CN101083991A - 二酮二硫代哌嗪抗生素用于制备抗血管生成药物组合物的用途 - Google Patents
二酮二硫代哌嗪抗生素用于制备抗血管生成药物组合物的用途 Download PDFInfo
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Abstract
本发明涉及二酮二硫代哌嗪抗生素特别是毛壳素与胶霉毒素用于制备抗肿瘤疗法中的药物组合物的用途。
Description
本发明涉及二酮二硫代哌嗪抗生素、特别是毛壳素与胶霉毒素用于制备具有抗血管生成活性的药物的用途。
现有技术
毛壳素(I)
和毛壳菌素(II)
是表多硫二氧代哌嗪抗生素的代表性实例，是由毛壳菌属的真菌产生的有抗菌及细胞毒活性的霉菌的次级代谢产物(C.Leigh，A.Taylor，“真菌毒素与真菌代谢物相关的食品问题”，ed.J.V.Rodricks，p.228，Am.Chem.Soc.，Washington，D.C.，1976；G.W.Kirby，D.J.Robins，真菌毒素的生物合成，ed.P.S.Stenyl，p.301，Academic Press，New York，1980。为了从属于C.thielavioideum的毛壳菌属培养物及从Farrowia sp.Strain中分离毛壳素，见S.Udagawa等人，“通过毛壳菌属与相关真菌产生的球毛壳甲素、柄曲菌素、O-甲基柄曲菌素与毛壳素”，Can.J.Microbiol.1979，25(2)：170-7，和S.Sekita等人，“毛壳菌属与相关真菌产生的真菌毒素”，Can.J.Microbiol.1981，27(8)：766-72)。此类化合物的特征是有二硫键。
除了毛壳素与毛壳菌素以外，表多硫二氧代哌嗪抗生素的另外的实例是胶霉毒素(III)
(P.Waring，J.Baever，“胶霉毒素与相关的表多硫二氧代哌嗪抗生素”，Gen Pharmacol.27，1311-1316，1996)，葚孢菌素(Chem.Ber.105(11)：3658-61，1972)，阿拉诺丁(N.Neuss等人，“阿拉诺丁与相关代谢物。II.两种新代谢物的分离、鉴别和结构”，Tetrahedron Letters，42，4467-4471，1968)，轮枝孢菌素(Chem.Ber.105(11)：3658-61，1972)，榅桲杀菌素(F.Reusser，“一种烟酸生物合成抑制剂——榅桲杀菌素的作用模式”；J.Bacteriol.96(4)：1285-1290，1968)与稻氯曲菌素(亦称为抗生素A-30641或aspirochlorine：K.Sakata等人，aspirochlorine(＝抗生素A30641)，“一种由曲霉菌属产生新的表二硫哌嗪-2，5-二酮的结构修饰”，TetrahedronLetters，28(46)，5607-5610，1987)。K.Michel等人在J.Antibiot.27，57(1974)公开的同样是Penicilium turbatum的代谢物，有着表多硫二氧代哌嗪的结构。
毛壳素的结构与绝对构型已由H.P.Weber公开(Helv.Chim.Acta，53(5)：1061-73，1970；Acta Crystallogr.B28，2945(1972))。毛壳素与其二羟基衍生物，11α，11α’-二羟基毛壳素(榅桲杀菌素，IV)的细胞毒活性亦有报道，对白血病HeLa细胞的IC50约为0.03μg/mL(T.Saito等人，Chetracin A，“一种来自毛壳属Chaetomium abuense和C.retardatum的四硫桥接的新表多硫二氧代哌嗪化合物”，Tetrahedron Letters，26，(39)，4731-4734，1985)。
血管内皮细胞生长因子(VEGF)对生理性与生理病理性的血管发生过程起主要作用。有不同机制涉及到VEGF基因的调控，调控过程与组织氧压是高度相关的，这一点可通过体内与体外缺氧条件下VEGF mRNA水平可逆性升高得到证明。VEGF mRNA表达的增加主要由与VEGF基因启动子结构域识别位点结合的低氧诱导因子-1(Hif-1)的转录介导。
大量的试验数据显示Hif-1是氧稳态的整体调节基因，且受损的Hif-1活性促进了肿瘤细胞的生存、增殖、发病和转移(G.L.Semenza，NatureReview Cancer，3，2003，721-732)。因此可猜测针对抑制Hif-1活性的治疗策略可提高癌症患者的存活率(Semenza GL.HIF-1与肿瘤的演化：病理生理学与治疗学，Trends Mol.Med.2002 8：S62)。
