CN102863472A - Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs - Google Patents

Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs Download PDF

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CN102863472A
CN102863472A CN 201210388825 CN201210388825A CN102863472A CN 102863472 A CN102863472 A CN 102863472A CN 201210388825 CN201210388825 CN 201210388825 CN 201210388825 A CN201210388825 A CN 201210388825A CN 102863472 A CN102863472 A CN 102863472A
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combretastatin
analogue
op
cancer
oxazole
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CN 201210388825
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CN102863472B (en )
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王鹏
李静
韩福国
戚欣
李明
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中国海洋大学
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Abstract

The invention provides a combretastatin A-4 analogue. The structure of the combretastatin A-4 analogue is represented by general formula (I), wherein R1 represents -H, OH or a metal phosphate substituent group, R2 represents -OH or the metal phosphate substituent group, and the metal phosphate substituent group is -OP(O)(ONa)2, -OP(O)(OK)2, -OP(O)(OLi)2, -OP(O) O2Zn or -OP(O) O2Ca. A pharmacology experiment shows that the combretastatin A-4 analogue can inhibit polymerization of endothelial cell tubulin, damage forming of lumens and lead to tumour organization center necrosis, and the combretastatin A-4 analogue can be applied in anti-solid tumor drugs or in tumor vessel breakers and is wide in application prospects.

Description

考布他汀A-4类似物及其制备方法和在制备抗肿瘤药物中的应用 Cobb A-4 analog preparation method and statin in the preparation of anti-tumor drugs

技术领域 FIELD

[0001] 本发明属于药物领域,尤其涉及了考布他汀A-4类似物及其制备方法和在制备抗肿瘤药物中的应用。 [0001] The present invention belongs to the pharmaceutical field, in particular, it relates to a combretastatin A-4 analog preparation method and in the preparation of anti-tumor drugs.

背景技术 Background technique

[0002]目前靶向肿瘤血管系统的药物主要分为两种:一种是通过抑制肿瘤的新生血管生成而有效阻止肿瘤生长和转移的药物,称为肿瘤新生血管生成抑制剂(tumorangiogenesis inhibtor, TAI),另一种是通过破坏肿瘤内部血管而导致肿瘤坏死的药物,称为血管破坏剂(Vascular Disrupting Agent, VDA)。 [0002] It drug targeting tumor vasculature is divided into two: one is by inhibition of tumor angiogenesis and effective drugs to prevent tumor growth and metastasis, called angiogenesis inhibitors (tumorangiogenesis inhibtor, TAI ), the other is through the interior of the vessel and destroy tumor results in tumor necrosis drug, called vascular disrupting agents (vascular Disrupting agent, VDA).

[0003] 血管破坏剂是基于实体瘤血管网络混乱、分级不明显、血管内皮细胞形状不规则,·相互之间联系松散等特点而开发的一类抗肿瘤药物,它可以快速、选择性的破坏既存的肿瘤血管网络,从而引发肿瘤的坏死。 [0003] vascular disrupting agent is a solid tumor vascular network based on confusion, classification is not obvious, vascular endothelial cells of irregular shape, a loose connection between one another-and so developed a class of anticancer drugs, it can be quickly, selective destruction existing network of tumor blood vessels, causing tumor necrosis. 在作用机理上,血管破坏剂是通过抑制实体瘤血管内皮细胞微管蛋白聚合,改变细胞骨架结构,从而引起肿瘤血管内皮细胞变形,导致肿瘤内部血栓形成,阻断肿瘤内部氧气和营养的供应以及细胞代谢废物的排出,进而引起实体瘤内部肿瘤细胞的大面积坏死。 On the mechanism of action, vascular disrupting agents by inhibiting solid tumor vascular endothelial cells tubulin polymerization, changes in the cytoskeleton structure, thereby causing deformation of tumor vascular endothelial cells, leading to thrombosis within the tumor, tumor inner blocking supply of oxygen and nutrients and cellular metabolic waste discharge, thereby causing tumor cells of solid tumors inside large areas of necrosis. 目前,在欧美进入临床研究的众多血管破坏剂中,考布他汀A-4的磷酸钠盐(CA4P)和考布他汀AI的磷酸钠盐(CAlP)显示出非常好的开发前景。 Currently, numerous vascular disrupting agent to enter clinical studies in Europe and America, the combretastatin sodium phosphate (CA4P) A-4 and combretastatin AI sodium phosphate salt (CAlP) showed very good development prospects. CA4P具有优良的抗血管活性,对甲状腺癌、肝癌、肺癌等多种实体肿瘤具有显著疗效,已被美国FDA批准为治疗低分化甲状腺癌的孤儿药物;CA1P是其进一步改构的化合物,已进入临床研究阶段。 CA4P excellent antiangiogenic activity, has a significant effect on a variety of solid tumors, thyroid cancer, liver cancer, lung cancer, has been approved by the FDA as an orphan drug therapy poorly differentiated thyroid cancer; CA1P compound is further modified configuration, it has been entered clinical research stage. 因此开发新型的、相比CA4P更高效的肿瘤血管破坏剂仍然具有十分重要的意义。 Therefore, the development of new, more efficient compared to CA4P tumor vascular disrupting agent still has great significance.

发明内容 SUMMARY

[0004] 针对现有技术中抗肿瘤药物存在的不足和缺陷,本发明提供了考布他汀A-4类似物及其制备方法和在制备抗肿瘤药物中的应用,本发明依据考布他汀类血管破坏剂的结构特点,提供CA4的结构类似物,并将其制备成磷酸盐,该系列磷酸盐衍生物的水溶性好,生物利用度高,能够作为抑制微管蛋白聚合、靶向肿瘤血管的抗肿瘤药物。 [0004] The anticancer drugs for the prior art shortcomings and deficiencies exist, the present invention provides a preparation method and use analogs of combretastatin A-4 in the manufacture of anti-tumor drugs, according to the present invention Cobb statin structural features of vascular disrupting agents, to provide structural analogs CA4, and it was prepared as a phosphate, a good water-soluble phosphate derivative of the series, bioavailability, can be used as the polymerization inhibiting tubulin targeting tumor vasculature anticancer drugs.

