CN107072981A - 新型倍半萜烯衍生物及其在炎症以及癌症治疗中的用途 - Google Patents
新型倍半萜烯衍生物及其在炎症以及癌症治疗中的用途 Download PDFInfo
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- CN107072981A CN107072981A CN201580030480.9A CN201580030480A CN107072981A CN 107072981 A CN107072981 A CN 107072981A CN 201580030480 A CN201580030480 A CN 201580030480A CN 107072981 A CN107072981 A CN 107072981A
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Abstract
本发明公开了用于治疗癌性和炎性疾病的一类新型倍半萜烯衍生物。这些去氧地胆草素衍生物有效抑制患者癌细胞的增殖、迁移、移动、侵袭、生长和/或转移,或用于增强另一种抗癌药物在治疗患者时对癌细胞的抗增殖效果,或用于敏化和/或增强谷胱甘肽合成阻滞剂抑制三阴性乳腺癌细胞活性的抗癌效果、或用于治疗和/或预防患者的脂多糖刺激的炎性反应、或用于所有以上各项。本发明还公开了制备该去氧地胆草素衍生物的方法。
Description
技术领域
本发明总体上涉及倍半萜烯(sesquiterpene)衍生物,更具体涉及去氧地胆草素(deoxyelephantopin)衍生物。
背景技术
植物化合物由于其低毒性,但对癌症抑制有效的潜在优势,因此对其鉴定和确认已变成药学的重要方面。对于开发用于癌症疾病的新的治疗剂或预防剂的迫切需求刺激了对具有新的作用方式或改进的效能的生物活性植物化合物或它们衍生的类似物的研究。
美国专利第8,754,121号公开了去氧地胆草素(DET)及其类似物用于黑色素瘤治疗的用途。
发明内容
在一方面,本发明涉及式(I)的化合物
或其药学上可接受的盐,
其中R1选自氢、-羰基(C1-C8)烷基(C1-C8)烷叉基、-羰基(C1-C8)烷基(C1-C8)烷叉基(C1-C8)烷基、-羰基(C1-C8)烷叉基(C6-C20)芳基、-羰基(C1-C8)烷叉基(C1-C8)烷氧基(C6-C20)芳基、-羰基(C1-C8)烷叉基、-羰基(C1-C8)卤代烷基、-羰基(C1-C8)烷基、-羰基(C1-C8)烷基OCO(C1-C8)烷基、-羰基(C1-C8)烷叉基(C1-C8)烷基(C1-C8)烷叉基、-羰基(C1-C8)链烷醇(C1-C8)烷基、-羰基(C1-C8)烷叉基(C1-C8)烷基(C6-C20)芳基、-羰基(C1-C8)烷叉基卤代(C6-C20)芳基、-羰基(C1-C8)烷叉基(C3-C8)杂芳基、-羰基(C6-C20)芳基、-羰基(C1-C8)烷氧基(C6-C20)芳基、-羰基(C1-C8)烷基(C6-C20)芳基、-羰基卤代(C6-C20)芳基、-羰基(C3-C8)环烷基、(C1-C8)烷叉基(C1-C8)卤代烷基(C6-C20)芳基,以及-羰基(C1-C8)烷基(C1-C8)烷氧基(C6-C20)芳基。
在本发明的一个实施方式中,R1为氢、-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-(4-甲氧基苯基)、-CO-(4-甲基苯基)、-CO-(4-溴苯基)、-CO-CH2-萘-1-基、-CO-环丙基、-CO-环戊基、-CO-环己基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、或-CO-CH2-(萘-1-基)(C-6差向异构体)。
在本发明的另一个实施方式中,所述化合物选自在表2和6中列出的59个化合物。
在另一方面,本发明涉及制备式(I)的化合物或其药学上可接受的盐的方法,
其中R1选自氢、-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-(4-甲氧基苯基)、-CO-(4-甲基苯基)、-CO-(4-溴苯基)、-CO-CH2-萘-1-基、-CO-环丙基、-CO-环戊基、-CO-环己基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、以及-CO-CH2-(萘-1-基)(C-6差向异构体),所述方法包括以下步骤:
(1)使式(II)的化合物
与氢氧化钠水溶液反应以得到式(I)的化合物,
其中R1为氢;以及
(2)使其中R1为氢的式(I)的化合物与1-萘乙酸、偶氮二甲酸二乙酯(DEAD)以及三苯基膦(PPh3)反应以得到其中R1为-CO-CH2-(萘-1-基)的式(I)的化合物;或
(3)使其中R1为氢的式(I)的化合物与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCl)、二甲氨基吡啶(DMAP)以及式(III)的化合物
R2COOH
式(III)
反应,
其中R2选自-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-CH2-萘-1-基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、或-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、以及-CO-CH2-(萘-1-基),