HIF-1是由Hif-1α与Hif-1β亚单位组成、二聚并通过bHLH-PAS结构域与DNA结合的杂二聚体(Semenza GL等人，“缺氧诱导因子1的二聚化、DNA结合与转活性质”，J.Biol.Chem.1996 271：17771)。Hif-1α亚单位的表达是通过由VHL蛋白与Hif-1α结合介导的遍在蛋白化作用与蛋白体降解作用过程，严格受组织氧调控的(Semenza GL等人，“缺氧诱导因子1水平在氧压的生理学相关范围内呈指数改变”，Am.J.Physiol.1996 271：C1172)。这一相互作用仅当Hif-1α在402与564脯氨酸残基处水解时发生。氧对修饰Hif-1α的脯氨酰羟化酶是限制性底物(Epstein AC等人，“C.elegans EGL-9与哺乳动物类似物限定通过脯氨酰羟化调控HIF的二氧化酶家族”，Cell 2001 107：43)。Hif-1α的表达随着O2浓度的降低呈指数增加，并决定了Hif-1活性的全面水平。
Hif-1α的反式激活结构域功能亦受氧分压的负调控。N-末端反式激活结构域通过VHL以及与VHL及Hif-1α结合的抑制Hif-1α的因子(FIH-1)hystone deacilase的募集负调控(Semenza GL等人，“FIH-1：与Hif-1α及VHL相互作用调控HIF-1转录活性的新型蛋白质”，Genes Dev.2001 15：2675)。
Hif-1的活化是通过与Hif-1结构域的活化生理性地相互作用而促进基因样VEGF的转录的共激活剂p300/CBP发生的(Arany Z.等人，“p300/cbp在缺氧细胞响应的基本作用”，Proc.Nat.Acad.Sci.USA 199693；12969)。p300与CBP也是其他转录因子的共激活剂，例如Stat-3，NF-κB，p53。
p300/CBP与Hif-1的相互作用对转录是必需的，最新出版物已证实Hif-1/p300相互作用对肿瘤生长的重要性(Damert A.等人，“激活剂-蛋白质-1结合使缺氧诱导因子-1-介导的缺氧诱导在c6神经胶质瘤细胞的血管内皮细胞生长因子表达的转录激活成为可能”，Biochem J.1997 327：419)。Hif-1αC-末端反式激活结构域(C-TAD)与p300及已知为CH1的CBP结构域结合。CBP及p300与Hif-1α的结合通过803天门冬酰胺在C-末端FIH-1活化结构域的氧依赖羟基化作用负调控。因此，缺氧诱导了蛋白体降解的稳定化以及Hif-1的转录活性。
Hif-1α TAD-C与p300或CBP的CH1结构域相互作用的结构细节已经阐明(Eck MJ.等人，“缺血诱导因子-1α对CBP/p300募集的结构基础”，Proc.Natl.Acad.Sci.USA，2002 99：5367，Wright PE等人，“Hif-1α/CBP在细胞缺氧响应识别的结构基础”，Proc.Nat.Acad.Sci.USA，200299：5271)。p300/CBP与被认为是HIF-1α活性的负调节剂的CITED2蛋白质(亦称作p35srj)间相互作用细节亦已出版(Freedman，S.J.等人，NatureStructural Biology，2003，10(7)，504-12)。
Hif-1活化作用诱导涉及血管生成因子、葡萄糖载体、糖酵解酶及对肿瘤发展特别重要的存活、转移与侵入因子的大量基因的转录。
已在超过70％的人体肿瘤及其转移中已观察到Hif-1α蛋白质的异常表达，蛋白质的异常表达与血管化作用的增加及肿瘤演化相关联(Zhong，H.等人，“常见人体癌症与其转移中缺氧诱导因子1α的过度表达”，CancerResearch，1999，59，5830-5；Bos，R.等人，“在乳腺癌发生期间缺氧诱导因子1α的水平”，J.Nat.Cancer Inst.2001，93，309-14；Talks，K.I.等人，“缺氧诱导因子HIF-1α与HIF-2在正常人体组织中的表达与分布”)。在临床实践中，Hif-1α的异常表达已与许多肿瘤病理学上的治疗失败及死亡率增加相联系，例如非小细胞肺癌(Giatromanolaki，A.