[0005] 为实现上述发明目的,本发明采用下述技术方案予以实现: [0005] In order to achieve the above object, the present invention be implemented using the following technical scheme:

[0006] 一种考布他汀A-4类似物,其结构如通式(I)所示: [0006] A combretastatin A-4 analogs, such as the structure of formula (I) below:

[0007] [0007]

Figure CN102863472AD00041

[0008] 其中R1=-H' OH或金属磷酸盐取代基,R2=-OH或金属磷酸盐取代基,所述金属磷酸盐取代基为-OP (O) (ONa)2, -OP (O) (OK)2, -OP (O) (OLi)2, -OP (O) O2Zn 或-OP (O) O2Ca0 [0008] wherein R1 = -H 'OH or a metal phosphate substituent, R2 = -OH or a substituent group metal phosphate, the metallic phosphate substituent is -OP (O) (ONa) 2, -OP (O ) (OK) 2, -OP (O) (OLi) 2, -OP (O) O2Zn or -OP (O) O2Ca0

[0009] 对上述技术方案的进一步改进:所述R1和R2中至少有一个为金属磷酸盐取代基。 [0009] The above technical solution further improvement: R1 and R2 at least one of a metal phosphate substituents.

[0010] 本发明还提供了包含所述的考布他汀A-4类似物的药物组合物。 [0010] The present invention also provides a pharmaceutical composition comprising said combretastatin A-4 analogs.

[0011] 本发明还提供了含有有效剂量的所述的考布他汀A-4类似物和可药用赋形剂的药物组合物。 [0011] The present invention further provides a test cloth containing an effective dose of the statin A-4 analogs and pharmaceutically acceptable excipient thereof.

[0012] 本发明还提供了所述的考布他汀A-4类似物的制备方法,它包括以下步骤: [0012] The present invention further provides a method of preparing combretastatin A-4 analogs, comprising the steps of:

[0013] 将4-(3',4',5'-三甲氧基苯基)-5-(2",3" - 二羟基_4"-甲氧基苯基)_噁唑溶于N,N- 二甲基甲酰胺与乙腈的混合溶剂中,在惰性气体保护、低温条件下,依次添加四氯化碳、二甲氨基吡啶以及亚磷酸二苄酯反应制备噁唑类化合物的磷酸衍生物,所述的4-(3',4',5'-三甲氧基苯基)-5-(2〃,3" - 二羟基_4"-甲氧基苯基)-噁唑、四氯化碳、二甲氨基吡啶、亚磷酸二苄酯的摩尔比分别是I :5-15 :0. 1-0. 5 :2-8 ; [0013] 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ', 3' - dihydroxy _4 '- methoxyphenyl) oxazole was dissolved in N _ , N- mixed solvent of dimethylformamide and acetonitrile, under an inert atmosphere, low temperatures, followed by adding carbon tetrachloride, dimethylaminopyridine and the reaction of dibenzyl phosphite phosphorylation oxazole compounds derived was the 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 〃, 3 '- dihydroxy _4' - methoxyphenyl) - oxazole, tetrakis carbon chloride, dimethylaminopyridine, molar ratio of phosphorous acid benzyl ester are I: 5-15: 0 1-0 5: 2-8;..

[0014] 然后利用三甲基溴硅烷脱除苄基,再与甲醇钠、氢氧化钾、氢氧化锂、醋酸锌和氢氧化钙中一种或多种反应得到噁唑类化合物的磷酸盐粗品,所述的噁唑类化合物的磷酸衍生物与三甲基溴硅烷的摩尔比是I :4-8 ;所述的噁唑类化合物的磷酸衍生物与甲醇钠、氢氧化钾、氢氧化锂的摩尔比为1:1-5 ;所述的噁唑类化合物的磷酸衍生物与醋酸锌、氢氧化钙的摩尔比为1:1-3 ; [0014] then removed using bromotrimethylsilane benzyl, then with sodium methoxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, zinc acetate, and one or more compounds obtained by reacting an oxazole crude phosphate the molar ratio of said phosphoric acid derivative and an oxazole-based compound of trimethylsilyl bromide are I: 4-8; phosphoric acid derivative of the oxazole compounds with sodium methoxide, potassium hydroxide, lithium hydroxide the molar ratio of 1: 1-5; zinc acetate with the phosphoric acid derivatives of oxazole compounds, calcium hydroxide is a molar ratio of 1: 1-3;

[0015] 将所述磷酸盐粗品在水/丙酮中沉出,再在水与乙醇中结晶即得噁唑类化合物的磷酸盐。 [0015] The crude product was precipitated phosphate in water / acetone and recrystallization to give the oxazole-phosphate-based compound in water and ethanol.

[0016] 对上述技术方案的进一步改进:将所述粗品溶于水中,加入丙酮沉出3次,所需丙酮与水的体积比为3-5 :1,所得粗品在水与乙醇中结晶,水与乙醇的体积比为I :3-6。 [0016] Further improvement of the above technical solution: The crude product was dissolved in water, and precipitated three times with acetone, the desired ratio of 3-5 volumes of acetone to water is: 1, the resulting crude product was crystallized from ethanol and water, volume ratio of water and ethanol is I: 3-6.

[0017] 本发明还提供了所述的考布他汀A-4类似物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 [0017] The present invention further provides a Cobb said statin A-4 analogs in the manufacture of inhibiting tubulin polymerization or antitumor drugs.

[0018] 本发明还提供了所述的药物组合物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 [0018] The present invention also provides the pharmaceutical composition inhibits tubulin polymerization or use in the preparation of antitumor drugs.

[0019] 对上述技术方案的进一步改进:所述肿瘤是实体肿瘤,所述实体肿瘤是肺癌、肾癌、乳腺癌、胃癌、卡波氏肉瘤、结肠癌、肝癌、前列腺癌、甲状腺癌、神经母细胞瘤、卵巢癌或头颈部鳞癌、鼻咽癌。 [0019] Further improvement of the above technical solution: the tumor is a solid tumor, a solid tumor is lung cancer, renal cancer, breast cancer, stomach cancer, Kaposi's sarcoma, colon cancer, liver cancer, prostate cancer, thyroid cancer, nerve neuroblastoma, ovarian cancer, or head and neck squamous cell carcinoma, nasopharyngeal carcinoma.