以得到式(I)的化合物,
其中R1选自-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-CH2-萘-1-基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、以及-CO-CH2-(萘-1-基)(C-6差向异构体);或
(4)使其中R1为氢的式(I)的化合物与三乙胺和其中R3为-(4-甲氧基苯基)、-(4-甲基苯基)、-(4-溴苯基)、-环丙基、-环戊基、或环己基的式(IV)的化合物
R3COCl
式(IV)
反应以得到式(I)的化合物,其中R1为-CO-(4-甲氧基苯基)、-CO-(4-甲基苯基)、-CO-(4-溴苯基)、-CO-环丙基、-CO-环戊基、或-CO环己基。
再一个方面,本发明涉及一种组合物,其包含有效量的前述化合物或其药学上可接受的盐、以及药学上可接受的稀释剂或载体。
再一个方面,本发明涉及治疗有效量的前述化合物或其药学上可接受的盐在制造用于抑制患者癌细胞的增殖、迁移、移动、侵袭、生长和/或转移,或用于增强另一种抗癌药物在治疗患者时对癌细胞的抗增殖效果,或用于敏化和/或增强谷胱甘肽合成阻滞剂抑制三阴性乳腺癌细胞活性的抗癌效果、或用于治疗和/或预防患者的脂多糖刺激的炎性反应、或用于所有以上各项的药剂中的用途。
或者,本发明涉及治疗有效量的前述化合物或其药学上可接受的盐,其用于抑制患者癌细胞的增殖、迁移、移动、侵袭、生长和/或转移,或用于增强另一种抗癌药物在治疗患者时对癌细胞的抗增殖效果,或用于敏化和/或增强谷胱甘肽合成阻滞剂抑制三阴性乳腺癌细胞活性的抗癌效果、或用于治疗和/或预防患者的脂多糖刺激的炎性反应、或用于所有以上各项。
还或者,本发明涉及抑制患者癌细胞的增殖、迁移、移动、侵袭、生长和/或转移的方法,和/或增强另一种抗癌药物在治疗患者时对癌细胞的抗增殖效果的方法,和/或敏化和/或增强谷胱甘肽合成阻滞剂抑制三阴性乳腺癌细胞活性的抗癌效果的方法,和/或用于治疗和/或预防患者的脂多糖刺激的炎性反应的方法。
所述方法包括向患者施用治疗有效量的前述化合物或其药学上可接受的盐。所述施用步骤可进一步包括向患者施用有效量的另一种选自以下各项的抗癌药物:PLX4032、丁胱亚磺酰亚胺(buthionine sulfoximine)、柳氮磺吡啶紫杉醇(sulfasalazinepaclitaxel)、多西他赛(docetaxel)、顺铂(cisplatin)、奥沙利铂(oxaliplatin)、桦木酸(betulinic acid)、4-S-半胱胺基儿茶酚(4-S-cysteaminyl catechol)、4-S-半胱胺基苯酚(4-S-cysteaminyl phenol)、依维莫司(everolimus)、硼替佐米(bortezomib)、卡铂(carboplatin)、达卡巴嗪(dacarbazine)、塞来昔布(celecoxib)、替莫唑胺(temozolomide)、索拉菲尼(sorafenib)、沙利度胺(thalidomide)、来那度胺(lenalidomide)、丙戊酸(valproic acid)、长春碱(vinblastine)、甲磺酸伊马替尼(imatinib mesylate)、波生坦(bosentan)、apomine、三氧化二砷(arsenic trioxide)、卡莫司汀(carmustine)、兰布鲁唑(lambrolizuma)、抗CTLA-4药物、抗PD-1药物、易普利姆玛(ipilimumab)、多柔比星(doxorubicin)、MEK抑制剂、卡培他滨(capecitabine)、PARP抑制剂和他莫昔芬(tamoxifen)。可以向患者同时施用或顺序施用所述另一种抗癌药物。
所述脂多糖刺激的炎性反应可与选自炎症性皮肤病、炎性肠病、过敏性肺病、哮喘、过敏性鼻炎、自身免疫性疾病、急性和慢性炎性疾病、干燥综合征、人免疫缺陷病毒感染和癌症的炎性疾病相关。
所述谷胱甘肽合成阻滞剂可为γ-谷氨酰半胱氨酸合成酶抑制剂或半胱氨酸/谷氨酸转运体抑制剂。
所述另一种抗癌药物可选自PLX4032、丁胱亚磺酰亚胺、柳氮磺吡啶紫杉醇、多西他赛、顺铂、奥沙利铂、桦木酸、4-S-半胱胺基儿茶酚、4-S-半胱胺基苯酚、依维莫司、硼替佐米、卡铂、达卡巴嗪、塞来昔布、替莫唑胺、索拉菲尼、沙利度胺、来那度胺、丙戊酸、长春碱、甲磺酸伊马替尼、波生坦、apomine、三氧化二砷、卡莫司汀、兰布鲁唑、抗CTLA-4药物、抗PD-1药物、易普利姆玛、多柔比星、MEK抑制剂、卡培他滨、PARP抑制剂和他莫昔芬。
在本发明的一个实施方式中,所述药剂显示与另一种抗癌药物的协同作用。
所述癌症可选自乳腺癌、黑色素瘤、耐药性黑色素瘤、脑肿瘤、肺癌、淋巴瘤、神经上皮瘤、肾癌、前列腺癌、胃癌、结肠癌和子宫癌。
在又一方面,本发明涉及治疗有效量的前述化合物或其药学上可接受的盐以及治疗有效量的选自PLX4032、丁胱亚磺酰亚胺、柳氮磺吡啶紫杉醇、多西他赛、顺铂、奥沙利铂、桦木酸、4-S-半胱胺基儿茶酚、4-S-半胱胺基苯酚、依维莫司、硼替佐米、卡铂、达卡巴嗪、塞来昔布、替莫唑胺、索拉菲尼、沙利度胺、来那度胺、丙戊酸、长春碱、甲磺酸伊马替尼、波生坦、apomine、三氧化二砷、卡莫司汀、兰布鲁唑、抗CTLA-4药物、抗PD-1药物、易普利姆玛、多柔比星、MEK抑制剂、卡培他滨、PARP抑制剂和他莫昔芬的另一种抗癌剂在制造用于抑制患者的癌细胞的增殖、迁移、侵袭和/或转移的联合疗法的药剂中的用途。
