CN114051408A - 用于预防、改善、或治疗癌症的组合物 - Google Patents
用于预防、改善、或治疗癌症的组合物 Download PDFInfo
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- CN114051408A CN114051408A CN202080048363.6A CN202080048363A CN114051408A CN 114051408 A CN114051408 A CN 114051408A CN 202080048363 A CN202080048363 A CN 202080048363A CN 114051408 A CN114051408 A CN 114051408A
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Abstract
本发明的组合物不仅可以非常高效地抑制癌细胞生长,还可以非常高效地抑制癌细胞转移至其他组织,因此可以非常高效地应用于预防、改善、或治疗癌症,以及抑制癌症转移。
Description
技术领域
本发明涉及一种用于预防、改善、或治疗癌症的组合物。
背景技术
癌症是一种致死性疾病,其能够引起组织细胞异常地和无限地增殖,形成阻止器官行使其正常功能的肿瘤,从而威胁到患者的生命。2017年韩国的首位死因是恶性肿瘤(癌症),癌症引起的死亡占总死亡数的27.6%。虽然癌症的部位因种族、性别和地区因素而有所不同,但大部分国家男性中前列腺癌最多发,而女性中乳腺癌最多发。特别地,乳腺癌是全球范围内的女性癌症患者的最高死因,这是由于乳腺癌可以由环境和遗传等多种因素引起,其发病率正在逐年上升。
紫杉醇(Taxol)是一种现有的经FDA批准的抗癌药物,其被用于治疗卵巢癌、乳腺癌、肺癌等,作用机制为通过结合细胞纺锤体抑制细胞分裂,由此抑制无序增殖的肿瘤细胞的生长。因此,该抗癌药物的使用会引发各种不良反应,例如脱发、肌肉疼痛和腹泻。然而,即使存在这些不良反应,该抗癌制剂仍因为能非常有效地抑制肿瘤细胞分裂而已在临床实践中被持续应用。
同时,在一般抗癌药物表现不出治疗效果的恶性肿瘤中,经常观察到这样的现象:在患者的某一特定器官(原发器官)中发育的肿瘤细胞会随着癌症进展获得转移所必需的新遗传特征,随后侵犯血管和淋巴结,从原发器官起随着淋巴传播,沉积在其他器官的组织中,随后开始增殖。此类恶性肿瘤可使用局部疗法和系统疗法治疗。在已知具有肿瘤转移引起的严重局部症状的恶性肿瘤或已知手术治疗能够改善其临床进程的恶性肿瘤中,可以应用局部治疗方法如治疗性手术或放射疗法。然而,除了诸如淋巴瘤的极小一部分肿瘤之外,其他已发生转移的恶性肿瘤治愈率都非常低。
因此,急需开发这样一种抗癌药物,其能够预防肿瘤细胞转移至例如肺等器官,同时克服了至今为止为癌症治疗开发的抗癌药物的缺点,例如对癌细胞的特异性低和诸多不良反应。
发明内容
技术问题
本发明的一个目的是提供一种预防、改善、或治疗癌症的药物组合物、食品组合物和化妆品组合物。
本发明的另一个目的是提供一种抑制癌症转移的药物组合物、食品组合物和化妆品组合物。
本发明的另一个目的是提供一种预防或治疗癌症的方法。
本发明的另一个目的是提供一种抑制癌症转移的方法。
然而,本发明所要实现的目的并不限于上述目的,本领域普通技术人员可通过以下描述清楚地理解本文中未提及的其他目的。
技术解决方案
本发明的一个实施方式提供了一种预防、改善、或治疗癌症的组合物,所述组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基,C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:氢、C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间可以是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰基可以是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
式1所示的本发明的化合物能够非常高效地抑制失控的癌症细胞增殖(也称为瘤形成)。鉴于本发明的组合物能够引起失控细胞的死亡(调亡)并可能通过抑制细胞生长而抑制肿瘤生长,其可被非常高效地应用于预防、改善、或治疗肿瘤。
如本文所用的术语“芳基”是指衍生自具有单环或两个或更多个相互结合的环的C6-C40芳烃的一价取代基。此外,芳基还可以包括两个或更多个环彼此侧连(pendant)(例如简单连接)或稠合的形式。这种芳基的实例包括但不限于苯基、萘基、菲基、和蒽基。
如本文所用的术语“亚芳基”是指通过从芳烃中去除一个氢原子获得的一组原子,并且还包括具有稠合环的那些、或其中两个或更多个独立苯环或稠合环直接或通过诸如亚乙烯基的基团键合的那些。所述的亚芳基可以具有本文中描述的任何取代基,例如,烷氧基,并且除取代基外该部分的碳原子数一般为6-60个。此外,包括含取代基在内的亚芳基的碳原子总数一般为6-100个。此类亚芳基的实例包括但不限于,亚苯基、萘二基、二甲氧基苄基、蒽二基、联苯二基、三联苯二基、稠合化合物基团、芴二基、芪二基、联苯乙烯二基、苯并芴二基、二苯并芴二基、及类似物。
如本文所用的术语“亚杂芳基”是指二价单环芳基或二价多环芳基,其含有的至少一个芳环的环中含有一个或多个独立地选自O、S或N的杂原子。所述亚杂芳基的每个环可含有一个或两个O原子、一个或两个S原子、和/或1-4个N原子,前提是每个环中杂原子的总数为4个以下并且每个环含有至少一个碳原子。亚杂芳基的实例包括但不限于,亚苯并呋喃基、亚苯并咪唑基、亚苯并异噁唑基、亚苯并吡喃基、亚苯并噻二唑基、亚苯并噻唑基、亚苯并噻吩基、亚苯并三唑基、亚苯并噁唑基、亚呋喃并吡啶基、亚咪唑并吡啶基、亚咪唑并噻唑基、亚吲嗪基、亚吲哚基、亚吲唑基、亚异苯并呋喃基、亚异苯并噻吩基、亚异吲哚基、亚异喹啉基、亚异噻唑基、亚萘啶基、亚噁唑吡啶基、亚酞嗪基、亚蝶啶基、亚呋喃基(furinylene)、亚吡啶并吡啶、亚吡咯并吡啶基、亚喹啉基、亚喹噁啉基、亚喹唑啉基、亚噻二唑并嘧啶基、和亚噻吩并吡啶基。三环亚杂芳基的实例包括但不限于亚吖啶基、亚苯并吲哚基、亚咔唑基、亚二苯并呋喃基、亚咟啶基(perimidinylene)、亚菲咯啉基、亚菲啶基、亚吩吡嗪基(phenarsazinylene)、亚吩嗪基、亚吩噻嗪基、亚吩恶嗪基、及类似物。
如本文所用,术语“烷基”是指直链或支链的饱和一价烃基,其中所述烷基可选地可被一个或多个的本文中的取代基取代。烷基的实例包括但不限于甲基、乙基、丙基(包括其所有异构体形式)、正丙基、异丙基、丁基(包括其所有异构体形式)、正丁基、异丁基、仲丁基、叔丁基、戊基(包括其所有异构体形式)、和己基(包括其所有异构体形式)。
如本文所用,术语“烷基磺酰基”包括甲基磺酰基、乙基磺酰基、正丙基磺酰基、异丙基磺酰基、叔丁基磺酰基、及类似物。组成烷基磺酰基的碳原子数优选为1-10个,但不限于此。
如本文所用,术语“烯基”指含有一个或多个碳-碳双键的直链或支链一价烃基,其中碳-碳双键的个数在某一实施方式中为1-5个,在另一实施方式中为1个。所述烷基可选地可被一个或多个本文中的取代基取代。如本领域技术人员所知的,术语“烯基”包括具有“顺式”或“反式”结构或其组合、或者具有“Z”或“E”结构或其组合的基团。烯基的实例包括但不限于乙烯基、丙烯-1-基、丙烯-2-基、烯丙基、丁烯基和4-甲基丁烯基。
如本文所用,术语“芳氧基”是如RO-所示的一价取代基,其中R表示具有5-40个碳原子的芳基。芳氧基的实例包括但不限于苯氧基、萘氧基、二苯氧基、及类似物。
如本文所用,术语“杂环烷基”指具有3-20个环原子的一价单环系统,其中含有1-3个选自N、O、P或S的杂原子,其余环原子为C。所述杂环烷基中的一个或多个氢原子可选地可被取代。所述杂环烷基的实例包括但不限于吡咯烷基、吡唑啉基、咪唑烷基、哌啶基和哌嗪。
如本文所用,术语“烷氧基”是如R’O-所示的一价取代基,其中R’表示具有1-40个碳原子的烷基,其可能包括直链、直链或环结构。烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、1-丙氧基、叔丁氧基、正丁氧基、戊氧基、及类似物。
如本文所用,术语“芳基胺”指被具有6-40个碳原子的芳基取代的胺。
如本文所用,术语“环烷基”是衍生自具有3-40个碳原子的单环或多环的非芳香烃的一价取代基。此类环烷基的实例包括但不限于环丙基、环戊基、环己基、降莰基(norbornyl)、金刚烷、及类似物。
如本文所用,术语“卤素”是指氟、氯、溴和/或碘。
如本文所用,术语“取代的烷基”、“取代的亚烷基”、“取代的亚杂烷基”、“取代的烯基”、“取代的亚烯基”、“取代的亚杂烯基”、“取代的炔基”、“取代的亚炔基”、“取代的环烷基”、“取代的杂环烷基”、“取代的亚环烷基”、“取代的芳基”、“取代的芳氧基”、“取代的亚芳基”、“取代的芳烷基”、“取代的杂芳基”、“取代的亚杂芳基”、“取代的杂环”、或“取代的亚杂环基”是指所述取代的烷基、所述取代的炔基、所述取代的亚炔基、所述取代的环烷基、所述取代的杂环烷基、所述取代的亚环烷基、所述取代的芳基、所述取代的芳氧基、所述取代的亚芳基、所述取代的芳烷基、所述取代的杂芳基、所述取代的亚杂芳基、所述取代的杂环、或所述取代的亚杂环基可以各自独立地,进一步被一个或多个取代基取代,例如独立地选自下组的取代基:C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基、杂环基、羟基、oxo(=O)、卤素、氰基(-CN)、硝基(-NO2)、-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc、和-S(O)2NRbRc,其中Ra、Rb、Rc、和Rd可以各自独立地为(a)氢;或(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基、或杂环基;或(c)Rb和Rc可以和与他们相连的N原子一起形成取代的杂环基。
