A1 WO 2021204018A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
Definitions
- the present invention relates to the technical field of natural medicines, in particular to two compounds with PTP1B inhibitory activity and their applications.
- Diabetes is a metabolic disease characterized by chronic hyperglycemia caused by multiple causes. Hyperglycemia is caused by insulin secretion defects or impaired biological effects, or both. The long-term high blood sugar in diabetes causes chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Diabetes is one of the most important non-communicable diseases threatening global human health in the world. There are two main types of diabetes, type 1 diabetes (insulin-dependent) and type II diabetes (non-insulin-dependent), and type II diabetes accounts for more than 90% of the total number of diabetic patients.
- PTP1B is a member of the protein tyrosine phosphatase family. It negatively regulates insulin signal transduction through dephosphorylation of tyrosine residues on the insulin receptor or its substrate, and is also a treatment II Potentially important targets for type diabetes and obesity.
- the technical problem to be solved by the present invention is to provide two compounds with PTP1B inhibitory activity and their applications.
- the present invention takes the pseudotropical Ganoderma lucidum fruiting body as the research object, and the crude extracts are separated and purified to obtain two
- the novel hydroquinone heteroterpene compounds have been found to have good PTP1B inhibitory activity through biological activity evaluation, enhance insulin receptor sensitivity, and can be used to develop drugs for the treatment of type II diabetes.
- Ganoderma ahmadii Steyaret is a medicinal fungus of the genus Ganoderma of the family Ganodermataceae.
- the chemical components of Ganoderma lucidum mainly include polysaccharides, triterpenoids, bioalkali, sterol compounds, polypeptide nucleosides, amino acids and trace elements. With triterpenoids and polysaccharides as the main active ingredients, it has anti-tumor, liver protection, anti-HIV-4 and HIV-4 protease activities, anti-histamine release, inhibition of angiotensin and anti-oxidation.
- heteroterpenoids discovered from Ganoderma lucidum are another important type of active molecules in Ganoderma lucidum, which have biological activities such as liver protection and anti-allergic activity.
- the present invention provides two compounds with PTP1B inhibitory activity, which have the structure shown in Formula 1 or Formula 2:
- the present invention provides a preparation method of the above compound, which includes the following steps:
- the ethanol in step A) is preferably 95% ethanol.
- Said step B) is preferably specifically as follows:
- the ethanol extract was concentrated under reduced pressure, suspended in water, and then sequentially extracted with petroleum ether, ethyl acetate, and n-butanol.
- the ethyl acetate extract was taken and concentrated by distillation to obtain ethyl acetate extract.
- the eluent for normal phase silica gel column chromatography is preferably petroleum ether/ethyl acetate, and the volume ratio of the petroleum ether and ethyl acetate is 10:1 to 1:2, and gradient elution is performed. .
- Fr.6 is taken and subjected to reversed-phase C 18 column chromatography to obtain Fr.6-1 to Fr.6-5.
- the eluent of the reversed-phase C 18 column chromatography is preferably methanol/water, and the volume ratio of the methanol to water is preferably 30:1 to 100:0, and gradient elution is performed.
- Fr. 6-4 is taken and purified by semi-preparative high performance liquid chromatography to obtain the compound represented by Formula 1, which is referred to as Ganoduriporol F in the present invention.
- the mobile phase of the semi-preparative high performance liquid chromatography is preferably a mixed solvent of acetonitrile and trifluoroacetic acid.
- the flow rate of the mobile phase of the semi-preparative high performance liquid chromatography is preferably 4 mL ⁇ min -1 .
- Fr.7 is taken and subjected to reversed-phase C 18 column chromatography to obtain Fr.7-1 to Fr.7-6.
- the eluent of the reversed-phase C 18 column chromatography is preferably methanol/water, and the volume ratio of the methanol to water is preferably 20:1 to 100:0, and gradient elution is performed.
- Fr.7-1 ⁇ Fr.7-6 After obtaining Fr.7-1 ⁇ Fr.7-6, take Fr.7-5, chromatograph on Sephadex column LH-20, and eluted with methanol to obtain Fr.7-5-1 ⁇ Fr. .7-5-5.
- the mobile phase of the semi-preparative high performance liquid chromatography is preferably a mixed solvent of methanol and trifluoroacetic acid.