[0020] 对上述技术方案的进一步改进:其中抗肿瘤的机理是抑制内皮细胞微管蛋白聚合,或通过破坏肿瘤既成血管进行作用。 [0020] Further improvement of the above technical scheme: wherein the antitumor mechanism of the endothelial cell inhibiting tubulin polymerization, or by the action of de facto destruction of the tumor blood vessels.

[0021] 与现有技术相比,本发明的优点和积极效果是: [0021] Compared with the prior art, the advantages and positive effects of the present invention are:

[0022] 本发明提供了考布他汀A-4类似物,它通过4_(3',4',5'-三甲氧基苯基)-5-(2",3" - 二羟基-4"-甲氧基苯基)_噁唑与亚磷酸二苄酯反应制备得到。该系列磷酸盐衍生物的水溶性好,生物利用度高,能够作为抑制微管蛋白聚合、靶向肿瘤血管的抗肿瘤药物。 [0022] The present invention provides combretastatin A-4 analog which by 4_ (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ", 3" - dihydroxy-4 " - methoxyphenyl) oxazole _ with phosphorous acid dibenzyl ester prepared by the series of phosphate derivatives of good water solubility, the bioavailability, can be used as an anti-inhibiting tubulin polymerization targeting tumor vasculature. tumor drugs.

[0023] 本发明将药物分子与磷酸基团相连形成磷酸盐衍生物,有助于药物分子向细胞内转运,并且在进入药物靶点前具有很好的稳定性和较长的半衰期;磷酸盐前药在体内可被内源性的磷酸酯酶水解为母药释放出来,而癌细胞表面磷酸酯酶含量较高使水解具有选择性。 [0023] The present invention will be drug molecules linked to form a phosphate group and phosphate derivatives, facilitate the transport of drug molecules into the cell, and has a good stability and a longer half-life before entering the drug target; phosphate prodrugs can be hydrolyzed by endogenous phosphatase in vivo to release the parent drug, the cell surface content of high phosphatase selective hydrolysis. 通过磷酸盐前药给药可以提高药物分子的水溶性、选择性以及降低药物的毒副作用和不良反应。 Phosphate prodrug thereof can be improved by a water-soluble drug molecule, the selectivity and reducing drug side effects and adverse reactions. [0024] 本发明通过实验表明结构类似考布他汀A4的化合物能用于制备抑制微管蛋白聚合或抗肿瘤药物,应用前景广阔。 [0024] The present invention tubulin polymerization or antineoplastic application prospect experiments show structurally similar test compound combretastatin A4 can be used for the preparation of inhibition.

[0025] 结合附图阅读本发明的具体实施方式后,本发明的其他特点和优点将变得更加清楚。 [0025] The present invention is read in conjunction with the specific embodiments of the drawings Other features and advantages of the present invention will become more apparent.

附图说明 BRIEF DESCRIPTION

[0026] 图I为本发明中CA-IH对微管蛋白聚合的抑制作用。 [0026] FIG. CA-IH I Inhibition of tubulin polymerization of the present invention.

[0027] 图2为本发明中CA-IH对HUVEC细胞形态的影响。 [0027] FIG. 2 shows the impact of CA-IH HUVEC cell morphology of the present invention.

[0028] 图3为本发明中免疫荧光检测药物对HUVEC微管的影响图,其中上左为空白对照,上右为溶剂对照,下左为CA4,下右为CA-1H。 [0028] FIG. 3 shows immunofluorescence invention on HUVEC microtubule drugs influence diagram, wherein the left as blank control, solvent control on the right of the lower left to CA4, the right is the CA-1H.

[0029] 图4为本发明中免疫荧光检测药物对HUVEC微丝的影响图,其中上左为空白对照,上右为溶剂对照,下左为CA4,下右为CA-1H。 [0029] The present invention, FIG. 4 immunofluorescence Effects of drugs on HUVEC FIG microfilaments, wherein the left as blank control, solvent control on the right of the lower left to CA4, the right is the CA-1H.

[0030] 图5为本发明中CA-IH对HUVEC既成管腔的破坏图。 [0030] FIG. 5 to FIG. CA-IH damage HUVEC de facto lumen of the present invention.

[0031] 图6为本发明中CA-IH对HUVEC既成管腔在各个时间点的破坏率统计图。 [0031] FIG. 6 CA-IH lumen de facto destruction rate of HUVEC at various time chart of the present invention.

[0032] 图7为本发明中Western blotting检测CA-1HP对HUVEC内微管蛋白聚合的影响图。 [0032] FIG. 7 Effect of protein aggregation in FIG. CA-1HP detected by Western blotting of the present invention HUVEC microtubules.

[0033] 图8为本发明中CA-IHP引发NCI-H1975裸小鼠移植瘤组织内部坏死图。 [0033] FIG. 8 CA-IHP initiator NCI-H1975 nude mice transplanted tumor necrosis inside present invention FIG.

[0034] 图9为本发明中CA-IHP引发NCI-H1975裸小鼠移植瘤组织内部坏死统计图。 [0034] FIG. 9 CA-IHP initiator nude mice NCI-H1975 tumor necrosis internal chart of the present invention.

具体实施方式 detailed description

[0035] 下面结合附图和具体实施方式对本发明的技术方案作进一步详细的说明。 [0035] Next, the technical solution of the present invention will be described in further detail in conjunction with accompanying drawings and specific embodiments.