等人，“在可行手术的非小细胞肺癌中缺氧诱导因子1α及2α与肿瘤的血管生成/分子特性及存活率的关系”，Br.J.Cancer 85，881-890(2001))、口咽鳞状上皮细胞癌(Aebersold，D.M.等人，“缺氧诱导因子1α的表达：一种在口咽癌放射治疗中新的预测性与预后性参数”，Cancer Res.61，2911-2916(2001))、子宫颈癌早期阶段(Birner，P.等人，“缺氧诱导因子1α的过度表达在早期发病的子宫颈癌中是不良预后的标记物”，Cancer Res.60，4693-4696(2000))、头颈癌(Koukourakis，M.I.等人，“鳞状上皮细胞头颈癌的缺氧诱导因子(HiflA和Hif2A)、血管发生与化放疗结果”，Int.J.Radiat.Oncol.Biol.Phys.53，1192-1202(2002))、突变型-p53卵巢癌(Birner，P.等人，“缺氧诱导因子1α在上皮卵巢肿瘤中的表达”：对预后与化疗反应的影响，Clin.Cancer Res.7，1661-1668(2001))，少突神经胶质细胞瘤(Birner，P.等人，“缺氧诱导因子1α在少突神经胶质细胞瘤的表达：其对预后及新血管生成的影响”，Cancer 92，165-171(2001))和BCL-2阳性食管癌(Koukourakis，M.I.等人，“缺氧诱导因子(HIF-1α和HIF-2α)在早期食管癌中的表达以及对光动力学疗法及放疗的响应”，Cancer Res.61，1830-1832(2001))。
文献中对抑制Hif-1活性的不同方法已有描述。其中有些提示使用Hif-1α反义寡核苷酸或HIF-1α的负显性型。
在药理学方法中，通过间接机制起作用的Hif-1α活性抑制剂已有介绍，例如按照控制Hif-1α活性的信号转导起作用的PI3K-mTOR抑制剂(Zundel，W.等人，“PTEN的丢失促进HIF-1介导的基因表达”，GenesDev.14，391-396(2000)；Hudson，C.C.等人，“借助雷帕霉素哺乳靶对缺氧诱导因子1α表达与功能的调控”，Mol.Cell.Biol.22，7004-7014(2002))与MEKK抑制剂((Sodhi，A.等人，“卡波西肉瘤相关疱疹病毒G蛋白偶联受体通过细胞分裂素(丝裂原)活化蛋白激酶与p38途径转导作用在缺氧诱导因子1α上调血管内皮生长因子表达与分泌”，Cancer Res.60，4873-4880(2000))；HSP90侣伴蛋白质抑制剂(Mabjeesh，N.J.等人，“格尔德霉素通过前列腺癌细胞的蛋白体途径诱导缺氧诱导因子1α蛋白质的降解”，Cancer Res.62，2478-2482(2002))；修饰细胞氧化还原状态的硫氧还蛋白还原酶抑制剂(Welsh，S.J.等人，“硫氧还蛋白氧化-还原抑制剂1-甲基丙基2-咪唑基二硫化物与灰侧耳菌素抑制诱导缺氧诱导因子1α与血管内皮生长因子形成”，Mol.Cancer Ther.2，235-243(2003))；使微管不稳定的分子，例如甲氧雌二醇(Mabjeesh，N.J.等人，“2ME2通过破裂微管及使Hif失调抑制肿瘤生长与血管发生”，Cancer Cell 3，363-375(2003))及环氧聚微管素(Escuin，D.等人，“环氧聚微管素B抑制其微管稳定效应的Hif-1α下游”，美国癌症研究协会第95届年会的会议论文集，Abs.5427)。
最近，在人肿瘤移植裸鼠中对组成与被PX-478(美法仓N-氧化物)缺氧诱导的Hif-1α水平两者的抑制已有报道。化合物显示显著的抗肿瘤活性。但是，该化合物的作用机制尚未完全阐明(S Welsh等人，“PX-478，一种缺氧诱导因子1α抑制剂的抗肿瘤活性与药效学性质”，Mol.Cancer，3：233-244，(2004))。
最后，最近报道的毛壳菌素，一种干扰Hif-1α与p300结合的有二酮二硫代哌嗪结构的毛壳菌属真菌代谢物。该化合物的作用改变了p300的CH1结构域结构，因此防止了其与Hif-1α的相互作用。毛壳菌素给予荷瘤小鼠抑制在肿瘤与肿瘤生长中的缺氧诱导的转录(A.L.Kung等人，CancerCell，6，33-43，2004)。
胶霉毒素与毛壳素是从Sigma Aldrich购买的，且根据以上出版物描述的方法获得。胶霉毒素的全合成是由T.Fukuyama，S.Nakatsuka e Y.Kishi在胶霉毒素、去氢胶霉毒素与透明菌素的全合成，Tetrahedron，37(11)，2045-2078，1981中报道。