- the flow rate of the mobile phase is preferably 4 mL ⁇ min -1 .
- the present invention provides the application of the above-mentioned compound with PTP1B inhibitory activity or the compound with PTP1B inhibitory activity prepared by the above-mentioned preparation method in the preparation of a medicine for treating or alleviating diabetes.
- the diabetes is type II diabetes.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned compound with PTP1B inhibitory activity or the compound with PTP1B inhibitory activity prepared by the above-mentioned preparation method, and pharmaceutically acceptable excipients.
- the present invention does not specifically limit the auxiliary materials, and can be suitable auxiliary materials well known to those skilled in the art.
- the above-mentioned compound having PTP1B inhibitory activity or the above-mentioned pharmaceutical composition can also be used in combination with other drugs for the treatment or alleviation of diabetes.
- the present invention provides two compounds with PTP1B inhibitory activity, which have the structure shown in Formula 1 or Formula 2.
- the present invention discloses two hydroquinone-containing heteroterpene compounds discovered for the first time from pseudotropical ganoderma. After biological activity evaluation, it is found that such compounds have significant PTP1B inhibitory activity, enhance insulin receptor sensitivity, and have application prospects for the development of diabetes drugs.
- Figure 1 is the 1 HNMR spectrum of Ganoduriporol F
- Figure 2 is the 13 CNMR spectrum of Ganoduriporol F
- FIG. 3 shows the DEPT spectrum of Ganoduriporol F
- Figure 4 shows the HSQC spectrum of Ganoduriporol F
- Figure 5 is the HMBC spectrum of Ganoduriporol F
- Figure 6 is the 1 H- 1 H COSY spectrum of Ganoduriporol F
- Figure 7 is the ROESY spectrum of Ganoduriporol F
- Figure 8 is the HRESIMS spectrum of Ganoduriporol F
- Figure 9 is a 1 HNMR spectrum of Ganoduriporol G.
- Figure 10 is a 13 CNMR spectrum of Ganoduriporol G
- Figure 12 is the HSQC spectrum of Ganoduriporol G
- Figure 13 is the HMBC spectrum of Ganoduriporol G
- Figure 14 is the 1 H- 1 H COSY spectrum of Ganoduriporol G
- Figure 15 is the ROESY spectrum of Ganoduriporol G
- Figure 16 shows the HRESIMS spectrum of Ganoduriporol G.
- Fr. 7-5 (205.0 mg) was chromatographed on a dextran gel column LH-20 and eluted with methanol to obtain 5 components Fr. 7-5-1 to Fr. 7-5-5.
- the isolated compounds Ganoduriporol F and Ganoduriporol G were detected by nuclear magnetic resonance, infrared, mass spectrometry and other modern spectroscopy techniques, combined with chemical methods to identify their structures. After identification, the compounds Ganoduriporol F and Ganoduriporol G are new hydroquinone heteroterpenoids.
- Ganoduriporol F is a yellow oil, easily soluble in methanol.
- HRESIMS shows that the compound molecular formula is C 30 H 32 O 9 (calced for C 30 H 32 NaO 9 [M+Na] + 559.1938,found 559.1939), and the degree of unsaturation is 15.
- Ganoduriporol G is yellow oily and easily soluble in methanol. HRESIMS shows that the compound molecular formula is C 30 H 34 O 10 (calced for C 30 H 34 NaO 10 [M+Na] + 577.2046, found 577.2044).
- the 1 H-NMR and 13 C-NMR spectra of this compound (Table 1) are very similar to the data of Ganoduriporol F, suggesting that they have the same structural skeleton.
- H-2 'and H-4' related, H-10 'and H-12' associated prove ⁇ 2 'and ⁇ 10' double bond of configuration Z and E, respectively
- the coupling constant of H-2" and H-3" is 16.0 Hz, which proves that the configuration of the ⁇ 2" double bond is E.
- the physicochemical properties of the compounds Ganoduriporol F and Ganoduriporol G are as follows:
- Ganoduriporol F(1) yellow oil; UV-vis(MeOH) ⁇ max [log ⁇ (L ⁇ mol -1 ⁇ cm -1 )]: 307(4.4),224(4.0)nm; 1 H-NMR(CD 3 OD, 500MHz) and 13 C-NMR (CD 3 OD, 125MHz) data are shown in Table 1; IR(KBr) ⁇ max : 3436, 2925, 2851, 1630, 1388, 1168cm -1 ; HRESIMS calcd for C 30 H 32 NaO 9 [M+Na] + 559.1939, found 559.1938.