[0036] 实施例I [0036] Example I

[0037] 本发明的结构类似考布他汀A4的化合物通过4_(3',4',5'-三甲氧基苯基)-5-(2",3" - 二羟基-4"-甲氧基苯基)_噁唑与亚磷酸二苄酯反应进行制备,具体步骤如下: [0037] The structure of the present invention similar to the test compound by combretastatin A4 4_ (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ", 3" - dihydroxy-4 "- methoxy phenyl) oxazole _ with phosphorous acid dibenzyl ester prepared, the following steps:

[0038] [0038]

Figure CN102863472AD00061

[0039] 本发明中式(I)中当札、R2为-OH时,名称为4- (3' ,4' ,5'-三甲氧基苯基)-5- (2〃,3" - 二羟基-4"-甲氧基苯基)-噁唑,简称为CA-1H,分子式为C19H19NO7,分子量为373. 36,为淡黄色固体;其结构式如(II)所示: [0039] formula (I) according to the present invention, when the sheaf, when R2 is -OH, the name is 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 〃, 3 '- di hydroxy-4 '- methoxyphenyl) - oxazole, abbreviated as CA-1H, molecular formula is C19H19NO7, molecular weight of 373.36, as a pale yellow solid; as shown in the structural formula (II):

[0040] [0040]

Figure CN102863472AD00071

[0041] 式(I)中当R2为-OPO3Na2时,名称为4-(3 ' ,4' ,5'-三甲氧基苯基)-5-(4"-甲氧基苯基)-噁唑-2",3" -0,0-二磷酸四钠盐,简称为CA-1HP,分子式为C19H17NO13Na4P2,分子量为621. 24,为灰白色固体;其结构式如(III)所示: In [0041] formula (I) when R2 is -OPO3Na2, the name is 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (4 '- methoxyphenyl) - Evil oxazol-2 ", 3" -0,0-diphosphate tetrasodium salt, abbreviated as CA-1HP, formula C19H17NO13Na4P2, a molecular weight of 621.24, as an off-white solid; the structural formula (III) below:

[0042] [0042]

Figure CN102863472AD00072

[0043] [0043]

(III) (III)

[0044] —、本发明磷酸钠衍生物的制备 [0044] - preparation of the sodium derivative of the present invention

[0045]将0.7臟01的4-(3' ,4' ,5'-三甲氧基苯基)-5-(2",3" - 二羟基_4"-甲氧基苯基)-噁唑溶于6mL N, N- 二甲基甲酰胺与6mL乙腈的混合溶剂中,在氩气保护下置于-10°C的低温反应装置中,滴加7mmol的四氯化碳,搅拌10分钟后,加入O. 15mmol 二甲氨基吡啶,在搅拌5分钟后缓慢滴加4. 2mmol亚磷酸二苄酯反应,继续反应2小时,并于-5°C再反应2小时,加入IOmL磷酸二氢钾溶液(O. 5mol/L)终止反应,反应液用乙酸乙酯萃取(3 X 50mL),萃取液用无水硫酸钠干燥,减压浓缩,硅胶柱层析(石油醚/乙酸乙酯=2/1)得O. 5mmol的白色固体二磷酸四苄酯衍生物。Rf = O. 2 (石油醚/乙酸乙酯=2/1) ; 1HNMR (CDCl3, 600MHz) δ 7. 93 (s, 1H, H_2),7. 19-7. 28 (m, 17H, Ph-H),7. 04-7. 06 (m, 4H, Ph-H), [0045] The dirty 0.7 01 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ', 3' - dihydroxy _4 '- methoxyphenyl) - Evil oxazole was dissolved in low-temperature reaction unit 6mL N, N- dimethylformamide and a mixed solvent of acetonitrile 6mL placed at -10 ° C under argon, the carbon tetrachloride was added dropwise 7mmol, and stirred for 10 minutes after O. 15mmol dimethylaminopyridine was added, and after stirring for 5 minutes was slowly added dropwise 4. 2mmol diphosphite benzyl ester, the reaction was continued for 2 hours and allowed to react at -5 ° C 2 hours, dihydrogenphosphate IOmL a solution of potassium (O. 5mol / L) to terminate the reaction, the reaction solution was extracted with ethyl acetate (3 X 50mL), the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to give a white solid O. 5mmol tetrabenzyl diphosphate ester derivative .Rf = O. 2 (petroleum ether / ethyl acetate = 2/1); 1HNMR (CDCl3, 600MHz) δ 7. 93 (s, 1H, H_2), 7. 19-7. 28 (m, 17H, Ph-H), 7. 04-7. 06 (m, 4H, Ph-H),

6. 90 (d, J=8. 8Hz, 1H, Ph-H), 6. 8 8 (s, 2H, Ph-H),5. 14-5. 19 (m, 4H, Ph-CH2),4. 78-4. 81 (m, 2H, Ph-CH2),4. 69-4. 72 (m, 2H, Ph-CH2),3. 86 (s, 3H, OCH3),3. 76 (s, 3H, OCH3),3. 69 (s, 6H, OCH3X 2) ;13C NMR (D2O, 150MHz) δ 153. 8(C_3'),153. 2(C_5'),150. 2(C_2), 141. 2,137. 7,136. 2,135. 7,135. 7,135. 3,135. 2,128. 4,128. 4,128. 4,128. I, 127. 9,127. 8,116. 2,109. 6 (C_l”),103. 8(C-2',C-6'),69. 8(Ph-CH2), 60. 8(0CH3-4'),56. 5(0CH3-4”),56. 0(0CH3-3',0CH3-5')。 6. 90 (d, J = 8. 8Hz, 1H, Ph-H), 6. 8 8 (s, 2H, Ph-H), 5. 14-5. 19 (m, 4H, Ph-CH2), 4. 78-4. 81 (m, 2H, Ph-CH2), 4. 69-4. 72 (m, 2H, Ph-CH2), 3. 86 (s, 3H, OCH3), 3. 76 (s , 3H, OCH3), 3 69 (s, 6H, OCH3X 2);.. 13C NMR (D2O, 150MHz) δ 153. 8 (C_3 '.), 153 2 (C_5'), 150 2 (C_2), 141 . 2,137. 7,136. 2,135. 7,135. 7,135. 3,135. 2,128. 4,128. 4,128. 4,128. I, 127. 9,127. 8 , 116. 2,109. 6 (c_l "), 103. 8 (C-2 ', C-6'), 69. 8 (Ph-CH2), 60. 8 (0CH3-4 '), 56. 5 (0CH3-4 "), 56. 0 (0CH3-3 ', 0CH3-5').