这些以及其他方面将由下面的结合以下附图的优选实施方式的描述而变得显而易见,虽然在不脱离本公开的新理念的精神和范围的情况下可以对本文做出变化和修改。
附图与书面的说明书一起说明本发明的一个或多个实施方式,用于解释本发明的原理。只要可能,在整个附图中使用相同的附图标记来指代实施方式的相同的或类似的元素。
附图说明
图1A-B为显示分别用溶媒、DET、DETD-35以及PTX处理24小时的MDA-MB-231细胞的Boyden小室试验结果的代表性显微照片。(A)迁移试验以及(B)侵袭试验。细胞用DAPI染色。数据为三个独立实验的平均值±SEM。不同的字母表示显著性差异(*P<0.05,单因素方差分析)。
图2A-D显示用DET和DETD-35处理的MDA-MB-231细胞迁移的动力学特征。(A)视频帧的延时序列(Time-lapse sequence)。(B)在图表中显示经历各种处理的细胞的个体轨迹。(C)在整个观测期间以30分钟间隔显示的经历各种处理的细胞的平均迁移速度。(D)经历各种处理12小时后细胞的总迁移距离。数据为平均值±SEM,n≥12。用不同字母标记的条表示显著性差异(P<0.05,单因素方差分析)。
图3A-D显示DET和DETD-35抑制雌性NOD/SCID小鼠的正交各向异性MDA-MB-231乳腺肿瘤生长。(A)动物体重。(B)在有或没有DETD-35(10mg/kg,腹腔内)治疗的情况下在小鼠中所测量的MDA-MB-231肿瘤生长。(C)在第71天的肿瘤和肿瘤大小。(D)分析不同组小鼠的器官指数。
图4A-B显示DETD-35在异种移植SCID小鼠中对MD-MB-231三阴性乳腺肿瘤的肺转移的影响。(A)计算不同治疗组中在肺器官中转移性肺病灶的数目。(B)分析不同治疗组中的器官指数(P<0.05;单因素方差分析)。
图5A-D显示DETD-35和PTX或DETD-39和PTX对MDA-MB-231细胞的化合物-药物联合研究。(A)PTX、DETD-35和DETD-39对细胞增殖的抑制。用指定浓度处理细胞24小时。通过MTT比色法测定细胞活力。(B)条形图显示PTX和DETD-35,以及PTX和DETD-39的联合效应。(C)经典等效应图分析图以及(D)DETD-35或DETD-39与PTX联合处理的协同治疗指数(CI)图。CI<1表示协同作用;CI=1表示相加效应;以及CI>1表示拮抗作用。
图6A-B显示DET和DETD-35能有效降低用丁胱亚磺酰亚胺和氮磺胺吡啶预处理的MDA-MB-231细胞的活力。(A)用丁胱亚磺酰亚胺预处理后用DET和DETD-35抑制MDA-MB-231细胞增殖。用指定浓度的BSO预处理细胞30小时,之后用DET和DETD-35分别以12μM和3μM的浓度处理24小时。通过MTT比色法测定细胞活力。(B)用柳氮磺胺吡啶预处理后用DET和DETD-35抑制MDA-MB-231细胞增殖。用指定浓度的柳氮磺胺吡啶预处理细胞30小时,之后用DET和DETD-35分别以12μM和3μM的浓度处理24小时。通过MTT比色法测定细胞活力。
图7A-D显示用PLX4032和DETD-35抑制A375黑色素瘤细胞增殖。用指定浓度的PLX4032(A)或DETD-35(B)处理细胞72小时。通过MTT比色法测定细胞活力。(C)条形图显示PLX4032与DETD-35的联合效应。(D)DETD-35与PLX4032联合处理的协同治疗指数(CI)图。CI<1表示协同作用;CI=1表示相加效应;以及CI>1表示拮抗作用。
图8A-C显示DETD-35克服A375黑色素瘤细胞对PLX4032的抗性。(A)分别用指定浓度的PLX4032和DETD-35处理A375细胞和A375-R细胞72小时。通过MTT比色法测定细胞活力。(B)在用PLX4032处理的亲本A375细胞以及抗性A375-R细胞中参与MAPK信号通路的关键分子的表达图谱。对用PLX4032处理6小时的两种细胞中的总细胞蛋白进行蛋白质印迹分析。(C)PLX4032(1μM)、DETD-35(1μM和3μM)、MEK抑制剂PD0325901(1μM)、PLX4032+DETD-35或PLX4032+PD联合处理对于A375-R细胞中参与MAPK信号通路的关键分子的效果的蛋白质印迹分析。
图9A-D显示DET或DETD-35单独、或与PLX4032联合对A375黑色素瘤的体内抗肿瘤活性。(A)本研究的实验设计。(B)从各个治疗组分离的肿瘤组织的代表性照片。(C)在用或不用化合物治疗的情况下肿瘤细胞移植33天后的平均肿瘤体积。(D)各个治疗组的平均肿瘤质量。数据为平均值±SEM,n=8。没有共同字母的平均值不同,P<0.05(方差分析)。
图10A-D显示DETD-35克服小鼠异种移植模型中的获得性PLX4032耐药。(A)本研究的实验设计。(B)从各个治疗组分离的肿瘤组织的代表性照片。(C)在用或不用化合物治疗的情况下肿瘤细胞移植33天后的平均肿瘤体积。(D)各个治疗组的平均肿瘤质量。数据为平均值±SEM,n=8。没有共同字母的平均值不同,P<0.05(方差分析)。