- Ganoduriporol G(2) yellow oil; UV-vis(MeOH) ⁇ max [log ⁇ (L ⁇ mol -1 ⁇ cm -1 )]: 328(4.1), 288(3.8)nm; 1 H-NMR (CD 3 OD, 500MHz) and 13 C-NMR (CD 3 OD, 125MHz) data see Table 1; IR(KBr) ⁇ max :3414,2927,2859,1610,1474,1263,1195cm -1 ; HRESIMS calcd for C 30 H 34 NaO 10 [M+Na] + 577.2046, found 577.2044.
- the compounds Ganoduriporol F and Ganoduriporol G of Example 1 were tested for PTP1B inhibitory activity.
- the prepared compounds Ganoduriporol F and Ganoduriporol G were dissolved in DMSO to prepare the test sample solution with a concentration of 1mg/ml and different dilution gradients, and take different dilutions
- the gradient of the test sample solution was added to the bioassay system (50 ⁇ L buffer, 20 ⁇ L ddH 2 O
- the results are shown in Table 2.
- the compound Ganoduriporol F shown in formula 1 and the compound Ganoduriporol G shown in formula 2 both have good inhibitory activity on PTP1B, and have the application prospect of developing drugs for the treatment of type II diabetes.
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Abstract
本发明提供了两种具有PTP1B抑制活性的化合物,具有式(1)或式(2)所示结构。本发明公开了从拟热带灵芝中首次发现的两种含氢醌杂萜化合物。经过生物活性评价发现此类化合物具有显著的PTP1B抑制活性,增强胰岛素受体敏感性,具有开发糖尿病药物的应用前景。
Description
本申请要求于2020年04月09日提交中国专利局、申请号为202010273869.9、发明名称为“具有PTP1B抑制活性的化合物及其应用”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。
本发明涉及天然药物技术领域,尤其涉及两种具有PTP1B抑制活性的化合物及其应用。
糖尿病是一种由多病因引起的以慢性高血糖为特征的代谢性疾病,高血糖则是由于胰岛素分泌缺陷或其生物作用受损,或两者兼有引起。糖尿病时长期存在的高血糖,导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。糖尿病是当前世界上威胁全球人类健康最主要的非传染性疾病之一。糖尿病主要有两种类型,l型糖尿病(胰岛素依赖型)和II型糖尿病(非胰岛素依赖型),其中II型糖尿病占糖尿病患者总数的90%以上。据国际糖尿病联盟统计,2011年全球糖尿病患者约有3.7亿,而到2030年全球将有近5.7亿糖尿病患者,其中80%在发展中国家。2009年中国卫生部门给出的糖尿病患者人数是9200万,到2013年这个数字变为1.14亿人,四年间中国多出2200万糖尿病病人,平均每年增长550万例,每天增长1.5万例。PTP1B是蛋白质酪氨酸磷酸酶家族中的一员,它通过对胰岛素受体或其底物上的酪氨酸残基去磷酸化作用,对胰岛素信号转导进行负调节,也是一种治疗II型糖尿病和肥胖的潜在重要的目标靶点。
发明内容