[0046] 将0.5mmol的所述二磷酸四苄酯衍生物溶于IOmL 二氯甲烷中,冰浴下滴加 [0046] The diphosphate 0.5mmol benzyl ester derivative was dissolved in four IOmL of dichloromethane, was added dropwise under ice

3. Ommol的三甲基溴硅烷,反应45分钟,减压蒸馏的白色固体用石油醚(3X30mL)洗涤,将白色固体溶于IOmL无水乙醇,加入2mL新鲜制备的甲醇钠(lmol/L),减压浓缩,将所得的固体溶于IOmL水,加入40mL丙酮,析出固体物质过滤,将所得物再用水-乙醇(体积比为I :3-6)结晶得到本发明的磷酸钠衍生物(CA-IHP)151H NMR(CDCl3, 600MHz) δ 8. 24(s, 1H,H_2), 3. Ommol of trimethylsilyl bromide, 45 minutes, evaporated under reduced pressure to a white solid with petroleum ether (3X 30 mL), dried IOmL white solid was dissolved in absolute ethanol, 2 mL of freshly prepared sodium methoxide (lmol / L) , concentrated under reduced pressure, and the resulting solid was dissolved in IOmL of water, was added 40mL of acetone, and the precipitated solid material was filtered, and then the resultant was washed with water - ethanol (volume ratio of I: 3-6) to give the crystalline sodium phosphate derivatives of the invention ( CA-IHP) 151H NMR (CDCl3, 600MHz) δ 8. 24 (s, 1H, H_2),

6. 91 (s, 1H, Ph-H),6. 83 (d, J=8. 8Hz, 1H, Ph-H),6. 78 (s, 1H, Ph-H),6. 73 (t, J=8. 8Hz, 1H, Ph-H),3. 86 (s, 3H, OCH3),3. 72 (s, 3H, OCH3), 3. 71 (s, 3H, OCH3),3. 66 (d, J = 5. 5Hz, 3H, OCH3)。 6. 91 (s, 1H, Ph-H), 6. 83 (d, J = 8. 8Hz, 1H, Ph-H), 6. 78 (s, 1H, Ph-H), 6. 73 (t , J = 8. 8Hz, 1H, Ph-H), 3. 86 (s, 3H, OCH3), 3. 72 (s, 3H, OCH3), 3. 71 (s, 3H, OCH3), 3. 66 (d, J = 5. 5Hz, 3H, OCH3).

[0047] 二、本发明磷酸钠衍生物的药理实验 [0047] Second, the pharmacological experiments of the present invention sodium phosphate derivatives

[0048] I、CA-IH体外抑制微管蛋白聚合活性实验 [0048] I, CA-IH vitro tubulin polymerization inhibiting activity tests

[0049] 微管蛋白溶液在0-4 °C是无色透明液体,在37 °C时可以聚合成微管,其溶液在340nm的吸光度(0D值)随时间升高,并在一定时间内达到坪值。 [0049] The tubulin solution at 0-4 ° C was colorless and transparent liquid, at 37 ° C can be polymerized into microtubules which the solution increased with time in absorbance at 340nm (0D value), and at a certain time to plateau. 干扰微管聚合的药物可以影响微管溶液OD值的变化。 Interfere with microtubule drugs can affect polymerization of microtubules solution change OD value.

[0050] 本发明实验中采用的微管蛋白提取于猪脑。 [0050] The tubulin used in the experiment of the present invention in porcine brain extracts. 聚合体系为:微管蛋白用甘油一MES溶液(O. ImM MES, ImM EGTA,0. 5mM MgCl2, ImM GTP现加,4M甘油)稀释成浓度12 μ M,化合物的终浓度为10 μ M,I μ M,O. I μ M,同时做溶剂对照和阳性对照。 The polymerization system was: tubulin MES diluted with a solution of glycerol (O. ImM MES, ImM EGTA, 0 5mM MgCl2, ImM GTP now added, 4M glycerol.) At a concentration of 12 μ M, final concentration of compound of 10 μ M, I μ M, O. I μ M, while as solvent and positive controls. 设置酶标仪的温度为37°C,检测波长为340nm,每分钟混匀读取一次,连续读取30min。 Microplate reader set temperature of 37 ° C, detection wavelength of 340nm, read once per minute mix, a continuous reading 30min. 实验结果如图I所示,表明CA-IH对微管蛋白聚合具有明显的抑制作用。 The results shown in FIG. I, CA-IH showed significantly inhibited tubulin polymerization.

[0051] 2、CA-IH对HUVEC形态的影响 [0051] 2, CA-IH affect morphology of HUVEC

[0052] 消化HUVEC,以2000个细胞/孔种于96孔板;24小时细胞贴壁后加药,药物浓度为ΙμΜ,设正常组、溶剂对照组(DMS0 O. 1%)、CA4阳性药对照组;加药O. 5小时、I小时、2小时后开始在显微镜下观察细胞形态并拍照。 [0052] Digestion of HUVEC, at 2000 cells / well were seeded in 96-well plates; adherent cells 24 hours dosing, drug concentration ΙμΜ, into normal group, the solvent control group (DMS0 O. 1%), CA4 positive drug group; dosing O. 5 hours, the I hour, 2 hours after the start cell morphology was observed under microscope and photographed. 结果见图2。 The results shown in Figure 2.

[0053] 从图2中可以看出正常组细胞呈铺路石状伸展,给药O. 5小时后细胞开始收缩变圆,I小时后、2小时后细胞收缩更明显,表明所述CA-IH能够明显影响HUVEC的细胞形态。 [0053] As can be seen in FIG. 2 normal cobblestone shaped cells extending administration O. After 5 hours the cells began to shrink round, after I hour, 2 hours after the cells shrink more significant, indicating that the CA-IH It can significantly affect the morphology of HUVEC cells.