图11A-D显示DETD-35减小PLX4032在两阶段皮肤癌变模型中的皮肤副作用。(A)本研究的实验设计。(B)来自各个治疗组的皮肤乳头状瘤的代表性照片。(C)在用DMBA治疗一次,接着每周两次用TPA治疗13周之后,在用或不用化合物治疗的情况下各个治疗组的平均乳头状瘤的数目。(D)各个治疗组的平均乳头状瘤体积。数据为平均值±SEM,n=5。没有共同字母的平均值不同,P<0.05(方差分析)。
图12显示DETD-3的X射线晶体结构。
具体实施方式
定义
在本发明的上下文中,以及在使用每个术语的特定语境中,本说明书中所使用的术语,通常具有其在本领域中的普通的含义。在下文中或在本说明书的其他地方讨论用于描述本发明的某些术语以向从业者提供关于本发明的描述的额外的指引。为了方便起见,某些术语可被强调,例如使用斜体和/或引用符号。强调的使用对于术语的范围及含义没有影响;术语的范围及含义在相同的语境中是相同的,而不论其是否被强调。将理解为,相同的事物可以一种以上方式表达。因此,可使用替代的语言和同义词用于任何一个或多个本文中所讨论的术语,不管术语是否在本文中被详述或讨论不对其设置任何特殊的意义。对某些术语提供同义词。一个或多个同义词的提及不排除其他同义词的使用。在本说明书任何地方的实例(包括本文所讨论的任何术语的实例)的使用仅是说明性的,并且绝不限制本发明或任何示例性的术语的范围和含义。同样,本发明不限于在本说明书中给出的各种实施方式。
除非另外定义,在本文中使用的所有科技术语具有与本发明所属的领域的普通技术人员通常理解的含义相同的含义。在冲突的情况下,本文件,包括定义将适用。
如本文所使用的,“大致”、“约”或“大约”含义通常为在给定值或范围的20%内,优选在10%内,并且更优选在5%内。本文中给出的数值量为近似,含义是如果没有清楚说明,可推知为术语“大致”、“约”或“大约”。
术语“治疗(treating)”或“治疗(treatment)”指代以治愈、减轻、缓解、补救、改善、或预防疾病,疾病症状,或疾病倾向的目的而向对其需要的受试者施用有效量的治疗剂。该受试者可由医疗专业人员基于任何合适的诊断方法的结果来确定。
“有效量”是指赋予接受治疗的受试者治疗效果所需的活性剂的量。如由本领域的技术人员所认识到的,有效剂量将取决于给药途径、辅料使用、以及与治疗处理联合使用的可能性而有所改变,
美国健康与人类服务部食品药品管理局(U.S.Department of Health and HumanServices Food and Drug Administration)所公布的“行业和审核人在临床试验中评估治疗剂在成人健康志愿者中的安全起始剂量指南(Guidance for Industry and ReviewersEstimating the Safe Starting Dose in Clinical Trials for Therapeutics inAdult Healthy Volunteers)”公开了“人体等效剂量”可由以下公式计算得到:
HED=动物剂量mg/kg×(动物体重kg/人体重kg)0.33。
E和Z表示双键构型。R和S表示在分子平面以上和以下的位置。
术语“PLX4032”指代“维罗非尼”。
术语“CTLA-4”指代细胞毒性T-淋巴细胞相关蛋白4。抗CTLA-4药物包括,但不限于易普利姆玛(Ipilimumab)。
术语“PD-1”指代“程序性细胞死亡蛋白1”。抗PD-1药物包括,但不限于纳武单抗(nivolumab)。
MEK抑制剂是抑制丝裂原激活的蛋白激酶激酶酶MEK1和/或MEK2的化学品或药物。它们可被用来影响经常在一些癌症中过于活跃的MAPK/ERK通路。MEK抑制剂包括,但不限于曲美替尼(Trametinib)、司美替尼(Selumetinib)、Binimetinib、PD-325901,考比替尼(Cobimetinib)、CI-1040以及PD035901。
PARP抑制剂是酶—聚腺苷二磷酸-核糖聚合酶(PARP)的抑制剂,它们被开发用于多种适应症;最重要的是治疗癌症。PARP抑制剂包括,但不限于Iniparib、Talazoparib、奥拉帕尼(Olaparib)、瑞卡帕布(Rucaparib)、维利帕尼(Veliparib)、CEP 9722、MK4827以及BGB-290。
本发明还涉及提供预期延长癌症患者寿命的用于治疗癌症以及最小化化疗抗性的佐剂或替代策略和方法。例如,DET衍生物与抗BRAFV600E或与黑色素瘤药物维罗非尼(vemurafenib)的联合干预可以克服耐药性或减小副作用。
实施例
不意图限制本发明的范围,下面给出根据本发明的实施方式的示例性的仪器、装置、方法以及它们相关的结果。注意到为方便读者在实施例中使用小标题或副标题,它们绝不应限制本发明的范围。此外,在本文提出并公开了某些理论;然而,不论对错与否,它们绝不应限制本发明的范围,只要根据本发明实施本发明而不关心任何特殊的作用原理或方案。
材料和方法
试剂
3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)、二甲基亚砜(DMSO)和脂多糖(LPS)购自Sigma化学公司(圣路易斯(St.Louis),密苏里州(MO))、维罗非尼(PLX4032)以及MEK抑制剂(PD0325901)购自Selleckchem公司(休斯顿(Houston),得克萨斯州(TX))。柳氮磺胺吡啶购自Fluka公司(布克斯(Buchs),瑞士)。丁胱亚磺酰亚胺以及其他溶剂或化学品购自Sigma-Aldrich公司或为试剂级。
去氧地胆草素(DET)化合物的制备