有鉴于此,本发明要解决的技术问题在于提供两种具有PTP1B抑制活性的化合物及其应用,本发明以拟热带灵芝子实体为研究对象,对其粗提物进行了分离纯化,得到2个新颖的氢醌杂萜化合物,经过生物活性评价发现此类化合物具有良好的PTP1B抑制活性,增强胰岛素受体敏感性,可用于开发治疗II型糖尿病药物。
拟热带灵芝(Ganoderma ahmadii Steyaret)为灵芝科(Ganodermataceae)灵芝属(Ganoderma)药用真菌。灵芝属真菌的化学成分主要包括多糖、三萜类、生 物碱、甾醇类化合物、多肽核苷类、氨基酸及微量元素等成分。以三萜类和多糖为主要活性成分,具有抗肿瘤、保肝、抗HIV-4及HIV-4蛋白酶活性、抗组织胺释放、抑制血管紧张素和抗氧化等作用。近年从灵芝属中发现的杂萜类化合物是灵芝中另一类重要的活性分子,具有保肝和抗过敏等生物活性。
本发明提供了两种具有PTP1B抑制活性的化合物,具有式1或式2所示结构:
本发明提供了上述化合物的制备方法,包括以下步骤:
A)拟热带灵芝干燥子实体粉末经乙醇加热回流提取,得到乙醇提取液;
B)乙醇提取液经减压浓缩、加水混悬,然后用乙酸乙酯萃取,萃取液经蒸馏浓缩得到乙酸乙酯浸膏;
C)乙酸乙酯浸膏经正相硅胶柱色谱分离,得到组分Fr.1~Fr.7;
D-1)取Fr.6,经反相C
18柱层析,得到Fr.6-1~Fr.6-5;
E-1)取Fr.6-4,经半制备高效液相色谱进行纯化,得到式1所示化合物;
D-2)取Fr.7,经反相C
18柱层析,得到Fr.7-1~Fr.7-6;
E-2)取Fr.7-5,经葡聚糖凝胶柱LH-20层析,用甲醇进行洗脱,得到Fr.7-5-1~Fr.7-5-5;
F-2)取Fr.7-5-4,经半制备高效液相色谱进行纯化,得到式2所示化合物。
所述步骤A)的乙醇优选为95%乙醇。
所述步骤B)优选具体为:
乙醇提取液经减压浓缩、加水混悬,然后依次用石油醚、乙酸乙酯、正丁醇萃取,取乙酸乙酯萃取液,经蒸馏浓缩得到乙酸乙酯浸膏。
所述步骤C)中,正相硅胶柱色谱分离的洗脱剂优选为石油醚/乙酸乙酯,所述石油醚和乙酸乙酯的体积比为10:1~1:2,进行梯度洗脱。
在本发明的一些具体实施例中,用石油醚/乙酸乙酯体系(V:V=10:1,8:1,6:1,4:1,2:1,1:1,1:2)依次进行梯度洗脱,分段收集,每部分进行薄层层析色谱检测后合并,得到7个组分Fr.1~Fr.7。
取Fr.6,经反相C
18柱层析,得到Fr.6-1~Fr.6-5。
所述步骤D-1)中,反相C
18柱层析的洗脱剂优选为甲醇/水,所述甲醇和水的体积比优选为30:1~100:0,进行梯度洗脱。
得到Fr.6-1~Fr.6-5后,取Fr.6-4,经半制备高效液相色谱进行纯化,得到式1所示化合物,本发明记为Ganoduriporol F。
所述半制备高效液相色谱的流动相优选为乙腈和三氟乙酸的混合溶剂。
所述流动相进一步优选为V(乙腈):V(0.1%三氟乙酸水溶液)=42:58。
所述半制备高效液相色谱流动相的流速优选为4mL·min
-1。
取Fr.7,经反相C
18柱层析,得到Fr.7-1~Fr.7-6。
所述步骤D-2)中,反相C
18柱层析的洗脱剂优选为甲醇/水,所述甲醇和水的体积比优选为20:1~100:0,进行梯度洗脱。
得到Fr.7-1~Fr.7-6后,取Fr.7-5,经葡聚糖凝胶柱LH-20层析,用甲醇进行洗脱,得到Fr.7-5-1~Fr.7-5-5。
取Fr.7-5-4,经半制备高效液相色谱进行纯化,得到式2所示化合物,本发明记为Ganoduriporol G。
所述半制备高效液相色谱的流动相优选为甲醇和三氟乙酸的混合溶剂。
所述流动相进一步优选为V(甲醇):V(0.1%三氟乙酸水溶液)=72:28。
所述流动相的流速优选为4mL·min
-1。
本发明提供了上述具有PTP1B抑制活性的化合物或上述制备方法制备的具有PTP1B抑制活性的化合物,在制备用于治疗或减轻糖尿病的药物中的应用。
具体的,所述糖尿病为II型糖尿病。
本发明提供了一种药物组合物,包括上述具有PTP1B抑制活性的化合物或上述制备方法制备的具有PTP1B抑制活性的化合物,和药学上可以接受的辅料。
本发明对所述辅料没有特殊限定,可以为本领域技术人员熟知的适用辅料。
上述具有PTP1B抑制活性的化合物或上述药物组合物还可以与其他治疗或减轻糖尿病的药物联用。