[0054] 3、CA-IH对内皮细胞骨架的影响 [0054] 3 Effects CA-IH endothelial cytoskeleton

[0055] 铺玻片到24孔板,以血清在37°C包被30min ;消化HUVEC,以2 X IO4/孔种到玻片上;细胞贴壁后加入药物,药物浓度为I μ Μ,设空白对照、溶剂对照和阳性药CA4对照。 [0055] The slides were plated into 24-well plates, the serum to be packet 30min at 37 ° C; digestion of HUVEC to 2 X IO4 / species to the slide hole; adherent cells were added to the drug, a drug concentration of I μ Μ, provided blank control, solvent control, and positive control drug CA4. 药物作用30min后,吸去培养基,用PBS洗3次;4%多聚甲醛固定30min,吸去多聚甲醛,PBS洗3次;0. 1% Triton-100 打孔IOmin,吸去,PBS 洗3 次;加入1%BSA 封闭30min,吸去,PBS 洗3次;加入Tubulin抗体(Sigma公司产品,1:500稀释),4°C过夜;加入actin抗体(Sigma公司产品,1:500稀释)和Tubulin 二抗CY3( Sigma公司产品,1:1000稀释),室温放置30min,用激光共聚焦显微镜观察拍照。 Drugs after 30min, media was aspirated, washed three times with PBS; 4% paraformaldehyde for 30min, paraformaldehyde aspirated, washed three times with PBS;. 0 1% Triton-100 perforated IOmin, absorb, PBS 3 washes; was added 1% BSA blocking 30min, aspirated, PBS washed 3 times; added Tubulin antibody (Sigma products, 1: 500 dilution), 4 ° C overnight; added actin antibody (Sigma products, 1: 500 dilution ) and anti-Tubulin two CY3 (Sigma products, 1: 1000 dilution), room temperature for 30min, confocal laser microscope photographs. 结果见图3、图4。 The results shown in Figure 3, Figure 4.

[0056] 图3为药物对细胞微管的影响,图4为药物对细胞微丝的影响。 [0056] FIG. 3 is a drug effects on cellular microtubules, FIG. 4 is the effect of drugs on the cell microfilaments. 从图3中可以看出,正常细胞中微管成丝状结构,药物作用30min后细胞的微管网络结构遭到不同程度的破坏,呈现弥散、点状分布,荧光强度也减弱。 As can be seen from Figure 3, normal cells microtubule filaments, after 30min microtubule network structure of the cell was drugs varying degrees of damage, showing diffuse, punctate distribution of fluorescence intensity decrease. 从图4中可以看出,正常细胞中微丝分布均匀,少量微丝横跨整个细胞,在细胞周边有聚集。 As can be seen from Figure 4, normal cells microfilaments evenly distributed across the entire small amount of fibrils cells, in a cell surrounded by aggregation. 加入药物后,微丝的分布显著不同,大量微丝形成应力纤维聚集在细胞周边,使这一部位的荧光明显增强。 After addition of the drug, significantly different from the distribution of fibrils, fibrils formed a large number of stress fibers at the cell periphery aggregated, so that this portion significantly enhanced fluorescence. 表明CA-IH可以破坏内皮细胞的骨架结构。 CA-IH show skeletal structure can damage endothelial cells.

[0057] 4、CA-IH对HUVEC既成管腔的破坏实验 [0057] 4, CA-IH Failure Experiment lumen of HUVEC de facto

[0058] HUVEC能够在Matrigel上形成管腔,用以模拟肿瘤组织的血管。 [0058] HUVEC lumen can be formed on Matrigel, to simulate blood vessels of tumor tissue. 将内皮细胞加入到含有Matrigel (BD Biosciences公司产品)的96孔板孔中,每孔I. 8 X IO5个细胞,37°C培养12小时形成完整管腔,加入药物浓度为IuM作用后,在每一时间点选取统一视野拍照,统计管腔数,管腔形成的抑制率以下列公式计算: After endothelial cells were added to 96 well plate containing Matrigel (BD Biosciences Co.) in each well I. 8 X IO5 cells, 37 ° C for 12 hours for complete lumen, the drug was added at a concentration of IuM role in unity of each time point selected photographs, statistics lumen, lumen formation inhibition rate calculated by the following formula:

[0059] 抑制率(%)=(管腔数对照孔一管腔数给药孔)/管腔数对照孔X 100%,此对照为相应时间点的对照组管腔数。 [0059] Inhibition rate (%) = (Number of control wells lumen of the delivery opening a lumen number) / number of control wells lumen X 100%, the number of the control group this lumen corresponding point in time.

[0060] 结果见图5、图6。 [0060] The results shown in Figure 5, FIG. 6. 表明CA-IH能够破坏HUVEC形成的管腔,作用9小时破坏率达83. 59%ο CA-IH showed a lumen capable of disrupting the formation of HUVEC, the destruction rate of action 9 hours 83. 59% ο

[0061] 5、CA-IHP对HUVEC内微管蛋白聚合的影响 [0061] 5, CA-IHP on the micro-protein in HUVEC polymerization tube

[0062] 取对数生长期的HUVEC,接种于6孔板中,细胞贴壁过夜后,分别加入浓度为10 μ MU μ Μ、0· I μ M的CA-IHP,设空白对照、CA4P阳性对照。 [0062] HUVEC taking the logarithmic growth phase, and seeded in 6-well plates, the cells to adhere overnight were added at a concentration of 10 μ MU μ Μ, 0 · I μ M of CA-IHP, blank control, positive of CA4P control. 2小时后,每孔加入100 μ L裂解液(ImM EGTA, ImM MgSO4, 30% 甘油,5%DMS0,5mM GTP, 1% NP-40,0. IM PIPES pH 6.9),用细胞刮刀收集至离心管中,37°C 180,OOOg离心lh,聚合的微管蛋白被沉淀下来。 After 2 hours, each well was added 100 μ L lysis buffer (ImM EGTA, ImM MgSO4, 30% glycerol, 5% DMS0,5mM GTP, 1% NP-40,0. IM PIPES pH 6.9), collected with a cell scraper to centrifugation tube, 37 ° C 180, OOOg centrifuged lh, polymerized tubulin was precipitated. 将上清转移至对应离心管中,每管加入30 μ L 4\303上样缓冲液(2001111 Tris pH 6. 8,400mMDTT, 8%SDS ' O. 4%溴酚蓝,40%甘油),沉淀中加入130 μ L IX SDS上样缓冲液,混匀后沸水浴中加热lOmin。 The supernatant was transferred to a corresponding centrifuge tube, each tube was added 30 μ L 4 \ 303 loading buffer (2001111 Tris pH 6. 8,400mMDTT, 8% SDS 'O. 4% bromophenol blue, 40% glycerol), the precipitate the sample was added 130 μ L IX SDS buffer, heated in a boiling water bath after mixing lOmin. 将上清和沉淀裂解液分别取等量进行Western blot检测tubulin聚合情况。 The lysate supernatant and pellet were taken for Western blot analysis equal amounts of tubulin polymerization conditions. 结果见图7,P代表沉淀中的聚合的微管蛋白,S代表上清液中的解聚的微管蛋白。 The results shown in Figure 7, polymerized tubulin P represents the precipitate, S for tubulin depolymerization supernatant.