全干植物材料地胆草(菊科)用3体积的丙酮提取3天,并重复2~3次,然后用乙酸乙酯(EA)萃取粗提物以得到EA部分。采用己烷(H)/EA洗脱溶剂(H:E/3:1,H:E/1:1以及H:E/1:2,体积/体积)使EA提取物在硅胶柱上层析。通过薄层色谱或通过HPLC分析确认含有DET的部分。通过使用RP-18硅胶柱(5μ,150×4.6mm)并采用55%的MeOH洗脱执行确认DET部分或DET纯度的HPLC条件。收集富含DET的部分并在MPLC系统中在RP-C18柱上采用溶剂洗脱条件:30%甲醇(MeOH),2.5柱体积(CV),30-55%甲醇,5CV以及55%甲醇,9.5CV进行层析。收集富含DET的部分并将其通过旋转蒸发仪蒸发成干燥形式。将干燥的化学粉末溶解在丙酮中得到DET晶体。通过电喷雾电离质谱(ThermoFinnigan LCQ,圣何塞(San Jose),加州(CA),美国)以及1H NMR谱和13C NMR谱(Brüker ADVANCE 500AV)解析并通过与以前发表结果的光谱数据对比来确认DET的结构。
DET衍生物的有机合成
DETD-1:
合成DETD-1并且其结构通过下列方法及其他地方公布的数据得到确认。
DETD-3至DETD-62:
如反应式1所示,DETD-3衍生自DET,而DETD-4至DETD-62衍生自DETD-3。
DETD-3是一种新型C-8内酯DET。该新型C-8内酯衍生物DETD-3的合成涉及用强碱(如NaOH)水解DET之后用酸处理。
步骤:
在0℃下向DET(1.023g)的二噁烷(25mL)溶液中添加1N NaOH水溶液(25mL)。在室温下搅拌该混合物过夜并将其冷却至0℃。用2N HCl水溶液酸化该混合物并搅拌30分钟。用AcOEt接着用5%MeOH/AcOEt提取全液两次。有机层合并,用盐水洗涤,Na2SO4干燥,并真空浓缩。在SiO2上柱层析纯化残留物以得到所述新型C-8内酯DETD-3(0.744g,91%)。
DETD-3的光谱数据:
高分辨质谱:m/z以C15H16O5(M++Na)计算为299.0890,实测299.0883。质子核磁共振(1H-NMR,400MHz,2%CD3OD/CDCl3)σ6.94(1H,s),6.41(1H,dd,J=2.9和1.2Hz),6.32(1H,d,J=2.9Hz),5.47-5.43(1H,m),4.56(1H,br d,J=10.0Hz),4.27(1H,t,J=9.7Hz),4.10(1H,ddd,J=10.7,6.4和1.6Hz),3.19(1H,ddd,J=13.1,3.8和1.6Hz),2.89-2.82(1H,m),2.77(1H,dd,J=13.5和4.7Hz),2.67(1H,dd,J=13.1和10.7Hz),2.57(1H,br d,J=13.5Hz),1.71(3H,d,J=1.4Hz)。碳13核磁共振(13C-NMR,400MHz,DMSO-d6)σ172.9,169.4,155.2,140.3,136.3,127.2,126.2,125.7,80.9,78.5,67.7,50.9,40.5,31.8,19.0。
进行DETD-3的X射线晶体结构分析。图12显示DETD-3的X射线结构。在表1中示出晶体数据和结构精修参数。
表1
从DETD-3制备DET衍生物(DETD)
步骤:
可通过三种标准的方法将DETD-3的C-6位的醇进一步酯化以得到各种酯DETD-4至DETD-62。
[方法A]向DETD-3的二氯甲烷溶液中添加相关的羧酸(RCOOH)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)以及二甲氨基吡啶(DMAP)。将该混合物在室温下搅拌过夜。进行标准分离纯化以得到酯DETD-4至DETD-31、DETD-35、以及DETD-39至DETD-61。
[方法B]向DETD-3的二氯甲烷溶液中添加相关的酰氯(RCOCl)以及三乙基胺。将该混合物在室温下搅拌过夜。进行标准分离纯化以得到相关的酯DETD-32至DETD-34以及DETD-36至DETD-38。
[方法C]在室温下在标准的光延反应条件(Mitsunobu condition)[偶氮二甲酸二乙酯(DEAD)、三苯基膦(PPh3)]下用1-萘乙酸处理DETD-3的四氢呋喃溶液以提供DETD-62(epi-DETD-35)。
R基可为烷基、支链烷基、环烷基、取代的烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、烯基、炔基等。
光谱数据:DETD化合物的质子核磁共振在下文中示出。
DETD-4(方法A):(1H-NMR,400MHz,CDCl3)σ6.93(1H,s),6.40(1H,d,J=2.7Hz),7.516.10(1H,d,J=9.6Hzs),5.94(1H,d,J=2.1Hz),5.65(1H,s),5.45(1H,br s),5.39(1H,t,J=10.0Hz),4.57(1H,d,J=10.0Hz),4.23(1H,dd,J=10.1和6.5Hz),3.28(1H,d,J=13.1Hz),3.15(1H,ddd,J=10.0,6.5和3.3Hz),2.79(1H,dd,J=13.6和4.9Hz),2.68(1H,dd,J=13.1和10.8Hz),2.54(1H,d,J=13.6Hz),1.95(3H,s),1.87(3H,s).