在本发明中,式1所示的化合物可以是,但不限于下式2所示的化合物:
[式2]
其中
n、m、X和Y各自如上式1中所定义。
在本发明的一个优选实施例中,式2中n和m可以各自独立地为1或2的整数。
X和Y可以各自独立地选自下组:磺酰基、C1-C10烷基磺酰基、C1-C40烷氧基、-NR'R"、羟基、C6-C60芳氧基、和具有3-20个核原子的未取代或取代的杂环烷基;
R’和R”可以各自独立地为氢或C6-C60芳基磺酰基,并且
每个R’和R”中的芳基磺酰基可以未取代或被至少一个卤素取代。
在本发明的一个优选实施例中,式2中,
n可为1;
X可为-NR'R”或下式3所示的取代基;并且
R’和R”可以各自独立地为氢或下式4所示的取代基:
[式3]
[式4]
其中
R1可以选自下组:氢、氘、卤素、羟基、C1-C40烷基、和C2-C40烯基,并且优选地,R1可以是氢或羟基;并且
R2可以选自下组:氢、氘、卤素、羟基、和硝基,并且优选为卤素,更优选为氯,但不限于此。
在本发明的一个优选实施例中,上式2中,
Y可以是,但不限于羟基、C1-C6烷氧基、或下式5所示的取代基:
[式5]
在本发明的一个优选实施例中,式2中,
n可为1;
X可以是-NR'R";
R’和R”可以各自独立地为氢或上式5所示的取代基:
m可为2;
Y可以是但不限于C1烷氧基的取代基:
在本发明中,式1所示的化合物可以是,但不限于选自下组的任一化合物:
在本发明的另一实施方式中,所述化合物可以是,但不限于下列化合物:
在本发明的另一实施方式中,所述化合物可以是,但不限于下列化合物:
本文中所述的癌症可以是,选自下组的至少一种:乳腺癌、结直肠癌、肺癌、肝癌、胃癌、食道癌、胰腺癌、胆囊癌、肾癌、膀胱癌、前列腺癌、睾丸癌、结肠癌、宫颈癌、子宫内膜癌、绒毛膜癌、皮肤癌、卵巢癌、甲状腺癌、脑癌、血癌、头颈癌、恶性黑色素瘤、和淋巴瘤,并且优选地可以为乳腺癌,但不限于此。
本文中所述的乳腺癌可以是,但不限于三阴性乳腺癌。
如本文所用的术语“三阴性乳腺癌”是指雌激素受体、孕激素受体、和Her2受体阴性的乳腺癌,其易于复发和转移,并且不能被常规的用于乳腺癌的靶向治疗剂治愈。
如本文所用,术语“预防”可以包括,但不限于任何通过使用本发明的组合物起到的阻断、抑制或延缓由癌细胞不受控制的生长引起的症状的作用。
如本文所用,术语“改善”可以包括,但不限于任何通过使用本发明的组合物起到的缓解或有益地改变由癌细胞不受控制的生长等引起的症状的作用。
如本文所用,术语“治疗”可以包括,但不限于任何通过使用本发明的组合物起到的缓解或有益地改变由癌细胞不受控制的生长等引起的症状的作用。
本发明的另一个实施方式提供了一种抑制癌症转移的组合物,所述组合物含有下式1所示的化合物作为活性成分:
[式1]
其中n、m、X和Y分别如预防、改善、或治疗癌症的组合物的式1中所定义。
在本发明中,“癌症转移”是指这样的现象,其中原发器官中发育的肿瘤细胞会随着癌症进展获得转移所必需的新遗传特征,随后侵犯血管和淋巴结,从原发器官起随着淋巴传播,沉积在其他器官的组织中,随后开始增殖。就本发明而言,本发明的组合物能够通过抑制癌细胞从原发器官逃逸、侵犯血管和淋巴结、和沉积在其他器官中的一些或所有步骤,来抑制癌症转移,因此所述组合物可被非常高效地应用于抑制癌症转移的目的。优选地,本文所述的癌症转移可以指,但不限于肺转移,更优选地为乳腺癌的肺转移,即是在原发器官乳腺中生长的癌细胞在另一个器官肺中沉积并增殖的现象。
在本发明的抑制癌症转移的组合物中,式1所示的化合物和所述癌症的详情与上述用于预防,改善或治疗癌症的组合物中所述的详情相同,因此为避免使本说明书过于复杂,在此将省略其描述。
本发明的组合物可以表现为药物组合物、食物组合物或化妆品组合物。
此外,本发明的组合物可以进一步与其他抗癌药物联合应用。当所述组合物与其他抗癌药物联合应用时,可能通过更有效地抑制肿瘤生长或转移而表现出显著的预防或治疗肿瘤的效果。
本文所述的抗肿瘤药物可以是,但不限于选自下组的至少一种:氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄罗替尼、奈拉替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、塞马萨尼(semasanib)、博舒替尼、阿西替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、卡铂、索拉非尼、贝伐珠单抗、顺铂、西妥昔单抗、槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌司莫汀、吉妥珠单抗奥佐米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑珠单抗、丙卡巴肼、前列地尔、硝酸钬壳聚糖(holmium nitratechitosan)、吉西他滨、去氧氟尿苷、培美曲赛、替吉奥、卡培他滨、吉美拉西、奥替拉西、阿扎胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达加滨(fludagabine)、依托他滨、氟他滨、卡培他滨、地西他滨、巯嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟(carmopher)、雷替曲塞、多西他赛、紫杉醇、伊立替康、贝洛替康、托泊替康、长春瑞滨、依托泊苷、长春碱、伊达比星、丝裂霉素、博来霉素、放线菌素、吡柔比星、阿柔比星、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑(melparan)、六甲密胺(altretmine)、达卡巴嗪、噻替哌、尼莫司汀、苯丁酸氮芥、二溴卫矛醇(mitolactol)、亚叶酸、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本(nabelbine)、法曲唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏罗唑、比卡鲁胺、洛莫司汀、5FU、伏立诺他、恩替诺特、和卡莫司汀。
本发明的药物组合物可以是胶囊、片剂、颗粒剂、注射剂、软膏、粉剂或饮品形式,并且所述药物组合物可用于人。
本发明的药物组合物在使用时可以根据常规方法配制为口服剂型如粉剂、颗粒、胶囊、片剂、水悬液等,以及诸如外用制剂、栓剂和无菌注射溶液的形式,但不限于此。本发明的药物组合物可包含药学上可接受的载体。用于口服给药时,所述药学上可接受的载体可包括粘合剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、着色剂、矫味剂等。用于注射制剂时,所述药学上可接受的载体可包括缓冲剂、防腐剂、镇痛剂、增溶剂、等渗剂、稳定剂等。用于局部给药时,所述药学上可接受的载体可包括基质、赋形剂、润滑剂、防腐剂等。
本发明的药物组合物可以和上述药学上可接受的载体共同配制为多种剂型。例如,用于口服给药时,所述药物组合物可被配制为片剂、锭剂、胶囊、酏剂、悬液、糖浆、薄膜片等。用于注射给药时,所述药物组合物可被配制为单位剂量的安瓿或多剂量形式。另外,所述药物组合物也可以被制备为溶液、悬液、片剂、胶囊和缓释制剂。
在本发明中,适合用于配制的载体、赋形剂和稀释剂的实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、苯甲酸甲羟甲酯、苯甲酸丙基羟基酯、滑石粉、硬脂酸镁和矿物油。此外,本发明的药物组合物可以进一步包含填充剂、抗凝血剂、润滑剂、湿润剂、香精、乳化剂、防腐剂等。
本发明的药物组合物的给药途径包括但不限于,口服、静脉内、肌肉内、动脉内、髓内、硬膜内、心内、经皮、皮下、腹膜内、鼻内、胃肠道、局部、舌下和直肠内途径。优选口服或肠外给药。在本发明中,“肠外给药”包括皮下、经皮、静脉内、肌肉内、关节内、滑膜内、胸骨内、硬膜内、病灶内和颅内注射或输注技术。
本发明的药物组合物可因各种因素而变化,包括所用特定化合物的活性、患者的年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄率,药物含量以及所要预防或治疗的特定疾病的严重程度。所述药物组合物的剂量可根据患者状况、体重、疾病严重程度、药物剂型和给药途径及时间,由本领域技术人员适当地选择,并可以为0.0001-50mg/kg/天或0.001-50mg/kg/天。所述药物组合物可每日给药一次或多次。所述剂量并不旨在以任何方式限制本发明的范围。本发明的药物组合物可配制为丸剂、糖衣片剂、胶囊、液体、凝胶、糖浆、糊剂或悬液。
本发明的食品组合物可被制备成多种食品,例如,饮品,口香糖,茶,维生素复合物,粉剂,颗粒,片剂,胶囊,糖果,年糕,面包等。