[0063] 如图7所示,与空白对照组相比,CA-IHP能使P型微管明显减少,S型微管增多,表明CA-IHP可以剂量依赖性地引起细胞内聚合形式的微管蛋白解聚成游离形式的微管蛋白。 [0063] 7, compared with the control group, P-type CA-IHP can microtubules significantly decreased, S micro tube, CA-IHP showed a dose-dependent manner induced polymerized form intracellular microelectrode tubulin depolymerization to free tubulin form.

[0064] 6、CA-IHP引发肿瘤组织内部坏死 [0064] 6, CA-IHP induced tumor necrosis internal

[0065] 非小细胞肺癌易瑞沙耐药细胞株NCI-H1975接种于裸小鼠右腋下,待肿瘤体积生长至约IOOmm3时,随机分组给药,并设置生理盐水空白对照组、CA4P阳性药组,给药后24小时后脱颈处死小鼠,取出NCI-H1975瘤组织;将瘤组织以OCT包埋,_20°C冰冻切片,HE染色(苏木素为国药集团化学试剂公司产品,曙红Y为上海三爱思试剂有限公司产品)。 [0065] Non-small cell lung cancer drug Iressa NCI-H1975 cell line in nude mice inoculated with the right armpit, to be grown to about IOOmm3 tumor volume when administered randomization, and disposed saline control group, positive of CA4P drug group, after 24 hours after administration the mice were sacrificed, tumor tissue removed NCI-H1975; the tumor tissue in OCT embedding, _20 ° C frozen, HE staining (hematoxylin as Sinopharm chemical reagent company products, eosin Y is thinking reagent Co., Ltd. Shanghai three love the product). 显微镜下观察并拍照。 Microscope and photographed. 结果见图8、图9。 The results shown in Figure 8, Fig.

[0066] 如图所示,随着CA-IH给药剂量的增加肿瘤组织坏死面积增加,给药浓度为100mg/kg时,肿瘤组组织坏死面积占比为80. 5%,细胞核碎裂、溶解,与CA4P相比,CA-IHP更能够杀死肿瘤组织的边缘细胞。 [0066] As shown, with the increase in CA-IH dose increased tumor necrosis area, administered at a concentration of 100mg / kg, the area of ​​tumor necrosis group accounted for 80.5%, nuclear fragmentation, dissolution, as compared with CA4P, CA-IHP more edge cells capable of killing the tumor tissue. N= “坏死”,V= “存活”。 N = "necrosis", V = "surviving."

[0067] 本发明式(I)化合物可以为结晶或定形物形式。 [0067] The compounds of formula (I) may be present in the form of crystalline or amorphous form. 式(I)化合物的某些结晶形式可以以包括在本发明范围内的多晶型物形式存在。 Some of the crystalline forms of the compounds of formula (I) may exist in forms including polymorphs thereof within the scope of the present invention. 本发明还涉及含有有效剂量的本发明化合物和可药用赋形剂例如载体或稀释剂的药物组合物。 The present invention also relates to compounds and pharmaceutical compositions of a pharmaceutically acceptable excipient carrier or diluent, for example, contain an effective dose of the present invention.

[0068] 本发明化合物的相应制剂可用于治疗多种疾病和病症,包括微管蛋白聚合和各种肿瘤,尤其用于治疗各种实体肿瘤和抑制内皮细胞微管蛋白聚合。 [0068] The preparation of the corresponding compounds of this invention are useful for treating various diseases and disorders, including tubulin polymerization and various tumors, especially for the treatment of various solid tumors and inhibition of endothelial cell tubulin polymerization. 所述实体肿瘤是指肺癌、肾癌、乳腺癌、胃癌、卡波氏肉瘤、结肠癌、肝癌、前列腺癌、甲状腺癌、神经母细胞瘤、卵巢癌及头颈部鳞癌、鼻咽癌,包括但不限于实体肿瘤。 It refers to the solid tumor cancer, renal cancer, breast cancer, stomach cancer, Kaposi's sarcoma, colon cancer, liver cancer, prostate cancer, thyroid cancer, neuroblastoma, ovarian cancer and head and neck squamous cell carcinoma, nasopharyngeal carcinoma, including but not limited to solid tumors.

[0069] 总之,本发明提供了结构类似考布他汀A4的化合物,并将其制备成二磷酸盐,该系列磷酸盐衍生物的水溶性好,生物利用度高,能够作为抑制微管蛋白聚合、靶向肿瘤血管的抗肿瘤药物。 [0069] In summary, the present invention provides compounds of similar combretastatin A4, and it was prepared as diphosphate, good water-soluble phosphate derivative of the series, bioavailability, can be used as inhibit tubulin polymerization , anticancer drugs target the tumor vasculature.

[0070] 以上实施例仅用以说明本发明的技术方案,而非对其进行限制;尽管参照前述实施例对本发明进行了详细的说明,对于本领域的普通技术人员来说,依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或替换,并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。 [0070] The above embodiments are intended to illustrate the present invention, but not intended to be limiting;. Although the present invention has been described in detail embodiments, those of ordinary skill in the art, the foregoing can still the technical solutions described in the embodiments may be modified, or some technical features equivalents; as such modifications or replacements do not cause the essence of corresponding technical solutions to depart from the spirit and scope of the invention as claimed technical solution.