DETD-5(方法A,包括2%的顺式异构体):(1H-NMR,400MHz,CDCl3)σ6.91(1H,s),6.75(1H,dt,J=7.4和1.2Hz),6.39(1H,d,J=2.9Hz),7.515.93(1H,d,J=2.9Hz),5.48-5.40(1H,m),5.39(1H,t,J=10.0Hz),4.46(1H,d,J=10.0Hz),4.23(1H,ddd,J=10.7,6.6和1.6Hz),3.32-3.22(1H,m),3.19-3.02(2H,m),2.78(1H,dd,J=13.5和4.9Hz),2.68(1H,dd,J=13.1和10.8Hz),2.53(1H,d,J=13.5Hz),2.25-2.16(2H,m),1.86(3H,d,J=1.4Hz),1.83(3H,s),1.06(3H,t,J=7.5Hz).
DETD-6(方法A):(1H-NMR,400MHz,CDCl3)σ7.71(1H,d,J=16.0Hz),7.55-7.50(2H,m),7.44-7.38(3H,m),6.94(1H,s),6.41(1H,d,J=9.6Hz),7.516.40(1H,d,J=16.0Hz),6.00(1H,d,J=2.5Hz),5.50-5.44(2H,m),4.51(1H,d,J=10.0Hz),4.25(1H,ddd,J=10.5,6.5和1.6Hz),3.33-3.26(1H,m),3.19-3.11(1H,m),2.80(1H,dd,J=13.5和4.9Hz),2.69(1H,dd,J=13.1和10.7Hz),2.55(1H,d,J=13.5Hz),1.89(3H,d,J=1.4Hz).
DETD-7(方法A):(1H-NMR,400MHz,CDCl3)σ7.61(1H,d,J=15.8Hz),6.93(1H,s),6.74(2H,d,J=9.6Hzs),7.516.41(1H,d,J=2.8Hz),6.31(1H,s),6.27(1H,s),6.00(1H,d,J=2.8Hz),5.52-5.43(2H,m),4.50(1H,d,J=10.1Hz),4.26(1H,ddd,J=10.1,6.6和1.7Hz),3.89(9H,s),3.29(1H,dd,J=13.1和1.7Hz),3.14(1H,ddd,J=13.1,6.6和3.1Hz),2.81(1H,dd,J=13.1和4.8Hz),2.69(1H,dd,J=13.1和10.7Hz),2.54(1H,d,J=13.1Hz),1.89(3H,d,J=1.4Hz).
DETD-8(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),7.516.39(1H,d,J=2.9Hz),5.96(1H,d,J=2.9Hz),5.69(1H,s),5.47-5.41(1H,m),5.52-5.43(2H,m),5.34(1H,t,J=10.0Hz),4.45(1H,d,J=9.6Hz),4.25-4.17(1H,m),3.26(1H,d,J=13.1Hz),3.10-3.01(1H,m),2.78(1H,dd,J=13.1和4.9Hz),2.66(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.1Hz),2.16(3H,s),1.92(3H,s),1.86(3H,s).
DETD-9(方法A):(1H-NMR,400MHz,CDCl3)σ6.95(1H,s),6.50(1H,d,J=2.9Hz),6.19(1H,d,J=2.9Hz),5.93(1H,s),5.50-5.44(1H,m),5.32(1H,t,J=10.1Hz),4.20(1H,ddd,J=10.1,6.5,和1.5Hz),3.28(1H,br d,J=13.1Hz),3.21(1H,ddd,J=13.1,6.3,和3.1Hz),2.83(1H,dd,J=13.1和4.8Hz),2.69(1H,dd,J=13.1和10.7Hz),2.57(1H,d,J=13.1Hz),1.86(3H,d,J=1.2Hz).
DETD-10(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.42(1H,d,J=2.8Hz),5.97(1H,d,J=2.8Hz),5.46-5.42(1H,m),5.28(1H,t,J=10.1Hz),4.42(1H,d,J=10.0Hz),4.16(1H,ddd,J=10.0,6.5,和1.6Hz),3.26(1H,dd,J=13.1和1.6Hz),3.05(1H,ddd,J=13.0,6.2,和3.2Hz),2.79(1H,dd,J=13.1和4.8Hz),2.65(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.1Hz),2.24-2.14(2H,m),2.14-2.03(1H,m),1.84(3H,d,J=1.2Hz),0.93(6H,d,J=6.6Hz).