发明的公开
现已发现二酮二硫代哌嗪结构的抗生素，特别是毛壳素与胶霉毒素能够抑制Hif-1α与p300结合，并在缺氧条件下防止VEGF在维持细胞中的产生。
因此，在第一个实施方案中本发明涉及选自毛壳素及胶霉毒素的二酮二硫代哌嗪抗生素用于制备治疗要求抑制Hif-1α与p300结合的疾病的药物的用途，特别是制备抗血管生成药物。
发明的目的因此是作为抗血管生成、抗增殖与抗转移剂的毛壳素与胶霉毒素。
在进一步的实施方案中，本发明涉及含有选自毛壳素及胶霉毒素活性成分的二酮二硫代哌嗪抗生素及适当的载体与赋形剂的药物组合物。
本发明进一步涉及抑制VEGF在细胞中生成的方法，该方法包括将细胞与有效量的毛壳素或胶霉毒素相接触。
发明详述
二酮二硫代哌嗪抗生素，特别是毛壳素与胶霉毒素能够抑制Hif-1α与p300之间的相互作用，用改自Freedman SJ等人Nature StructuralBiology 2003，10(7)，504-512的荧光分析方法可证实。
毛壳素与胶霉毒素因此可用于控制血管生成及肿瘤生长。
这些化合物的药物组合物可方便地用于治疗许多其中血管生成作为致病因素的疾病，例如不同形式的实体瘤、糖尿病视网膜病变、类风湿性关节炎、牛皮癣、血管瘤、硬皮病、新生血管性青光眼。
对能够抑制Hif-1α与p300 CH1结构域结合的化合物特别敏感的实体瘤包括肺癌、乳腺癌、前列腺癌、成神经细胞瘤、多形性成胶质细胞瘤、黑素瘤、中枢神经系统肿瘤、口咽鳞状细胞癌、子宫颈、卵巢、食管、肾、结肠、头颈肿瘤与少突神经胶质细胞瘤。
为治疗用途，所说的酮二硫代哌嗪抗生素将通过口服、肠道外、透皮、直肠、局部或等效的施用途径施用，剂量将由本领域专家根据所选化合物的药理学-毒理学与药动学性质并根据病理学、患者的严重程度与进展状态及体重、性别与年龄确定。
但是，剂量一般地根据患者体重包含从0.1至100mg/Kg/天。
毛壳素与/或胶霉毒素任选用于与其他化疗药例如在化疗方案中与有不同作用机制及潜在协同作用的药物组合施用。
本发明的组合物实例包括胶囊、片剂、注射或口服溶液或混悬液、栓剂、控释剂型等等。所说的组合物可通过常规的技术与赋形剂制备，例如Remington’S Pharmaceutical Sciences Handbook，XVII ed.Mack Pub.，N.Y.，U.S.A.中公开的那些。
在下列实施例中详细地说明本发明。
实施例1-Biot-Hif-1α786-826/GST-p300323/423的抑制
毛壳素阻止Hif-1α和p300之间相互作用的能力通过Freedman SJ等(Nature Structural Biology 2003，10(7)，504-512)提供的荧光分析方法(DELFIATM)经适当修改后来评估。
人Hif-1α C末端786-826氨基酸残基生物素化片断(生物素化Hif-1α786-826)来自AnaSpec公司(San Josè，California，USA)，不经进一步纯化即使用。
表达GST-p300323-423片断的组建质粒转染BL21(DE3)大肠杆菌细胞株。用PCR(聚合酶链反应)方法获得编码p300中323-423氨基酸序列的DNA序列，将其克隆至pGEX-4T-1表达载体(Amersham n.27-45-80-01)从而获得表达GST-p300323-423片断的组建质粒。用1mM的异丙基硫代-β-D-半乳糖苷(IPTG)来诱导蛋白表达。将细菌在一种合适的缓冲液(50mM Tris.HCl pH 8.00、100mM NaCl、0.1mM ZnSO4、1mM DTT、0.1mg/ml溶菌酶，1片罗氏蛋白酶抑制剂)然后超声裂解，通过谷胱甘肽-琼脂糖4B树脂(Amersham Biosciences；no.27-4574-01)纯化溶液中的GST融合蛋白质。用Bradford公司Bioard测定确定蛋白质终浓度(Bradford M.，Anal.Biochem.，72，248，(1976))。通过SDS-PAGE来评估样品纯度。样品于50％甘油条件下存储于-80℃。