本发明的化合物作为食品组合物的活性成分时,可以按所述食品组合物总重量0.1-50wt%的量进行添加,但不限于此。
本发明的食品组合物被制备成饮品时,除了该饮品以标示出的百分比含有所述食品组合物外,没有特别的限定。所述饮品可能还含有各种调味剂或天然碳水化合物,如同常规的饮料。具体地,所述天然碳水化合物的实例包括单糖(如葡萄糖)、双糖(如果糖)、多糖(如蔗糖)、常规的糖(如糊精、环糊精等),以及糖醇(如木糖醇、山梨糖醇、赤藓糖醇)等。所述调味剂的实例包括天然调味剂(酸麦素、甜叶菊提取物,如莱鲍迪甙A、甘草甜素等)和人工调味剂(糖精,阿斯巴甜等)。
此外,本发明的食物组合物可进一步含有各种营养素,维生素,矿物质(电解质),调味剂(如合成调味剂和天然调味剂),着色剂,果胶酸及其盐,海藻酸及其盐,有机酸,保护性胶体增稠剂,pH调节剂,稳定剂,防腐剂,甘油,酒精,碳酸饮料中使用的碳化剂等。
本发明的食物组合物中包含的组分可以单独应用或联合应用。虽然这些添加剂的比例对本发明并不关键,但其可以选自,但不限于本发明食品组合物的100重量份中的0.1至约50重量份的范围。
本发明的化妆品组合物可被制备为皮肤柔软剂,滋养液,滋养精华,按摩霜,化妆沐浴用水添加剂,身体液,身体乳,沐浴油,婴儿油,婴儿爽身粉,沐浴露,沐浴乳,沐浴霜,防晒液,防晒霜,防晒霜,皮肤液,护肤霜,紫外线隔离化妆品,清洁乳,脱毛剂(用于化妆目的),面部和身体液,面部和身体霜,皮肤美白霜,护手液,护发液,化妆霜,茉莉花油,沐浴皂,液体肥皂,化妆用皂,洗发水,洗手液,药用肥皂(用于非医疗目的),乳霜肥皂,洁面剂,身体清洁剂,头皮清洁剂,洗发剂,香皂,牙齿美白凝胶,牙膏等的形式。为此,本发明的组合物还可以含有常规的用于制备化妆品组合物的溶剂、或合适的载体、赋形剂或稀释剂。
在本发明中,可进一步添加到化妆品组合物中的溶剂的类型没有特别限制,并且所述溶剂的实例可以包括水、盐水、DMSO、或其组合。此外,载体、赋形剂或稀释剂的实例包括但不限于纯化水、油、蜡、脂肪酸、脂肪酸醇、脂肪酸酯、表面活性剂、保湿剂、增稠剂、抗氧化剂、粘度稳定剂、螯合剂、缓冲剂、低级醇等。此外,如有需要,本发明的化妆品组合物可含有美白剂,保湿剂,维生素,紫外线隔离剂,香料,染料,抗生素,抗菌剂和抗真菌剂。
在本发明中,油的实例包括氢化植物油、蓖麻油、棉籽油、橄榄油、棕榈仁油、荷荷巴油和鳄梨油,蜡的实例可包括蜂蜡、精蜡、巴西棕榈蜡、小烛树蜡、褐煤蜡、地蜡、液体石蜡和羊毛脂。
在本发明中,脂肪酸的实例包括硬脂酸、亚油酸、亚麻酸和油酸;脂肪酸醇的例子包括鲸蜡醇、辛基十二烷醇、油醇、泛醇、羊毛脂醇、硬脂醇和十六烷醇;脂肪酸酯的实例包括肉豆蔻酸异丙酯、棕榈酸异丙酯和硬脂酸丁酯。表面活性剂的实例包括阳离子表面活性剂、阴离子表面活性剂和非离子表面活性剂,其均为本领域已知的。在这些表面活性剂中,如果可能的话,优选来源于天然产品的表面活性剂。
除上述成分外,本发明的化妆品组合物还可以含有保湿剂、增稠剂、抗氧化剂等,其在化妆品领域是广为人知的,并且其种类和量是本领域已知的。
本发明的另一个实施方式提供了一种预防或治疗癌症的方法,所述方法包括步骤:给有需要的受试者施用有效量的如下式1所示的化合物:
[式1]
其中n、m、X和Y分别如预防、改善、或治疗癌症的组合物的上式1中所定义。
在本发明的预防或治疗癌症的方法中,式1所示的化合物和所述癌症的详情与用于预防,改善或治疗癌症的组合物中所述的详情相同,为避免使本说明书过于复杂,在此将省略其描述。
本发明的另一个实施方式提供了一种抑制癌症转移的方法,所述方法包括步骤:给有需要的受试者施用有效量的如下式I所示的化合物:
[式1]
其中n、m、X和Y分别如预防、改善、或治疗癌症的组合物的上式1中所定义。
在本发明的抑制癌症转移的方法中,式1所示的化合物和所述癌症的详情与用于抑制癌症转移的组合物中所述的详情相同,因此为避免使本说明书过于复杂,在此将省略其描述。
如本文所用,术语“施用”是指以任意适当的方式向受试者提供本发明给定的化合物。
在本发明中,术语需要用药的“受试者”可以包括哺乳动物和非哺乳动物。在此,所述哺乳动物的实例包括,但不限于,人类;非人类灵长类动物,如黑猩猩,或其他猿类或猴类;农场动物,如牛、马、绵羊、山羊、猪;家畜,如兔子、狗和猫;实验动物,包括啮齿动物,如大鼠、小鼠或豚鼠。此外,在本发明中,所述非哺乳动物的实例包括,但不限于,鸟类或鱼类。
在本发明中,如上所述施用的化合物的制剂形式没有特别限制,并且该组合物可以作为固体制剂、液体制剂或用于吸入的气溶胶制剂施用,并且可以作为用于在口服或肠胃外给药使用前快速转化为液体形式制剂的固体形式制剂使用。本发明的化合物可被配制和施用为口服剂型如粉剂、颗粒、胶囊、片剂、水悬液等,以及诸如外用制剂、栓剂和无菌注射溶液的形式,但不限于此。
此外,在本发明中,药学上可接受的载体可以额外地和本发明的化合物共同应用。在此,用于口服给药时,所述药学上可接受的载体可包括粘合剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、色素、矫味剂等。用于注射时,所述药学上可接受的载体可包括缓冲剂、防腐剂、镇痛剂、增溶剂、等渗剂、稳定剂等。用于局部给药时,所述药学上可接受的载体可包括基质、赋形剂、润滑剂、防腐剂等。本发明的化合物的制剂可以通过和上述药学上可接受的载体混合以多种方法制备。例如,用于口服给药时,所述化合物可被配制为片剂、锭剂、胶囊、酏剂、悬液、糖浆、薄膜片等。用于注射给药时,所述化合物可被配制为单位剂量的安瓿或多剂量形式。另外,所述化合物也可以被制备为溶液、悬液、片剂、胶囊和缓释制剂。
其中,适合用于配制的载体、赋形剂和稀释剂的实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、苯甲酸甲羟甲酯、苯甲酸丙基羟基酯、滑石粉、硬脂酸镁和矿物油。此外,所述组合物可以进一步包含填充剂、抗凝血剂、润滑剂、湿润剂、香精、乳化剂、防腐剂等。
本发明的化合物的给药途径包括但不限于,口服、静脉内、肌肉内、动脉内、髓内、硬膜内、心内、经皮、皮下、腹膜内、鼻内、胃肠道、局部、舌下和直肠内途径。优选口服或肠外给药。
在本发明中,“肠外给药”包括皮下、经皮、静脉内、肌肉内、关节内、滑膜内、胸骨内、硬膜内、病灶内和颅内注射或输注技术。本发明的药物组合物还可以被制备为用于直肠内给药的栓剂。
在本发明中,术语“药学有效量”是指能够提供期望的生物学结果的足够药物剂量。所述的结果可以是减轻和/或缓解疾病的体征,症状或原因,或生物系统的任何其他期望的改变。例如,用于治疗的“有效量”是提供疾病的临床显著减轻所需的本发明化合物的量。在任意个案中,适当的“有效”量可以由本领域普通技术人员通过常规实验确定。因此,“有效量”一般是指具有治疗作用的活性物质的量。在本发明中,所述活性物质是癌症细胞生长抑制剂、癌症的预防、改善、或治疗剂、和癌症转移抑制剂。
本发明的化合物剂量可因各种因素而变化,包括所用特定化合物的活性、患者的年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄率,药物含量以及所要预防或治疗的特定疾病的严重程度。所述化合物的剂量可根据患者状况、体重、疾病严重程度、药物剂型和给药途径及时间,由本领域技术人员适当地选择,并可以为0.0001-100mg/kg/天或0.001-100mg/kg/天。所述化合物可每日给药一次或多次。所述剂量并不旨在以任何方式限制本发明的范围。本发明的化合物可配制为丸剂、糖衣片剂、胶囊、液体、凝胶、糖浆、糊剂或悬液。
本发明的化合物可以单独应用或和手术,放疗,激素治疗,化疗和生物反应调节剂方法联合应用。
此外,本发明的化合物可以进一步与其他抗癌药物联合应用。其中,所述的抗肿瘤药物可以是,但不限于选自下组的至少一种:氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄罗替尼、奈拉替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、塞马萨尼(semasanib)、博舒替尼、阿西替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、卡铂、索拉非尼、贝伐珠单抗、顺铂、西妥昔单抗、槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌司莫汀、吉妥珠单抗奥佐米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑珠单抗、丙卡巴肼、前列地尔、硝酸钬壳聚糖(holmium nitrate chitosan)、吉西他滨、去氧氟尿苷、培美曲赛、替吉奥、卡培他滨、吉美拉西、奥替拉西、阿扎胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达加滨(fludagabine)、依托他滨、氟他滨、卡培他滨、地西他滨、巯嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟(carmopher)、雷替曲塞、多西他赛、紫杉醇、伊立替康、贝洛替康、托泊替康、长春瑞滨、依托泊苷、长春碱、伊达比星、丝裂霉素、博来霉素、放线菌素、吡柔比星、阿柔比星、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑(melparan)、六甲密胺(altretmine)、达卡巴嗪、噻替哌、尼莫司汀、苯丁酸氮芥、二溴卫矛醇(mitolactol)、亚叶酸、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本(nabelbine)、法曲唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏罗唑、比卡鲁胺、洛莫司汀、5FU、伏立诺他、恩替诺特、和卡莫司汀。