DETD-11(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,br s),6.50-6.42(1H,m),6.17-5.95(1H,m),5.44(1H,br s),5.31-5.11(1H,m),4.46-4.32(1H,m),4.24-4.15(1H,m),3.26(1H,br d,J=12.9Hz),3.14-3.02(1H,m),2.80(1H,dd,J=13.5和4.9Hz),2.70-2.61(1H,m),2.60-2.51(1H,m),2.06(3H,s),1.84(3H,br s),0.88(3H,t,J=7.6Hz).
DETD-12(方法A):(1H-NMR,400MHz,CDCl3)σ6.91(1H,s),6.40(1H,d,J=2.5Hz),5.96(1H,d,J=2.5Hz),5.63(1H,s),5.46-5.41(1H,m),5.34(1H,t,J=10.1Hz),4.46(1H,d,J=10.1Hz),4.24-4.16(1H,m),3.30-3.22(1H,m),3.10-3.02(1H,m),2.78(1H,dd,J=13.5和4.7Hz),2.66(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.5Hz),2.44-2.34(1H,m),2.12(3H,d,J=1.3Hz),1.86(3H,d,J=1.3Hz),1.07(3H,t,J=6.8Hz).
DETD-13(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.43(1H,d,J=2.8Hz),6.0和5.98(1H,d,J=2.8Hz,1:1),5.46-5.41(1H,m),5.25(1H,t,J=10.1Hz),4.41(1H,d,J=10.3Hz),4.19(1H,dd,J=10.3和6.3Hz),3.07(1H,ddd,J=13.1,6.4和3.3Hz),2.79(1H,dd,J=13.5和4.9Hz),2.66(1H,dd,J=13.1和10.5Hz),2.53(1H,d,J=13.5Hz),2.40-2.30(1H,m),1.84(3H,brs),1.72-1.58(1H,m),1.55-1.40(1H,m),1.13和1.12(3H,d,J=7.0Hz,1:1),0.88和0.87(3H,t,J=7.4Hz,1:1).
DETD-14(方法A):(1H-NMR,400MHz,CDCl3)σ6.93(1H,s),6.48-6.32(1H,m),6.06-5.88(1H,m),5.44(1H,br s),5.40-5.20(1H,m),5.16-5.01(1H,m),4.51-4.39(1H,m),4.24-4.13(1H,m),3.29-3.20(1H,m),3.14-3.00(1H,m),2.84-2.50(4H,m),2.17和2.14(3H,br s),1.86和1.83(3H,br s),1.99-1.56(10H,m).
DETD-16(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.44(1H,dd,J=3.1和0.8Hz),6.02(1H,dd,J=2.6和0.8Hz),5.46-5.41(1H,m),5.26(1H,t,J=10.1Hz),4.40(1H,br d,J=10.1Hz),4.18(1H,ddd,J=10.1,6.3和1.7Hz),3.26(1H,dd,J=13.0和2.2Hz),3.07(1H,ddd,J=13.0,6.1和3.0Hz),2.79(1H,dd,J=13.5和4.6Hz),2.65(1H,dd,J=13.0和10.7Hz),2.53(1H,br d,J=13.5Hz),2.22-2.14(1H,m),1.85(3H,d,J=1.4Hz),1.66-1.44(4H,m),0.86(3H,t,J=1.4Hz),0.85(3H,t,J=1.4Hz).
DETD-17(方法A):(1H-NMR,400MHz,CDCl3)σ6.93(1H,s),6.43(1H,dd,J=3.1和0.8Hz),5.96(1H,dd,J=2.7和0.8Hz),5.47-5.42(1H,m),5.28(1H,t,J=10.0Hz),4.44(1H,br d,J=10.0Hz),4.18(1H,ddd,J=10.7,6.4和1.7Hz),3.27(1H,ddd,J=13.3,3.8和1.7Hz),3.05(1H,ddd,J=13.0,6.4和3.1Hz),2.79(1H,dd,J=13.5和4.9Hz),2.65(1H,dd,J=13.0和10.7Hz),2.53(1H,br d,J=13.5Hz),2.06(3H,s),1.83(3H,d,J=1.4Hz).
DETD-18(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.43(1H,d,J=3.1Hz),5.97(1H,d,J=2.7Hz),5.46-5.41(1H,m),5.28和5.27(1H,t,J=10.0Hz,1:1),4.42(1H,d,J=10.0Hz),4.18(1H,dd,J=10.6和6.1Hz),3.26(1H,br d,J=13.3Hz),3.09-3.01(1H,m),2.79(1H,dd,J=13.5和4.8Hz),2.65(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.5Hz),2.32和2.28(1H,dd,J=15.0和6.1Hz,1:1),2.14-2.03(1H,m),1.92-1.80(1H,m),1.84(3H,d,J=1.2Hz),1.39-1.15(4H,m),0.92-0.85(6H,m).
DETD-19(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.40(1H,d,J=3.1Hz),6.12(1H,d,J=0.6Hz),5.93(1H,d,J=2.7Hz),5.61(1H,d,J=1.4Hz),5.47-5.42(1H,m),5.41(1H,t,J=10.0Hz),4.47(1H,d,J=10.0Hz),4.23(1H,ddd,J=10.5,6.5和1.7Hz),3.28(1H,dd,J=13.3和1.8Hz),3.14(1H,ddd,J=12.8,6.5,和3.3Hz),2.79(1H,dd,J=13.5和4.9Hz),2.68(1H,dd,J=13.1和10.6Hz),2.53(1H,d,J=13.5Hz),2.38-2.26(2H,m),1.86(3H,d,J=1.4Hz),1.07(3H,t,J=7.4Hz).