与现有技术相比,本发明提供了两种具有PTP1B抑制活性的化合物,具有式1或式2所示结构。本发明公开了从拟热带灵芝中首次发现的两种含氢醌杂萜化合物。经过生物活性评价发现此类化合物具有显著的PTP1B抑制活性,增强胰岛素受体敏感性,具有开发糖尿病药物的应用前景。
图1为Ganoduriporol F的
1HNMR谱图;
图2为Ganoduriporol F的
13CNMR谱图;
图3为Ganoduriporol F的DEPT谱图;
图4为Ganoduriporol F的HSQC谱图;
图5为Ganoduriporol F的HMBC谱图;
图6为Ganoduriporol F的
1H-
1H COSY谱图;
图7为Ganoduriporol F的ROESY谱图;
图8为Ganoduriporol F的HRESIMS谱图;
图9为Ganoduriporol G的
1HNMR谱图;
图10为Ganoduriporol G的
13CNMR谱图;
图11为Ganoduriporol G的DEPT谱图;
图12为Ganoduriporol G的HSQC谱图;
图13为Ganoduriporol G的HMBC谱图;
图14为Ganoduriporol G的
1H-
1H COSY谱图;
图15为Ganoduriporol G的ROESY谱图;
图16为Ganoduriporol G的HRESIMS谱图。
为了进一步说明本发明,下面结合实施例对本发明提供的具有PTP1B抑制活性的化合物及其应用进行详细描述。
实施例1
Ganoduriporol F和Ganoduriporol G的分离纯化
拟热带灵芝干燥子实体样品(5.0kg),粉碎成粉末后用95%的乙醇加热回流提取3次,提取液经过减压浓缩合并后得到乙醇提取物,浸膏混悬后,依次用石油醚、乙酸乙酯和正丁醇萃取3次,萃取液减压浓缩后得到石油醚、乙酸乙酯和正丁醇部分。
拟热带灵芝粗提物乙酸乙酯部分(50.0g)经正相硅胶柱色谱分离,用石油醚/乙酸乙酯体系(V:V=10:1,8:1,6:1,4:1,2:1,1:1,1:2)依次进行梯度洗脱,分段收集,每部分进行薄层层析色谱检测后合并,得到了7个组分Fr.1~Fr.7。
Fr.6(5.0g)经反相C
18柱,用甲醇/水(V:V=30:1~100:0)依次进行梯度洗脱,用薄层硅胶板检测后合并,得到了5个组分Fr.6-1~Fr.6-5。取Fr.6-4(65.0mg)经半制备高效液相[V(乙腈):V(0.1%三氟乙酸水溶液)=42:58,流速4mL·min
-1]进行纯化后得到化合物Ganoduriporol F(3.2mg,t
R=15min)。
Fr.7(6.0g)经反相C
18柱,用甲醇/水(V:V=20:1~100:0)依次进行梯度洗脱,用薄层硅胶板检测后合并,得到了6个组分Fr.7-1~Fr.7-6。取Fr.7-5(205.0mg)经葡聚糖凝胶柱LH-20层析,用甲醇进行洗脱,得到5个组分Fr.7-5-1~Fr.7-5-5。Fr.7-5-4(45.0mg)经半制备高效液相[V(甲醇):V(0.1%三氟乙酸水溶液)=72:28,流速4mL·min
-1]进行纯化后得到化合物Ganoduriporol G(3.0mg,t
R=14.2min)。
实施例2
Ganoduriporol F和Ganoduriporol G的结构鉴定
对所分离得到的化合物Ganoduriporol F和Ganoduriporol G分别进行核磁共振、红外、质谱检测等多种现代波谱技术并结合化学方法鉴定了它们的结构。经鉴定,化合物Ganoduriporol F和Ganoduriporol G为新的氢醌杂萜类化合物。
Ganoduriporol F的结构式如下:
Ganoduriporol G的结构式如下:
化合物Ganoduriporol F和Ganoduriporol G的结构鉴定:
Ganoduriporol F为黄色油状,易溶于甲醇。HRESIMS显示化合物分子式为C
30H
32O
9(calced for C
30H
32NaO
9[M+Na]
+559.1938,found 559.1939),不饱和度为15。化合物Ganoduriporol F的
1H-NMR谱(表1)中给出1个1,2,4-三取代的苯二酚结构片段δ
H 7.13(d,J=2.9Hz,1H),δ