有益效果
本发明的组合物不仅可以非常高效地应用于预防、改善、或治疗癌症,还可以通过抑制癌细胞生长和非常高效地抑制癌细胞转移至其他组织,来抑制癌症转移。
附图简述
图1显示了在本发明的一个实施例中通过蛋白质印迹实验评估增加AMPK蛋白稳定性的结果。
图2a和2b显示了在本发明的一个实施例中通过细胞存活率测定(a)和克隆生成测定(b)评估抑制癌细胞系存活和生长效果的结果。
图3a显示了在本发明的一个实施例中通过细胞存活率测定评估抑制癌细胞系存活和生长效果的结果。
图3b显示了在本发明的一个实施例中通过p-AMPK(Thr172)表达水平评估癌细胞中AMPK激活能力的结果。
图4a-4c显示了在本发明的一个实施例中评估AMPK激活剂、制备实施例6的化合物和具有相似结构的制备实施例8的化合物,针对胃癌、脑癌和胰腺癌细胞系的生存率抑制效果和AMPK激动能力的结果。
图5显示了在本发明的一个实施例中使用流式细胞术测定评估诱导癌细胞系调亡效果的结果。
图6显示了在本发明的一个实施例中使用蛋白质印迹实验评估诱导癌细胞系调亡效果的结果。
图7a和7b显示了在本发明的一个实施例中使用蛋白质印迹实验评估抑制癌细胞系EMI效果的结果。
图8a-8d显示了在本发明的一个实施例中评估动物模型中肿瘤消退效果的结果。
图9a和9b显示了在本发明的一个实施例中评估动物模型中抑制肿瘤转移效果的结果。
最优方式
本发明的一个实施方式涉及一种预防、改善、或治疗癌症的组合物,所述组合物含有下式1所示的化合物作为活性成分:
本发明的另一个实施方式涉及一种抑制癌症转移的组合物,所述组合物含有下式1所示的化合物作为活性成分:
本发明的另一个实施方式指向一种预防或治疗癌症的方法,所述方法包括步骤:给有需要的受试者施用有效量的如下式1所示的化合物:
本发明的另一个实施方式指向一种抑制癌症转移的方法,所述方法包括步骤:给有需要的受试者施用有效量的如下式I所示的化合物:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:氢、C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间可以是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰可以是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
发明实施方式
下面,将通过结合实施例更详细地描述本发明。显然,对本领域技术人员而言,这些实施例仅用于更详细地解释本发明,并且根据本发明的主题,本发明的范围不受这些实施例的限制。
实施例
[制备实施例1-15]候选化合物的合成
下表1所示的制备实施例1-15的化合物使用方法1或方法2制备。
[表1]
[方法1]
方法包括步骤:在乙醇溶剂中加入苯乙酮衍生物(1当量),苯甲醛衍生物(1当量)和NaOH(1当量),然后在室温下搅拌;反应完成后,向反应混合物中加入水,然后用乙酸乙酯萃取;并收集有机溶剂层,收集到的物质用水洗涤一次,用无水MgSO4干燥洗涤的材料,减压蒸馏除去溶剂,残留物用硅胶色谱法纯化。
[方法2]
方法包括步骤:在乙醇溶剂中加入苯乙酮衍生物(1当量),4-(四氢-2H-吡喃-2-基)氧基)苯甲醛衍生物(1当量)和NaOH(1当量),然后在室温下搅拌;反应完成后,向反应混合物中加入4M HCl,然后搅拌20分钟,加入水,然后用乙酸乙酯萃取;并收集有机溶剂层,收集到的物质用水洗涤一次,用无水MgSO4干燥洗涤的材料,减压蒸馏除去溶剂,残留物用硅胶色谱法纯化。
[实施例1](E)-1-(4-氨基苯基)-3-(2,4-二甲氧基苯基)丙-2-烯-1-酮(YE-01)
根据上述方法1,以4-氨基苯乙酮(0.30g,2.22mmol)、2,4-二甲氧基苯甲醛(0.37g,2.22mmol)和NaOH(0.09g,2.22mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:2→1:1)纯化,得到制备实施例1的化合物(0.15g,收率23.0%),为黄色固体。Rf0.33(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.85(s,3H),3.89(s,3H),6.47(d,J=2.0Hz,1H),6.52(dd,J=8.4,2.4Hz,1H),6.69(d,J=8.4Hz,2H),7.55(d,J=15.6Hz,1H),7.56(d,J=8.8Hz,1H),7.92(d,J=8.4Hz,2H),8.02(d,J=15.6Hz,1H);13C-NMR(100MHz,CDCl3)55.6,55.7,98.7,105.5,114.1,117.8,120.7,129.4,130.8,131.1,139.0,150.9,160.4,162.8,189.1ppm。
[实施例2](E)-1-(4-氨基苯基)-3-(2,5-二甲氧基苯基)丙-2-烯-1-酮(YE-02)
根据上述方法1,以4-氨基苯乙酮(0.50g,3.70mmol)、2,5-二甲氧基苯甲醛(0.62g,3.70mmol)和NaOH(0.15g,3.70mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:2→1:1)纯化,得到制备实施例2的化合物(0.66g,收率62.5%),为黄色固体。Rf0.36(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.81(s,3H),3.85(s,3H),4.19(br s,2H),6.69(d,J=8.8Hz,2H),6.86(d,J=8.8Hz,1H),6.91(dd,J=8.8,2.8Hz,1H),7.16(d,J=2.8Hz,1H),7.58(d,J=15.6Hz,1H),7.92(d,J=8.8Hz,2H),8.04(d,J=15.6Hz,1H);13C-NMR(100MHz,CDCl3)56.0,56.3,112.7,113.9,114.1,116.8,123.3,125.2,128.9,131.3,138.6,151.2,153.4,153.7,188.8ppm。
[实施例3](E)-1-(3-氨基苯基)-3-(4-甲氧基苯基)丙-2-烯-1-酮(YE-03)
根据上述方法1,以3-氨基苯乙酮(1.00g,7.40mmol)、4-甲氧基苯甲醛(1.00g,7.40mmol)和NaOH(0.30g,7.40mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:2→1:1)纯化,得到制备实施例3的化合物(0.83g,收率62.5%),为橙色固体。Rf0.40(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.83(br s,2H),3.85(s,3H),6.88(ddd,J=8.0,2.4,0.8Hz,1H),6.93(d,J=8.8Hz,2H),7.27(dd,J=8.0,7.6Hz,1H),7.31(dd,J=2.0,1.6Hz,1H),7.36(d,J=15.6Hz,1H),7.38(ddd,J=7.6,1.6,0.8Hz,1H),7.59(d,J=8.8Hz,2H),7.76(d,J=15.6Hz,1H);13C-NMR(100MHz,CDCl3)56.0,56.3,112.7,113.9,114.1,116.8,123.3,125.2,128.9,131.3,138.6,151.2,153.4,153.7,188.8ppm。
[实施例4](E)-1-(3-氨基苯基)-3-(4-羟基-2-甲氧基苯基)丙-2-烯-1-酮(YE-
04)
根据上述方法2,以3-氨基苯乙酮(0.40g,2.96mmol)、2-甲氧基-4-((四氢-2H-吡喃-2-基)氧基)苯甲醛(0.70g,2.96mmol)和NaOH(0.12g,2.96mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:1)纯化,得到制备实施例4的化合物(0.28g,收率35.1%),为橙色固体。Rf 0.25(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.71(s,3H),6.30(d,J=2.4Hz,1H),6.34(dd,J=8.4,2.0Hz,1H),6.72(ddd,J=8.0,2.4,0.8Hz,1H),7.08(dd,J=8.4,8.0Hz,1H),7.13(d,J=2.4Hz,1H),7.16(ddd,J=7.6,7.6,0.8Hz,1H),7.29(d,J=15.6Hz,1H),7.32(d,J=8.4Hz,1H),7.85(d,J=15.6Hz,1H),9.35(br s,1H);13C-NMR(100MHz,CDCl3)55.3,99.1,108.2,114.1,115.3,118.1,118.7,119.3,129.1,130.6,139.8,140.3,147.0,60.5,161.4,191.1ppm。