用NUNC Maxisorp96孔板按以下步骤来进行分析。C96 NUNCMaxisorp孔板(Nunc，产品号446612)中加入溶于PBS(磷酸盐缓冲盐水10mM磷酸钠，150mM氯化钠pH7.4)中终浓度为1μg/ml的抗生物素链菌素(Sigma；产品号S 4762)，孵育过夜。每孔用300μl的TBST缓冲液(50mMTris-HCl pH 8.0、150mM NaCl、0.05％(v/v)吐温20)洗涤三次。然后每孔加入100μl溶于TBSB(50mM Tris-HCl pH8.0、150mM NaCl、5％(w/v)BSA(Sigma，产品号A 2153))的浓度为10nM生物素化Hif-1α786-826溶液，25℃孵育1小时。孔板的最后一排只加TBSB缓冲液。每孔用300μl的TBST缓冲液洗涤三次。准备好的孔板用于分析。
同时准备每孔含有10μl溶解于DMSO的浓度为10μM的受试化合物溶液的孔板(子孔板)。然后加入100μl稀释于孵育缓冲液(加入0.1％(v/v)吐温20、0.5mM DTT、10μM ZnCl2的TBSB)中浓度为111pM的GST-p300323-423溶液，混匀溶液。将子孔板中100μl混合物立即转移到分析孔板。
每个子孔板准备浓度为10μM的毛壳素，最后2排加入10μlDMSO，作为阳性对照(第11排，加Hif-1)和阴性对照(第12排，不加Hif-1)。
25℃孵育1小时后，每孔用300μlTBST缓冲液(50mM Tris-HCl pH8.0、150mM NaCl、0.05％(v/v)吐温20)洗涤三次。然后每孔加入60.8ng铕标记的抗GST抗体(DELFIA Eu-N1标记；Perkin Elmer；产品号AD0251)，抗体溶解于100μl含10μM ZnCl2的TBSB缓冲液。室温孵育1小时后，每孔用300μlTBST缓冲液洗涤三次，然后加入100μl信号放大溶液(Enhancement Solution，Perkin Elmer，产品号1244-105)。
用FUSION alpha-FP-HT(Perkin Elmer)以时间分辨率荧光模式读孔板。
毛壳素活性按以下方法计算。每孔的荧光值减去检测孔板第12排阴性对照的平均荧光值，得到的每孔的荧光值除以第11排阳性对照的平均荧光值(该值定义为最大信号值，100％)，结果用百分率表示。抑制值为100和每孔信号百分值的差。
用由10个浓度梯度的化合物构成的子孔板，其浓度梯度为每排90μM到0.178μM之间，从IC50值(化合物浓度能够抑制50％信号)可以计算出浓度反应曲线。11和12排只含有溶剂作为对照。
检测中，毛壳素能够抑制Biot-Hif-1α786-826和GST-p300323/423间的相互作用，IC50值为12.5μM。
实施例2-VEGF产物的抑制
本发明的化合物使用一种基于遗传修饰的人肝癌Hep3B细胞系(Hep3B-VEGF萤光素酶细胞)的细胞测试(该细胞系能够稳定表达一个载体，该载体中萤光素酶基因开放阅读框被置于大鼠VEGF基因启动子下)来评估。
用去铁胺(能诱导低氧)诱导的HIF-1能通过激活VEGF启动子诱导萤光素酶的转录，萤光素酶活性的增加能通过一种商业化的试剂盒检测。和HIF-1α/p300复合物作用的化合物可抑制HIF依赖的萤光素酶活化，导致萤光素酶活性的降低。因此，该分析方法能够评估针对VEGF启动子的化合物的活性，启动子活性对于VEGF的产生和后续的肿瘤血管生成是必不可少的。
Hep-3B-VEGF萤光素酶细胞系通过以下方法获得。
人肝癌Hep3B细胞(ATCC参考号HB-8064)按照2.5×105细胞/孔的密度接种于6孔板，培养基为2ml DMEM/10％胎牛血清，第二天用Fugene 6(Roche Biochemicals)转染。每孔的转染混合物包含6μl转染试剂Fugene6，1μg报告质粒pxp2-VEGF-萤光素酶(大鼠VEGF启动子，NCBIGenBank登记号U22373，Levy等人，J.Biol.Chem.270(22)，13333-13340，1995)，和10ng使细胞对新霉素抗性的pcDNA 3.1(+)质粒(INVITROGEN)。转染按照厂家说明书方法进行。
用“极限稀释”法(Sambrook J.，Fritsch E.F.和Maniatis T.(1989)Molecular Cloning，A.Laboratory Manual；Cold Spring HarborLaboratori)挑选适宜的细胞群体(表型上能抗新霉素)。用筛选得到的稳定转染细胞检测萤光素酶表达/活性“萤光素酶分析”和上清液中分泌的VEGF量(分泌的VEGF的ELISA检测)。
采用下列实验方案。