H 7.05(dd,J=9.0,2.9Hz,1H)和δ
H 6.89(d,J=9.0Hz,1H),1个对羟基苯环结构片段δ
H 7.44(d,J=8.4Hz,2H)和δ
H 6.80(d,J=8.4Hz,2H),2个反式耦合的烯烃信号δ
H 6.31(d,J=15.9Hz,1H)和δ
H 7.60(d,J=15.9Hz,1H),1个甲基信号δ
H 1.65(s,3H),2个连氧亚甲基信号δ
H 4.53(s,2H)和δ
H 4.07(s,2H)。综合分析其
13C-NMR和DEPT谱,共给出了30个碳信号包括1个甲基信号(CH
3)、5个亚甲基信号(CH
2)、14个次甲基信号(CH)和10个季碳信号(C)。该化合物
1H-NMR和
13C-NMR谱与参考文献(Liu,J.Q.;Lian,C.L.;Hu,T.Y.;Wang,C,F.;Xu,Y.;Xiao,L.;Liu,Z.Q.;Qiu,S.Q.;Cheng,B.H.Two new farnesyl phenolic compounds with anti-inflammatory activities from Ganoderma duripora.Food Chemistry.2018,04,97.)中ganoduriporol A的数据非常相似,主要区别是与ganoduriporol A核磁谱图中的CH
2-2'和CH-3'的信号被化合物Ganoduriporol F核磁图谱中一个烯烃季碳信号(δ
C)和一个烯烃次甲基(δ
C/H)信号取代,推测化合物Ganoduriporol F中的C-2'与C-3'以双键存在。H-2'和H
2-4'与C-3'的HMBC信号相关证明了化合物Ganoduriporol F中的。在ROESY谱图中,H-2'和H-4'相关,H-6'和H-8'相关,H-10'和H-12'相关,证明Δ
2',Δ
6'和Δ
10'双键的构型分别为Z,Z和E。H-2”和H-3” 的耦合常数为15.9Hz,证明Δ
2”双键的构型为E。
Ganoduriporol G为黄色油状,易溶于甲醇。HRESIMS显示化合物分子式为C
30H
34O
10(calced for C
30H
34NaO
10[M+Na]
+577.2046,found 577.2044)。该化合物
1H-NMR和
13C-NMR谱(表1)与Ganoduriporol F的数据非常相似,暗示它们具有相同的结构骨架。主要区别是化合物Ganoduriporol G在C-6”位上多了一个羟基(OH),除此之外在CH(6')=C(7')双键取代CH(6')-C(7')结构片段。以上推测结论由H-5”与C-6”,H-8”与C-6”;及H-15'与C-6',C-7',C-8'的HMBC相关信号确定。在ROESY谱图中,H-2'和H-4'相关,H-10'和H-12'相关,证明Δ
2'和Δ
10'双键的构型分别为Z和E。H-2”和H-3”的耦合常数为16.0Hz,证明Δ
2”双键的构型为E。
表1 化合物Ganoduriporol F和Ganoduriporol G的
1H-NMR(500MHz)和
13C-NMR(125MH)数据,溶剂为CD
3OD
化合物Ganoduriporol F和Ganoduriporol G的理化性质如下:
化合物Ganoduriporol F
Ganoduriporol F(1):黄色油状;UV-vis(MeOH)λ
max[logε(L·mol
-1·cm
-1)]:307(4.4),224(4.0)nm;
1H-NMR(CD
3OD,500MHz)和
13C-NMR(CD
3OD,125MHz)数据见表1;IR(KBr)ν
max:3436,2925,2851,1630,1388,1168cm
-1;HRESIMS calcd for C
30H
32NaO
9[M+Na]
+559.1939,found 559.1938。
化合物Ganoduriporol G
Ganoduriporol G(2):黄色油状;
UV-vis(MeOH)λ
max[logε(L·mol
-1·cm
-1)]:328(4.1),288(3.8)nm;
1H-NMR(CD
3OD,500MHz)和
13C-NMR(CD
3OD,125MHz)数据见表1;IR(KBr)ν