[实施例5](E)-1-(3-氨基苯基)-3-(2,5-二甲氧基苯基)丙-2-烯-1-酮(YE-05)
根据上述方法1,以4-氨基苯乙酮(0.50g,3.70mmol)、2,5-二甲氧基苯甲醛(0.62g,3.70mmol)和NaOH(0.15g,3.70mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:3)纯化,得到制备实施例5的化合物(0.27g,收率25.4%),为黄色固体。Rf 0.62(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.81(s,3H),3.86(s,3H),6.87(d,J=8.8Hz,1H),6.88(ddd,J=8.4,2.0,0.8Hz,1H),6.94(dd,J=8.8,2.8Hz,1H),7.16(d,J=2.8Hz,1H),7.27(dd,J=8.0,8.0Hz,1H),7.31(dd,J=2.8,2.8Hz,1H),7.38(ddd,J=8.0,2.0,1.6Hz,1H),7.53(d,J=15.6Hz,1H),8.06(d,J=15.6Hz,1H);13C-NMR(100MHz,CDCl3)56.1,56.3,112.7,113.9,114.7,117.4,119.1,119.4,123.6,124.8,129.6,139.8,140.0,147.0,153.5,153.7,191.4ppm。
[实施例6](E)-4-氯-N-(4-(3-(2,5-二甲氧基苯基)丙烯酰基)苯基)苯磺酰胺
(YE-06)
在制备实施例2的化合物(0.67g,2.36mmol)和三乙胺(TEA,0.26g,2.60mmol)的CH2Cl2溶液中,加入4-氯苯磺酰氯(0.75g,3.54mmol),并将混合物在室温下搅拌24小时。向反应混合物中加入水,随后用乙酸乙酯萃取。收集有机溶剂层,用饱和NaHCO3洗涤,并用无水MgSO4干燥。随后减压蒸馏除去溶剂,将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:2)纯化,得到制备实施例6的化合物(0.55g,收率50.9%),为黄色固体。Rf0.18(乙酸乙酯/正己烷=1:2);1H-NMR(400MHz,DMSO-d6)δ3.74(s,3H),3.80(s,3H),6.84(d,J=8.8Hz,1H),6.88(dd,J=8.8,2.4Hz,1H),7.16(d,J=2.4Hz,1H),7.20(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),7.54(d,J=15.6Hz,1H),7.74(d,J=8.4Hz,2H),7.85(d,J=8.4Hz,2H),7.91(d,J=15.6Hz,1H),10.58(s,1H);13C-NMR(100MHz,DMSO-d6)55.2,55.6,112.1,112.7,117.0,118.0,121.6,123.5,128.0,128.1,128.7,129.4,132.9,137.8,138.3,141.5,152.5,152.9,187.9ppm。
[实施例7](E)-4-氯-N-(3-(3-(4-甲氧基苯基)丙烯酰基)苯基)苯磺酰胺(YE-07)
在乙醇溶剂中加入N-(3-乙酰苯基)-4-氯苯磺酰胺(0.10g,0.32mmol)、4-甲氧基苯甲醛(0.04g,0.32mmol)和NaOH(0.03g,0.80mmol),随后室温下搅拌72小时。向反应混合物中加入稀盐酸水溶液,随后用乙酸乙酯萃取。收集有机溶剂层,用水洗涤,并用无水MgSO4干燥。减压蒸馏除去溶剂,将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:3→1:1)纯化,得到制备实施例7的化合物(0.01g,收率6.5%),为黄色固体。1H-NMR(400MHz,CDCl3)δ3.84(s,3H),6.92(d,J=8.8Hz,2H),7.28(d,J=15.6Hz,1H),7.33(dd,J=8.0,7.6Hz,1H),7.36(d,J=8.8Hz,2H),7.41(ddd,J=8.0,2.0,1.2Hz,1H),7.57(d,J=8.8Hz,2H),7.68(ddd,J=7.6,1.6,1.2Hz,1H),7.71-7.78(m,4H),9.25(s,1H);13C-NMR(100MHz,CDCl3)55.6,114.6,119.5,121.1,124.9,125.0,127.6,128.8,129.4,129.7,130.5,137。
[实施例8](E)-4-氯-N-(3-(3-(2,5-二甲氧基苯基)丙烯酰基)苯基)苯磺酰胺
(YE-08)
在制备实施例5的化合物(0.12g,0.43mmol)和三乙胺(0.03g,2.60mmol)的CH2Cl2溶液中,加入4-氯苯磺酰氯(0.09g,0.43mmol),并将混合物在室温下搅拌24小时。向反应混合物中加入水,随后用乙酸乙酯萃取。收集有机溶剂层,用饱和NaHCO3洗涤,并用无水MgSO4干燥。随后减压蒸馏除去溶剂,将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:3)纯化,得到制备实施例8的化合物(0.08g,收率37.3%),为黄色固体。Rf 0.33(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.82(s,3H),3.88(s,3H),6.88(d,J=8.8Hz,1H),6.96(dd,J=8.4,2.8Hz,1H),7.15(d,J=2.8Hz,1H),7.40(d,J=8.8Hz,2H),7.41-7.43(m,2H),7.55(d,J=16.0Hz,1H),7.73(d,J=8.8Hz,2H),7.71-7.72(m,1H),7.76-7.79(m,1H),8.08(d,J=16.0Hz,1H);13C-NMR(100MHz,CDCl3)56.1,56.3,112.7,114.5,117.9,121.6,122.8,124.4,125.5,125.8,128.9,129.7,130.0,137.1,137.7,139.9,140.0,141.6,153.7,153.8,190.3ppm。
[实施例9](E)-4-氯-N-((4-氯苯基)磺酰基)-N-(3-(3-(2,5-二甲氧基苯基)丙烯
酰基)苯基)苯磺酰胺(YE-09)
在制备实施例5的化合物(0.22g,0.78mmol)和三甲胺(0.22g,2.12mmol)的CH2Cl2溶液中,加入4-氯苯磺酰氯(0.25g,1.17mmol),并将混合物在室温下搅拌24小时。向反应混合物中加入水,随后用乙酸乙酯萃取。收集有机溶剂层,用饱和NaHCO3洗涤,并用无水MgSO4干燥。随后减压蒸馏除去溶剂,将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:4)纯化,得到制备实施例8的化合物(0.20g,收率39.8%),为黄色固体。Rf 0.77(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ3.83(s,3H),3.86(s,3H),6.89(d,J=9.2Hz,1H),6.97(dd,J=9.2,3.2Hz,1H),7.13(d,J=2.8Hz,1H),7.19(dd,J=8.4,2.0Hz,1H),7.42(d,J=16.0Hz,1H),7.52(d,J=8.4Hz,1H),7.54(d,J=8.8Hz,4H),7.66(dd,J=1.6,1.6Hz,1H),7.89(d,J=8.8Hz,4H),8.05(d,J=16.0Hz,1H),8.09(d,J=8.0Hz,1H),;13C-NMR(100MHz,CDCl3)56.1,56.3,112.7,114.3,117.9,122.9,124.3,129.8,129.9,130.3,130.6,131.6,134.6,135.2,137.8,140.2,141.4,141.8,153.7,153.8,189.9ppm。
[实施例10](E)-1-(4-氨基苯基)-3-(4-(哌啶-1-基)苯基)丙-2-烯-1-酮(YE-10)
根据上述方法1,以4-氨基苯乙酮(0.40g,2.96mmol)、4-(哌啶-1-基)苯甲醛(0.56g,2.96mmol)和NaOH(0.12g,2.96mmol)为原料。将残留物用硅胶色谱法(显影溶剂:MeOH:CHCl3=1:19)纯化,得到制备实施例10的化合物(0.28g,收率30.9%),为橙色固体。Rf00.43(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ1.62-1.71(m,6H),3.29(t,J=5.2Hz,4H),4.10(br s,2H),6.69(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),7.37(d,J=15.6Hz,1H),7.53(d,J=8.8Hz,2H),7.75(d,J=15.6Hz,1H),7.95(d,J=8.8Hz,2H)。
[实施例11](E)-1-(3-氨基苯基)-3-(4-(哌啶-1-基)苯基)丙-2-烯-1-酮(YE-11)