第一天，Hep-3B-VEGF萤光素酶细胞按1×104细胞/孔的密度接种于96孔板，每孔添加125μl培养基，然后在37℃/5％CO2恒温培养箱培养过夜以使细胞贴壁。
第二天，将75μl3.2×工作液化合物(已准备于培养基中，DMSO浓度为1.6％v/v)添加到细胞中(体积/孔＝ 200μl，化合物浓度＝1.2×，DMSO浓度＝0.6％)。恒温培养箱中孵育1小时后，通过向每孔添加40μl6×(600μM)去铁胺储存液进行化学诱导低氧(每孔终体积＝240μl，化合物终浓度＝1×，DMSO终浓度＝0.5％，去铁胺终浓度＝1×≈100μM)。将孔板放置于恒温培养箱中18-20小时。
第三天，按照以下方法进行萤光素酶分析和分泌的VEGF的ELISA检测。
分泌VEGF的ELISA检测
用“DuoSet Elisa Development System human VEGF”试剂盒(R&DSystems)对分泌的VEGF进行定量。
将接种有Hep3B/VEGF萤光素酶克隆细胞的空白96孔板的上清液(100μl/孔)转移至半透明96孔板(Maxisorp)，按照试剂盒说明书进行分析。
在ELISA检测分泌的VEGF的抑制中，毛壳素和胶霉毒素的IC50分别为0.1μM和0.2μM。
萤光素酶分析
萤光素酶报告基因表达量用Bright Glo Reagent(Promega)进行分析。在弃去上清液后，用PBS洗涤一次，按照40μl/孔的量向空白96孔板(即没有人肝癌Hep3B/VEGF萤光素酶细胞的孔板)中加入Bright Glo Reagent。根据从发光测量计读出孔板的值确定报告基因表达水平。
在抑制VEGF启动子的萤光素酶分析中，毛壳素和胶霉毒素的IC50(能够抑制50％萤光素酶信号时的化合物浓度)分别为0.04μM和0.05μM。
Claims (9)
1.除了毛壳菌素外的二酮二硫代哌嗪抗生素用于制备治疗其中要求抑制Hif-1α和p300的结合的疾病的药物组合物的用途。
2.根据权利要求1用于制备抗血管生成药物的用途。
3.根据权利要求1或2用于预防或治疗实体瘤的用途。
4.根据权利要求3的用途，其中的肿瘤选自肺癌、乳腺癌、前列腺癌、成神经细胞瘤、多形性成胶质细胞瘤、黑素瘤、中枢神经系统癌、口咽鳞状细胞癌、子宫颈、卵巢、食管、肾、结肠、头颈癌与少突神经胶质细胞瘤。
5.根据权利要求1至4的任意一项的用途，其中的抗生素是毛壳素或胶霉毒素。
6.作为血管生成抑制剂的毛壳素和胶霉毒素。
7.作为抗增殖和抗转移剂的毛壳素和胶霉毒素。
8.包含作为活性成分的毛壳素和/或胶霉毒素并与适宜的载体和赋形剂混合的药物组合物。
9.抑制VEGF在细胞中生成的方法，该方法包括用有效量的毛壳素或胶霉毒素接触所述的细胞。
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ212051A (en) * | 1984-05-18 | 1988-10-28 | Univ Australian | Immune response suppression; certain epipolythio- dioxopiperazine derivatives and their preparation |
| JPS61277617A (ja) * | 1985-05-31 | 1986-12-08 | Yakult Honsha Co Ltd | 坑血小板凝集剤 |
| KR19990082168A (ko) * | 1996-12-02 | 1999-11-25 | 에가시라 구니오 | 글리오톡신 유도체 및 이를 함유하는 항암제 |
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2004
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- 2005-12-14 AU AU2005318535A patent/AU2005318535A1/en not_active Abandoned
- 2005-12-14 KR KR1020077014106A patent/KR20070102492A/ko not_active Application Discontinuation
- 2005-12-14 WO PCT/EP2005/013457 patent/WO2006066775A1/en not_active Application Discontinuation