max:3414,2927,2859,1610,1474,1263,1195cm
-1;HRESIMS calcd for C
30H
34NaO
10[M+Na]
+577.2046,found 577.2044。
实施例3
化合物Ganoduriporol F和GanoduriporolG的PTP1B抑制活性测定
本实施例将实施例1的化合物Ganoduriporol F和Ganoduriporol G进行PTP1B抑制活性的测定,测定方法参考文献(Li-Man Zhou,Fan-Dong Kong,Peng Fan,Qing-Yun Ma,Qing-Yi Xie,Jiu-Hui Li,Hai-Zhou Zheng,Zhi-Hui Zheng,Jing-Zhe Yuan,Hao-Fu Dai,Du-Qiang Luo,You-Xing Zhao.Indole-Diterpenoids with Protein Tyrosine Phosphatase InhibitoryActivities from the Marine-Derived Fungus Penicillium sp.KFD28.Journal of Natural Products,2019,82:2638-2644.),制备得到的化合物Ganoduriporol F和Ganoduriporol G用DMSO溶解,配制浓度为1mg/ml以及不同稀释梯度的待测样品溶液,取不同稀释梯度的待测样品溶液分别加到测活体系(50μL buffer,20μL ddH
2O,3μL pNPP底物溶液),通过非线性拟合的反应结果判断其待测化合物的抑制活性,并其计算IC
50值。阳性对照;正钒酸钠,反应温度为37℃,测定波长为405nm处的光吸收。
结果见表2,式1所示的化合物Ganoduriporol F与式2所示的化合物 Ganoduriporol G对于PTP1B都具有较好的抑制活性,具有开发治疗II型糖尿病药物的应用前景。
表2 化合物对PTP1B的抑制活性IC
50(μM)
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (9)
- 权利要求1所述的化合物的制备方法,包括以下步骤:A)拟热带灵芝干燥子实体粉末经乙醇加热回流提取,得到乙醇提取液;B)乙醇提取液经减压浓缩、加水混悬,然后用乙酸乙酯萃取,萃取液经蒸馏浓缩得到乙酸乙酯浸膏;C)乙酸乙酯浸膏经正相硅胶柱色谱分离,得到组分Fr.1~Fr.7;D-1)取Fr.6,经反相C 18柱层析,得到Fr.6-1~Fr.6-5;E-1)取Fr.6-4,经半制备高效液相色谱进行纯化,得到式1所示化合物;D-2)取Fr.7,经反相C 18柱层析,得到Fr.7-1~Fr.7-6;E-2)取Fr.7-5,经葡聚糖凝胶柱LH-20层析,用甲醇进行洗脱,得到Fr.7-5-1~Fr.7-5-5;F-2)取Fr.7-5-4,经半制备高效液相色谱进行纯化,得到式2所示化合物。
- 根据权利要求2所述的制备方法,其特征在于,所述步骤C)中,正相硅胶柱色谱分离的洗脱剂为石油醚/乙酸乙酯,所述石油醚和乙酸乙酯的体积比为10:1~1:2。
- 根据权利要求2所述的制备方法,其特征在于,所述步骤D-1)中, 反相C 18柱层析的洗脱剂为甲醇/水,所述甲醇和水的体积比为30:1~100:0。
- 根据权利要求2所述的制备方法,其特征在于,所述步骤E-1)中,半制备高效液相色谱的流动相为乙腈和三氟乙酸的混合溶剂。
- 根据权利要求2所述的制备方法,其特征在于,所述步骤D-2)中,反相C 18柱层析的洗脱剂为甲醇/水,所述甲醇和水的体积比为20:1~100:0。
- 根据权利要求2所述的制备方法,其特征在于,所述步骤F-2)中,半制备高效液相色谱的流动相为甲醇和三氟乙酸的混合溶剂。
- 权利要求1所述的具有PTP1B抑制活性的化合物或权利要求2~7任一项所述的制备方法制备的具有PTP1B抑制活性的化合物,在制备用于治疗或减轻糖尿病的药物中的应用。
- 一种药物组合物,包括权利要求1所述的具有PTP1B抑制活性的化合物或权利要求2~7任一项所述的制备方法制备的具有PTP1B抑制活性的化合物,和药学上可以接受的辅料。
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