根据上述方法1,以3-氨基苯乙酮(0.40g,2.96mmol)、4-(哌啶-1-基)苯甲醛(0.56g,2.96mmol)和NaOH(0.12g,2.96mmol)为原料。将残留物用硅胶色谱法(显影溶剂:MeOH:CHCl3=1:19)纯化,得到制备实施例11的化合物(0.45g,收率49.6%),为橙色固体。Rf0.47(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ1.61-1.72(m,6H),3.31(t,J=5.6Hz,4H),3.80(br s,2H),6.86(ddd,J=8.0,2.4,0.8Hz,1H),6.89(d,J=8.8Hz,2H),7.28(dd,J=8.0,8.0Hz,1H),7.30(d,J=15.6Hz,1H),7.31(dd,J=2.0,2.0Hz,1H),7.37(ddd,J=8.8,1.2,1.2Hz,1H),7.53(d,J=8.8Hz,2H),7.75(d,J=15.6Hz,1H);13C-NMR(100MHz,CDCl3)24.6,25.7,49.3,114.7,115.0,118.4,119.0,119.1,124.7,129.5,130.4,140.3,145.4,146.9,153.4,191.1ppm。
[实施例12](E)-1-(4-羟基苯基)-3-(4-(哌啶-1-基)苯基)丙-2-烯-1-酮(YE-12)
根据上述方法2,以1-4-(四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(0.50g,2.27mmol)、4-(哌啶-1-基)苯甲醛(0.43g,2.27mmol)和NaOH(0.09g,2.27mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:3→1:1)纯化,得到制备实施例12的化合物(0.24g,收率33.7%),为橙色固体。Rf 0.17(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ1.58-1.65(m,6H),3.25(t,J=5.6Hz,4H),6.84(d,J=8.8Hz,2H),6.87(d,J=8.8Hz,2H),7.32(d,J=15.6Hz,1H),7.48(d,J=8.8Hz,2H),7.68(d,J=15.6Hz,1H),7.90(d,J=8.8Hz,2H),9.34(s,1H);13C-NMR(100MHz,CDCl3)24.4,25.5,49.2,114.9,115.6,117.8,124.8,130.1,130.6,130.9,144.2,153.1,161.7,189.0ppm。
[实施例13](E)-1-(2,4-二羟基苯基)-3-(4-(哌啶-1-基)苯基)丙-2-烯-1-酮
(YE-13)
根据上述方法2,以1-4-(四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(0.50g,2.12mmol)、4-(哌啶-1-基)苯甲醛(0.40g,2.12mmol)和Ba(OH)2·8H2O(0.73g,2.33mmol)为原料。将残留物用硅胶色谱法(显影溶剂:乙酸乙酯/正己烷=1:1)纯化,得到制备实施例13的化合物(0.12g,收率16.8%),为橙色固体。Rf 0.66(乙酸乙酯/正己烷=1:1);1H-NMR(400MHz,CDCl3)δ1.58-1.65(m,6H),3.27(t,J=5.6Hz,4H),6.37-6.40(m,2H),6.84(d,J=8.8Hz,2H),7.34(d,J=15.2Hz,1H),7.49(d,J=8.8Hz,2H),7.73(d,J=8.4Hz,1H),7.76(d,J=15.2Hz,1H),9.64(s,1H),13.6(s,1H)。
[实施例14](E)-3-(4-羟基-2-甲氧基苯基)-1-(4-(哌嗪-1-基)苯基)丙-2-烯-1-
酮(YE-14)
根据上述方法2,以1-4-(四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(0.50g,2.45mmol)、2-甲氧基-4-(四氢-2H-吡喃-2-基)氧基)苯甲醛(0.58g,2.45mmol)和NaOH(0.20g,4.90mmol)为原料。去除溶剂后,得到的固体用乙酸乙酯/正己烷的混合溶剂处理。将得到的固体过滤并在真空中干燥,得到生产实施例14的化合物(0.28g,收率33.8%),为橙色固体。1H-NMR(400MHz,DMSO-d6)δ2.89(dd,J=7.2,3.2Hz,4H),3.26(dd,J=7.2,4.0Hz,4H),3.82(s,3H),6.40(dd,J=8.8,2.0Hz,1H),6.41(d,J=1.6Hz,1H),6.89(d,J=8.8Hz,2H),7.51(d,J=15.6Hz,1H),7.55(d,J=8.8Hz,1H),7.87(d,J=15.6Hz,1H),7.90(d,J=8.8Hz,2H);13C-NMR(100MHz,DMSO-d6)45.1,47.5,55.1,98.7,107.9,112.9,114.7,118.0,127.7,129.7,129.8,137.7,153.7,159.7,161.2,186.8ppm。
[实施例15](E)-3-(4-羟基苯基)-1-(4-(甲基哌嗪-1-基)苯基)丙-2-烯-1-酮
(YE-15)
根据上述方法2,以1-(4-(四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(0.50g,2.29mmol)、4-(四氢-2H-吡喃-2-基)氧基)苯甲醛(0.47g,2.29mmol)和NaOH(0.09g,2.29mmol)为原料。去除溶剂后,得到的固体用乙酸乙酯/正己烷的混合溶剂处理。将得到的固体过滤并在真空中干燥,得到生产实施例15的化合物(0.70g,收率94.8%),为橙色固体。1H-NMR(400MHz,,CDCl3)δ2.33(s,3H),2.55(t,J=5.2Hz,4H),3.37(t,J=5.2Hz,4H),6.86(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),7.38(d,J=15.6Hz,1H),7.49(d,J=8.8Hz,2H),7.72(d,J=15.6Hz,1H),7.95(d,J=8.8Hz,2H);13C-NMR(100MHz,CDCl3)46.2,47.4,54.8,113.7,116.2,118.8,126.8,128.7,130.3,130.6,143.7,154.0,159.7,188.4ppm。
[实验方法]
[实验方法1]测试用细胞系及细胞系培养方法
使用人细胞系(VERO、HFL-1、L929、NIH 3T3和CHO-K1)评估本发明制备实施例6的化合物的细胞毒性。此外,使用下列肿瘤细胞系以评估本发明制备实施例6的化合物和13个化合物(包括制备实施例1-5和8-15的结构相似的化合物(YE-01、02、03、04、05、08、09、10、11、12、13、14和15))抑制肿瘤细胞系生长的能力:人胃癌细胞系(NCI-N87、和SNU-216)、人脑癌细胞系(U-87MG、和Hs 683)、人胰腺细胞系(AsPC-1、和MIA PaCa-2)、人乳腺癌细胞系(BT549、MDA-MB-231和Hs578t)和小鼠乳腺癌细胞系4T1或4T1-luc(一种经构建的细胞系,使得荧光素酶可以在4T1细胞系中表达,并且可以通过简单的预处理直观地确认细胞的位置)。
每个细胞系都由ATCC(美国模式培养物保藏所),JCRB细胞库(日本研究生物资源细胞库)或韩国细胞系库(KCRB)提供。每种细胞系按ATCC官网记载的培养基和培养条件培养。此外,为避免可能影响细胞系中基因表达的支原体感染,在细胞系培养期间常规检查是否出现支原体感染,确认支原体感染时,使用抗支原体抗生素处理1-2周。在此,4T1-luc细胞系用于构建异种/原位动物模型。
[实验方法2]使用制备实施例6的化合物处理细胞系的条件
将制备实施例6的化合物以1-50μM的浓度溶解在DMSO中。随后,检测制备实施例6的化合物对于实验方法1的每个乳腺癌细胞系表现出最佳存活率的浓度和时间以及清晰趋势。同时,制备实施例6化合物疗法的对照组仅使用DMSO治疗。为避免引发诸如抑制细胞存活率的干扰,进行DMSO疗法时DMSO不超过培养基总量5%。
[实验方法3]测量稳定和激活AMPK(AMP活化蛋白激酶)的方法
进行细胞热位移分析(CTSA)以检测制备实施例6的化合物和13个化合物(包括制备实施例1-5和8-15的结构相似的化合物(YE-01、02、03、04、05、08、09、10、11、12、13、14和15))是否结合于AMPK上的AMP结合位点。具体地,使用胰蛋白酶从培养皿中分离培养的人乳腺癌来源细胞(BT549或MDA-MB-231细胞系)。将分离的细胞系稀释在PBS中,将在每个试管中分配等量的细胞系进行PCR,并加热3分钟从室温加热至65℃。加热完毕后,使用液氮从细胞系中分离蛋白质,并进行蛋白质印迹实验确认AMPK发生高温变性的温度。
[3-1]使用浓度在0-30μM的制备实施例6的化合物处理上述实验方法1的乳腺癌细胞系,随后培养24小时。之后,收集细胞并在在RIPA缓冲液中裂解,使用SDS-PAGE进行蛋白电泳,之后使用特异性抗AMPK和phospho-AMPK(Thr172)的抗体分析蛋白表达水平。使用GAPDH或β-肌动蛋白作为蛋白定量的内参对照。