Claims (10)

  1. 1. 一种考布他汀A-4类似物,其特征在于:其结构如通式(I)所示: A combretastatin A-4 analogue, characterized in that: the structure of the general formula (I) below:
    Figure CN102863472AC00021
    其中R1= -H、OH或金属磷酸盐取代基,R2= -OH或金属磷酸盐取代基,所述金属磷酸盐取代基为-OP (O) (ONa)2, -OP (O) (OK)2, -OP (O) (OLi)2, -OP (O) O2Zn 或-OP (O) 02Ca。 Wherein R1 = -H, OH or a metal phosphate substituent, R2 = -OH or a substituent group metal phosphate, the metallic phosphate substituent is -OP (O) (ONa) 2, -OP (O) (OK ) 2, -OP (O) (OLi) 2, -OP (O) O2Zn or -OP (O) 02Ca.
  2. 2.根据权利要求I所述的考布他汀A-4类似物,其特征在于:所述R1和R2中至少有一个为金属磷酸盐取代基。 The combretastatin A-4 analogue according to claim I, wherein: R1 and R2 at least one substituent is a metal phosphate.
  3. 3.包含权利要求I所述的考布他汀A-4类似物的药物组合物。 I claim 3 comprising the pharmaceutical composition combretastatin A-4 analogs thereof.
  4. 4.含有有效剂量的权利要求3所述的考布他汀A-4类似物和可药用赋形剂的药物组合物。 Cobb claimed in claim 3 comprising an effective dose of claim statin A-4 analogs and pharmaceutically acceptable excipient thereof.
  5. 5.根据权利要求I所述的考布他汀A-4类似物的制备方法,其特征在于包括以下步骤: 将4-(3' ,4' ,5'-三甲氧基苯基)-5-(2〃,3" - 二羟基_4"-甲氧基苯基)-噁唑溶于N,N-二甲基甲酰胺与乙腈的混合溶剂中,在惰性气体保护、低温条件下,依次添加四氯化碳、二甲氨基吡啶以及亚磷酸二苄酯反应制备噁唑类化合物的磷酸衍生物,所述的4-(3',4',5'-三甲氧基苯基)-5-(2〃,3" - 二羟基_4"-甲氧基苯基)-噁唑、四氯化碳、二甲氨基吡啶、亚磷酸二苄酯的摩尔比分别是I :5-15 :0. 1-0. 5 :2-8 ; 然后利用三甲基溴硅烷脱除苄基,再与甲醇钠、氢氧化钾、氢氧化锂、醋酸锌和氢氧化钙中一种或多种反应得到噁唑类化合物的磷酸盐粗品,所述的噁唑类化合物的磷酸衍生物与三甲基溴硅烷的摩尔比是I :4-8 ;所述的噁唑类化合物的磷酸衍生物与甲醇钠、氢氧化钾、氢氧化锂的摩尔 The Cobb I according to claim statin preparation of analogs A-4, comprising the steps of: 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 〃, 3 '- dihydroxy _4' - methoxyphenyl) - oxazole was dissolved in N, N- mixed solvent of dimethylformamide and acetonitrile, under an inert atmosphere, low temperatures, sequentially Add carbon tetrachloride, dimethylaminopyridine and dibenzyl phosphite ester acid derivatives of oxazole-based compound, the 4- (3 ', 4', 5'-trimethoxyphenyl) -5 - (2 〃, 3 '- dihydroxy _4' - methoxyphenyl) - oxazole, carbon tetrachloride, dimethylaminopyridine, molar ratio of phosphorous acid benzyl ester are I: 5-15: 0. 1-05: 2-8; and then removed using bromotrimethylsilane benzyl, then with sodium methoxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, zinc acetate and of one or more reaction oxazole to give the crude phosphate compound, the molar ratio of phosphate derivatives of oxazole compound with trimethylsilyl bromide are I: 4-8; phosphoric acid derivative of the oxazole compounds and methanol mole of sodium, potassium, lithium hydroxide 比为1:1-5 ;所述的噁唑类化合物的磷酸衍生物与醋酸锌、氢氧化钙的摩尔比为1:1-3; 将所述磷酸盐粗品在水/丙酮中沉出,再在水与乙醇中结晶即得噁唑类化合物的磷酸盐。 Ratio of 1: 1-5; zinc acetate with the phosphoric acid derivatives of oxazole compounds, calcium hydroxide is a molar ratio of 1: 1-3; the crude phosphate precipitated in water / acetone, recrystallization to give the oxazole-phosphate compounds in water and ethanol.
  6. 6.根据权利要求5所述的考布他汀A-4类似物的制备方法,其特征在于:将所述粗品溶于水中,加入丙酮沉出3次,所需丙酮与水的体积比为3-5 :1,所得粗品在水与乙醇中结晶,水与乙醇的体积比为I :3-6。 Cobb according to claim 5, wherein the preparation of statin A-4 analogs, wherein: the crude product was dissolved in water, precipitated by adding acetone three times, the desired volume ratio of acetone to water is 3 -5: 1, the resulting crude product was crystallized from ethanol with water, the volume ratio of water and ethanol is I: 3-6.
  7. 7.根据权利要求I所述的考布他汀A-4类似物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 According to claim I of the combretastatin A-4 in the manufacture of analogs inhibit tubulin polymerization or use of antitumor drugs.
  8. 8.权利要求3所述的药物组合物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 The pharmaceutical composition according to claim 3 in the manufacture of inhibiting tubulin polymerization or use of antitumor drugs.
  9. 9.根据权利要求7或8所述的制备抑制微管蛋白聚合或抗肿瘤药物中的用途,其特征在于:所述肿瘤是实体肿瘤,所述实体肿瘤是肺癌、肾癌、乳腺癌、胃癌、卡波氏肉瘤、结肠癌、肝癌、前列腺癌、甲状腺癌、神经母细胞瘤、卵巢癌或头颈部鳞癌、鼻咽癌。 Preparation according to claim 7 or claim 8 for inhibiting tubulin polymerization or antineoplastic, wherein: the tumor is a solid tumor, a solid tumor is lung cancer, renal cancer, breast cancer, stomach cancer , Kaposi's sarcoma, colon cancer, liver cancer, prostate cancer, thyroid cancer, neuroblastoma, ovarian cancer, or head and neck squamous cell carcinoma, nasopharyngeal carcinoma.
  10. 10.根据权利要求7或8所述的制备抑制微管蛋白聚合或抗肿瘤药物中的用途,其特征在于:其中抗肿瘤的机理是抑制内皮细胞微管蛋白聚合,或通过破坏肿瘤既成血管进行作用。 10. The preparation of claim 7 or claim 8 for inhibiting tubulin polymerization or antineoplastic, wherein: is wherein the antitumor mechanism of inhibition of endothelial cell tubulin polymerization, or by destruction of tumor blood vessels de facto effect.
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