- 2005-12-14 ZA ZA200704915A patent/ZA200704915B/xx unknown
- 2005-12-14 MX MX2007007503A patent/MX2007007503A/es not_active Application Discontinuation
- 2005-12-14 CA CA002592002A patent/CA2592002A1/en not_active Abandoned
- 2005-12-14 US US11/793,860 patent/US20080255099A1/en not_active Abandoned
- 2005-12-14 EP EP05824988A patent/EP1827442A1/en not_active Withdrawn
- 2005-12-14 CN CNA2005800440034A patent/CN101083991A/zh active Pending
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104755084A (zh) * | 2012-08-29 | 2015-07-01 | 南加州大学 | 抑制缺氧诱导型转录因子复合体的活性的组合物和方法及其治疗肿瘤的用途 |
| CN104755084B (zh) * | 2012-08-29 | 2018-04-03 | 南加州大学 | 抑制缺氧诱导型转录因子复合体的活性的组合物和方法及其治疗肿瘤的用途 |
| CN105229013B (zh) * | 2013-05-24 | 2018-09-14 | 梨花女子大学校产学协力团 | 桥二硫双氧代哌嗪化合物或它的衍生物，及其用途 |
| CN103550222A (zh) * | 2013-11-05 | 2014-02-05 | 南京医科大学 | 毛壳素在制备预防和治疗糖尿病药物中的应用 |
| CN107261137A (zh) * | 2017-05-22 | 2017-10-20 | 中国人民解放军第二军医大学 | 两种抗her2抗体‑毛壳素偶联物及其制备方法和抗肿瘤应用 |
| CN107261137B (zh) * | 2017-05-22 | 2021-04-13 | 中国人民解放军第二军医大学 | 两种抗her2抗体-毛壳素偶联物及其制备方法和抗肿瘤应用 |
| CN114641294A (zh) * | 2019-08-28 | 2022-06-17 | 瓦西特拉有限公司 | 用于预防或治疗实体癌的含有桥二硫二氧代哌嗪衍生物或其药学上可接受的盐的药物组合物 |
| CN112626039A (zh) * | 2020-12-22 | 2021-04-09 | 广东省微生物研究所（广东省微生物分析检测中心） | 一种氧化还原酶GliT及其在抵抗真菌毒素中应用 |
| CN112626039B (zh) * | 2020-12-22 | 2022-10-25 | 广东省微生物研究所（广东省微生物分析检测中心） | 一种氧化还原酶GliT及其在抵抗真菌毒素中应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200704915B (en) | 2008-11-26 |
| AU2005318535A1 (en) | 2006-06-29 |
| ITMI20042477A1 (it) | 2005-03-23 |
| US20080255099A1 (en) | 2008-10-16 |
| MX2007007503A (es) | 2007-09-11 |
| EP1827442A1 (en) | 2007-09-05 |
| JP2008525336A (ja) | 2008-07-17 |
| KR20070102492A (ko) | 2007-10-18 |
| CA2592002A1 (en) | 2006-06-29 |
| IL184114A0 (en) | 2007-10-31 |
| WO2006066775A1 (en) | 2006-06-29 |
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