[3-2]使用浓度为10μM的制备实施例6化合物和13个化合物(包括制备实施例1-5和8-15的结构相似的化合物(YE-01、02、03、04、05、08、09、10、11、12、13、14和15))分别处理实验方法1的三种乳腺癌细胞系(4T1、BT549、和MDA-MB-231),随后培养24小时。此外,使用浓度为10μM的制备实施例6的化合物或制备实施例8的具有相似结构的化合物分别处理两种类型的胃癌细胞系、脑癌细胞系和胰腺癌细胞系,随后培养12小时。之后,收集细胞并在在RIPA缓冲液中裂解,使用SDS-PAGE进行蛋白电泳,之后使用特异性抗AMPK和phospho-AMPK(Thr172)的抗体分析蛋白表达水平。使用GAPDH或β-肌动蛋白作为蛋白定量的内参对照。
[实验方法4]测定肿瘤细胞系生长抑制和调亡水平的方法
[4-1]细胞存活率测定
[4-1-1]使用浓度在0-30μM的5-氨基咪唑-4-甲酰胺核糖核苷酸(非制备实施例6的化合物)或制备实施例6的化合物处理实验方法1的乳腺癌细胞系,随后培养24小时、48小时和72小时。之后,使用WST-1试剂处理培养的细胞,随后测量450nm波长处的吸光度。在此,WST-1试剂能够通过依据细胞中存在的线粒体脱氢酶的水平改变培养基的颜色来测定细胞存活率。
[4-1-2]使用浓度为0-50μM的制备实施例6化合物和13个化合物(包括制备实施例1-5和8-15的结构相似的化合物(YE-01、02、03、04、05、08、09、10、11、12、13、14和15))分别处理实验方法1的乳腺癌细胞系(4T1、BT549、或MDA-MB-231),随后培养24小时。使用浓度为0μM的制备实施例6的化合物或制备实施例8的具有相似结构的化合物分别处理三种类型的胃癌细胞系、脑癌细胞系和胰腺癌细胞系,随后培养24小时。之后,按照制造商说明,使用WST-1试剂处理培养的细胞,在一定时间后测量450nm波长处的吸光度。在这里,WST-1试剂能够通过依据细胞中存在的线粒体脱氢酶的水平改变培养基的颜色来测定细胞存活率。
[4-2]克隆生成测定
将实验方法1的乳腺癌细胞系以1-2×103个细胞/孔的密度分配至6孔板中。细胞充分附着后,使用浓度在0-30μM的制备实施例6的化合物处理细胞,并培养10天至14天。之后,使用4%甲醛固定培养的细胞并用用1%结晶紫染色,在显微镜下进行克隆计数。
[4-3]流式细胞测定
使用浓度在0-30μM的制备实施例6的化合物处理实验方法1的乳腺癌细胞系,并培养24小时。之后,使用胰蛋白酶分离培养的细胞,随后用膜联蛋白V(识别细胞凋亡)和PI(碘化丙啶;识别细胞坏死)进行双重染色,随后使用流式细胞术测定细胞凋亡的模式和水平。
[实验方法5]测定肿瘤细胞系中上皮-间充质转化(EMT)的方法
将实验方法1中乳腺癌细胞系的培养基替换为无血清培养基。随后,使用2ng/mL的TGF-β1和制备实施例6的化合物处理细胞,并培养20-24小时。之后,如实验方法3所述,使用特异性抗EMT相关蛋白的抗体测定蛋白表达水平。
[实验方法6]乳腺癌细胞系异种移植/原位动物模型的构建
购买4周龄无胸腺裸鼠(雌),随后令小鼠在动物饲养室环境中适应7天并同时仅挑选健康小鼠。为识别每只小鼠,使用耳号钳标记耳部。此外,通过附上写有测试编号,测试物质名称,测试项目,接收日期,测试日期,测试内容以及测试负责人的小鼠识别卡来识别饲养箱。动物饲养室的环境保持在温度22±3℃,相对湿度50±20%,10-15次通风/小时,12小时光照(8:30-20:30)/黑暗循环,光照亮度150-300lux。此外,这些动物在饲养期间喂食饲料和饮用水,并在适应和测试期间进行检疫。
用2.5%异氟醚吸入麻醉裸鼠,然后用无菌注射器给小鼠注射实验方法1的乳腺癌细胞系4T1-luc。细胞稀释在100μl PBS(磷酸缓冲液)中,从而能够给每个裸鼠注射1-2.5x106细胞,随后将稀释液注射到侧腹或乳腺脂肪垫中。通过将乳腺癌细胞系注射到侧腹中获得的异种移植动物模型的构成如下表2所示。此外,通过将乳腺癌细胞系注射到乳腺脂肪垫中获得的原位动物模型的构成如下表3所示。
[表2]
[表3]
同时,在动物适应期剔除异常小鼠、体重不正常增长的小鼠和不健康的小鼠后,对小鼠进行分组,使平均体重和肿瘤大小一致。
[实验方法7]在动物模型中评估制备实施例6的化合物效果的方法
[7-1]在异种移植动物模型中评估效果的方法
从小鼠乳腺癌细胞系4T1-luc注射日到实验结束(解剖日期)的一段时间内,每天测量肿瘤体积。当肿瘤体积达到约80-100mm3时,将制备实施例6的化合物以4mg/kg的浓度注射到动物模型的尾静脉中,每3天一次,共6次。为了确认肿瘤消退效果,在给予制备实施例6的化合物之前测量肿瘤的体积,并在制备实施例6的化合物首次施用后的第28天,对动物实施安乐死,切除原发肿瘤并比较其体积。
[7-2]在原位动物模型中评估增加生存率效果的方法
从小鼠乳腺癌细胞系4T1-luc注射日到实验结束(解剖日期)的一段时间内,每3天一次测量肿瘤体积,并每天检查动物模型的生存率。当肿瘤体积达到约80-100mm3时,将制备实施例6的化合物以20mg/kg的浓度注射到动物模型的腹腔中,每3天一次,共6次。同时,为了动物模型的尊严,实验在对照组原发肿瘤体积达到3000mm3的时间点(第32天)终止,将动物模型安乐死。
[7-3]在原位动物模型中评估效果的方法
从小鼠乳腺癌细胞系4T1-luc细胞系注射日到实验结束(解剖日期)的一段时间内,每隔1-2天检查肿瘤细胞系的肺转移。用2.5%异氟醚吸入麻醉动物模型后,使用体内成像系统(IVIS)测量荧光强度。通过测量转移到肺部的4T1-luc细胞系的位置和数量来实时检查肺转移。从制备实施例6的化合物的首次注射日到实验结束(解剖日期)的一段时间内,持续地每隔2天腹腔内注射20mg/kg制备实施例6化合物。
结果:
[实施例1]提高AMPK蛋白稳定性效果评估
通过实验方法3描述的CTSA方法检测制备实施例6的化合物是否结合于AMPK上的AMP结合位点,结果如图1所示。
如图1所示,当AMPK蛋白单独存在时,蛋白的水平从50℃起降低(Tm值为50℃),而当用制备实施例6的化合物处理细胞时,在高达55℃时仍维持AMPK蛋白水平(Tm值为55℃)。
从上述结果可见,本发明的化合物能够通过结合于AMPK的AMP结合位点增加AMPK蛋白的热稳定性。
[实施例2]癌细胞系生存和生长的抑制效果和AMPK激活能力的评估
[2-1]癌细胞系生存和生长的抑制效果的评估
通过实验方法4描述的细胞存活率测定(a)和单克隆形成测定(b)评估降低癌细胞系生存率和抑制其生长的效果,结果如图2a和2b所示。
如图2a和2b所示,当用阳性对照AICAR处理细胞系时,细胞存活率在1mM时受到50%以上的抑制,而当4T1和BT549细胞系都用10μM制备实施例6的化合物处理时,细胞活力受到50%以上的抑制(见图2a)。此外,当使用10μM制备实施例6的化合物处理细胞系时,4T1、BT549和MDA-MB-231细胞系中的菌落形成均显著减少(见图2b)。
从上述结果可见,本发明的化合物能够降低癌细胞系生存率和抑制癌细胞生长。
[2-2]抑制癌细胞系生长的效果评估
通过实验方法4-1描述的细胞存活率测定评估抑制癌细胞系生长的效果,结果如图3a和4a-4c所示。如图3a所示,经验证,当使用总共14种化合物中的各个化合物(包括制备实施例6化合物和制备实施例1-5和8-15的结构相似的化合物(YE-01、02、03、04、05、08、09、10、11、12、13、14和15)))的多种浓度处理乳腺癌细胞系4T1、BT549和MDA-MB-231 24小时时,制备实施例6的化合物或制备实施例8的化合物在10μM的浓度下能够在所有三种乳腺癌细胞系中抑制癌细胞存活率达50%以上。此外,经验证,使用多种浓度的制备实施例6的化合物或制备实施例8的化合物处理胃癌、脑癌和胰腺癌三种细胞系24小时,癌细胞存活率被有效抑制了50%以上(见图4a-4c)。从上述结果可见,本发明的制备实施例6的化合物和具有相似结构的制备实施例8的化合物能够更有效地降低乳腺癌细胞的存活率以及胃癌、脑癌和胰腺癌细胞的存活率。
[2-3]癌细胞系中AMPK激活能力的评估
根据上述实验方法3中描述的方法,通过p-AMPK(Thr172)表达水平评估癌细胞系中的AMPK激活能力,结果如图3b所示。在此,通过计算每个印迹相对内参(GAPDH)的标准化值来绘制p-AMPK/AMPK的比率。如图3b所示,经验证,当使用制备实施例6化合物和制备实施例8的化合物各自处理乳腺癌细胞系4T1、BT549和MDA-MB-231 24小时,制备实施例6的化合物和制备实施例8的化合物在三种细胞系中均有效地增加了p-AMPK水平。此外,经验证,使用浓度为10μM的制备实施例6的化合物、制备实施例8的化合物和AICAR处理胃癌、脑癌和胰腺癌三种细胞系12小时,相比于未处理组(对照组),制备实施例6的化合物和制备实施例8的化合物均使p-AMPK表达增加(见图4a-4c)。在此,可以看出,与制备实施例6的化合物和制备实施例8的化合物相比,用作阳性对照的AICAR的作用并不显著,而与AMPK激活剂AICAR相比,除乳腺癌细胞外,本发明的制备实施例6的化合物和具有相似结构的制备实施例8的化合物能够更有效地诱导胃癌、脑癌和胰腺癌细胞中AMPK的活化。
[实施例3]诱导癌细胞系调亡的效果评估
通过实验方法4描述的流式细胞测定和实验方法3描述的蛋白质印迹测定检测诱导癌细胞系调亡的效果,结果如图5和6所示。
如图3b所示,经验证,当使用制备实施例6的化合物处理4T1细胞系和MDA-MB-231细胞系时,调亡标志物裂解PARP(多聚(ADP-核糖)聚合酶)蛋白以浓度依赖性方式随磷酸化AMPK蛋白增加而增加,并且Bcl-2和Cyclin D1蛋白水平减低。
如图6所示,当使用制备实施例6的化合物处理4T1细胞系和MDA-MB-231细胞系时,被膜联蛋白V或PI染色的细胞以浓度依赖性方式增加。
从上述结果可见,本发明的化合物能够诱导癌细胞调亡。
[实施例4]抑制癌细胞系生长的效果评估
通过实验方法5描述的方法测定癌细胞系EMT,结果如图7a和7b所示。在此,MMP2(基质金属蛋白酶2)和MMP9(基质金属蛋白酶9)是降解IV型胶原蛋白的酶,IV型胶原蛋白是基底膜的重要组成部分,且大部分与癌症迁移和转移直接相关。因此,检测MMP2和MMP9蛋白的分泌水平。
如图7a所示,当使用TGF-β1处理BT549、MDA-MB-231和4T1细胞系时,EMT蛋白标记物α-SMA、Vimentin、ZEB-1和Slug蛋白增加,当使用TGF-β1联合制备实施例6的化合物一起处理这些细胞系时,EMT蛋白标记物减少。
如图7b所示,通过使用制备实施例6的化合物处理,分泌的MMP2和MMP9(使用TGF-β1处理时BT549细胞系中存在的EMT蛋白标记物)的水平显著降低。
从上述结果可见,本发明的化合物能够通过抑制癌细胞的EMT而非常有效地抑制癌细胞侵袭和癌症转移。
[实施例5]动物模型中肿瘤消退效果的评估
根据实验方法7的方法7-1评估制备实施例6的化合物的肿瘤消退效果,结果如图8a-8c所示。此外,根据实验方法7的方法7-2评估制备实施例6的化合物增加生存率的效果,结果如图8d所示。
如图8a-8c所示,在动物模型中,与未施用制备实施例6的化合物的情况(对照)相比,施用制备实施例6的化合物的组(YE-06)中肿瘤的体积饲养时间依赖性的方式减少(图8a和8b)。此外,观察到在未施用制备实施例6的化合物的情况(对照)和施用制备实施例6的化合物的情况(YE-06)中,体重均不随饲养时间减轻(图8c)。
此外,如图8d所示,验证了相比未施用制备实施例6的化合物的组(对照),施用制备实施例6的化合物的组(YE-06)中生存率显著增加。
从上述结果可见,本发明的化合物在动物模型中无毒性,并且施用该化合物能够非常有效地抑制肿瘤生长。进一步地,可以看出在动物模型中,本发明的化合物能够通过有效抑制肿瘤生长和转移,显著增加患癌个体的总体生存率。
[实施例6]动物模型中抑制肿瘤转移效果的评估
根据实验方法7的方法7-3,评估制备实施例6的化合物抑制肿瘤转移效果,结果如图9a和9b所示。
此外,如图9a和9b所示,验证了仅在肺、肝、脾和肾中,仅观察到肺部的4T1-luc转移,并且在未施用制备实施例6的化合物的情况(对照)中,在原位动物模型的肺部观察到非常高的荧光强度,而在施用了制备实施例6的化合物的情况(YE-06)下,原位动物模型肺部的发光强度显著降低。
从上述结果可见,在动物模型中,本发明的化合物能够非常有效地抑制肿瘤转移,特别是肺转移。
尽管结合具体特征对本发明进行了详细描述,但本领域技术人员显而易见的是,此种描述仅是本发明的一种优选的实施方式,并不限定本发明的范围。因此,本发明的实质范围应为所附权利要求和其等价物所定义的范围。
工业适用性
本发明的组合物不仅可以非常高效地应用于预防、改善、或治疗癌症,还可以通过抑制癌细胞生长和非常高效地抑制癌细胞转移至其他组织,来抑制癌症转移。
Claims (14)
1.一种用于预防或治疗癌症的药物组合物,所述药物组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:氢、C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
2.权利要求1所述的药物组合物,其中:
L1和L2各自为亚苯基;
n和m各自独立地为1或2的整数;
X和Y各自独立地选自下组:磺酰基、C1-C10烷基磺酰基、C1-C40烷氧基、-NR'R"、羟基、C6-C60芳氧基、和具有3-20个核原子的未取代或取代的杂环烷基;
R’和R”各自独立地为氢或C6-C60芳基磺酰基,并且
每个R’和R”中的芳基磺酰基是未取代或被至少一个卤素取代的。
6.权利要求1所述的药物组合物,其中所述的癌症为选自下组的至少一种:乳腺癌、结直肠癌、肺癌、肝癌、胃癌、食道癌、胰腺癌、胆囊癌、肾癌、膀胱癌、前列腺癌、睾丸癌、结肠癌、宫颈癌、子宫内膜癌、绒毛膜癌、皮肤癌、卵巢癌、甲状腺癌、脑癌、血癌、头颈癌、恶性黑色素瘤、和淋巴瘤。
7.权利要求1所述的药物组合物,其进一步含有抗癌药物。
8.一种用于抑制癌症转移的药物组合物,所述药物组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
9.一种用于预防或改善癌症的食品组合物,所述食品组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
10.一种用于抑制癌症转移的食品组合物,所述食品组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
11.一种用于预防或治疗癌症的化妆品组合物,所述化妆品组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
12.一种用于抑制癌症转移的化妆品组合物,所述化妆品组合物含有下式1所示的化合物作为活性成分:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
13.一种预防或治疗癌症的方法,所述方法包括步骤:给有需要施用的受试者施用有效量的如下式1所示的化合物:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
14.一种抑制癌症转移的方法,所述方法包括步骤:给有需要施用的受试者施用有效量的如下式1所示的化合物:
[式1]
其中:
L1和L2各自独立地选自下组:C3-C40亚环烷基、C6-C60亚芳基、和具有5-60个核原子的杂亚芳基;
X和Y各自独立地选自下组:氘、卤素、氰基、硝基、磺酰基、C1-C10烷基磺酰基、叠氮化物基团、羟基、C1-C40烷基、C2-C40烯基、C1-C40烷氧基、未取代或取代的C6-C60芳氧基、未取代或取代的C3-C40环烷基、具有3-20个核原子的未取代或取代的杂环烷基、未取代或取代的C6-C60芳基、未取代或取代的具有5-60个核原子的杂芳基、和-NR'R";
R’和R”各自独立地选自下组:C1-C10烷基、C6-C60芳基、C3-C40环烷基、C6-C60芳基磺酰基、和具有5-60个核原子的杂芳基;
n和m各自独立地为0-5的整数,前提是n和m不能同时为0;
当X或Y有多个时,多个X或Y之间是彼此相同或不同的;并且
每个R’和R”中的芳基磺酰是未取代或经至少一个选自下组的取代基取代的:氘、卤素、和硝基。
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CN101528210A (zh) * | 2006-12-07 | 2009-09-09 | 首尔大学校产学协力财团 | 筛选抑制tm4sf5功能的抗癌化合物和含有查耳酮化合物的抗癌组合物的方法 |
US20090252694A1 (en) * | 2006-04-03 | 2009-10-08 | Industry-Academic Cooperation Foundation Gyeongsang National Universtiy | Novel Chalcone Derivatives, Pharmaceutically Acceptable Salt, Method for Preparation and Uses Thereof |
KR20140147619A (ko) * | 2013-06-20 | 2014-12-30 | 이화여자대학교 산학협력단 | 신규한 칼콘 유도체 및 이의 용도 |
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US20090252694A1 (en) * | 2006-04-03 | 2009-10-08 | Industry-Academic Cooperation Foundation Gyeongsang National Universtiy | Novel Chalcone Derivatives, Pharmaceutically Acceptable Salt, Method for Preparation and Uses Thereof |
CN101528210A (zh) * | 2006-12-07 | 2009-09-09 | 首尔大学校产学协力财团 | 筛选抑制tm4sf5功能的抗癌化合物和含有查耳酮化合物的抗癌组合物的方法 |
KR20140147619A (ko) * | 2013-06-20 | 2014-12-30 | 이화여자대학교 산학협력단 | 신규한 칼콘 유도체 및 이의 용도 |
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