DETD-20(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,br s),6.44(1H,d,J=3.1Hz),6.02-5.96(1H,m),5.46-5.42(1H,m),5.24和5.23(1H,t,J=10.1Hz,1:1),4.40(1H,d,J=9.8Hz),4.18(1H,dd,J=9.8和6.4Hz),3.27(1H,dd,J=13.1和1.6Hz),3.12-3.04(1H,m),2.79(1H,dd,J=13.6和4.8Hz),2.66(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.5Hz),2.48-2.36(1H,m),1.84(3H,br s),1.68-1.55(1H,m),1.44-1.22(3H,m),1.13和1.12(3H,d,J=6.9Hz,1:1),0.89(3H,t,J=7.2Hz).
DETD-21(方法A):(1H-NMR,400MHz,CDCl3)σ6.94(1H,br s),6.43(1H,d,J=2.9Hz),6.01(1H,d,J=2.5Hz),5.46-5.42(1H,m),5.26(1H,t,J=10.3Hz),4.40(1H,d,J=10.0Hz),4.22-4.14(1H,m),3.25(1H,dd,J=13.1和1.8Hz),3.12-3.03(1H,m),2.79(1H,dd,J=13.5和4.9Hz),2.66(1H,dd,J=13.1和10.7Hz),2.52(1H,d,J=13.5Hz),2.28-2.20(1H,m),1.85(3H,d,J=1.2Hz),1.69-1.38(4H,m),1.35-1.10(4H,m),0.92-0.81(6H,m).
DETD-22(方法A):(1H-NMR,400MHz,CDCl3)σ6.93(1H,br s),6.43(1H,br d,J=3.1Hz),6.00(1H,br d,J=2.5Hz),5.47-5.42(1H,m),5.24(1H,t,J=10.0Hz),4.41(1H,d,J=10.0Hz),4.18(1H,ddd,J=10.7,6.3和1.6Hz),3.25(1H,dd,J=13.1和2.0Hz),3.07(1H,ddd,J=12.7,6.4,和3.1Hz),2.79(1H,dd,J=13.5和4.8Hz),2.66(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.5Hz),2.45-2.34(1H,m),1.84(3H,d,J=1.4Hz),1.70-1.54(2H,m),143-1.16(4H,m),1.13(3H,d,J=7.0Hz),0.88(3H,t,J=7.0Hz).
DETD-23(方法A):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.45(1H,d,J=3.1Hz),5.99(1H,d,J=2.5Hz),5.48-5.42(1H,m),5.29(1H,t,J=10.1Hz),4.41(1H,br d,J=10.1Hz),4.19(1H,ddd,J=10.1,6.4和1.6Hz),3.76(1H,br s),3.26(1H,dd,J=13.1和2.0Hz),3.12-3.04(1H,m),2.80(1H,dd,J=13.4和4.8Hz),2.66(1H,dd,J=13.1和10.0Hz),2.52(1H,br d,J=13.4Hz),2.40(2H,s),1.98-1.88(2H,m),1.83(3H,d,J=1.4Hz),0.91(6H,t,J=7.3Hz),0.89-0.82(6H,m).
DETD-24(方法A):(1H-NMR,400MHz,CDCl3)σ7.01(1H,dq,J=15.4和6.9Hz),6.93(1H,s),6.39(1H,d,J=3.1Hz),5.94(1H,d,J=2.7Hz),5.83(1H,dd,J=15.4和1.8Hz),5.48-5.42(1H,m),5.38(1H,t,J=10.1Hz),4.46(1H,br d,J=10.0Hz),4.22(1H,ddd,J=10.7,6.6和1.6Hz),3.26(1H,dd,J=13.1和2.0Hz),3.10(1H,ddd,J=12.8,6.6和3.2Hz),2.78(1H,dd,J=13.4和4.9Hz),2.67(1H,dd,J=13.4和10.7Hz),2.53(1H,br d,J=13.4Hz),1.91(3H,dd,J=6.9和1.8Hz),1.85(3H,d,J=1.4Hz).
DETD-25(方法A):(1H-NMR,400MHz,CDCl3)σ7.05(1H,dt,J=15.6和6.4Hz),6.93(1H,s),6.40(1H,dd,J=8.5和3.0Hz),5.96(1H,dd,J=14.6和2.5Hz),5.79(1H,dt,J=15.6和1.7Hz),5.48-5.42(1H,m),5.38(1H,t,J=10.1Hz),4.45(1H,t,J=10.0Hz),4.26-4.15(1H,m),3.31-3.20(1H,m),3.16-3.00(2H,m),2.78(1H,dd,J=13.7和4.9Hz),2.54(1H,br d,J=13.5Hz),2.30-2.20(1H,m),1.85(3H,d,J=1.4Hz),1.08(3H,t,J=7.4Hz).
DETD-26(方法A):(1H-NMR,400MHz,CDCl3)σ7.66(1H,d,J=15.9Hz),7.47(2H,d,J=8.9Hz),6.92(1H,s),6.91(2H,d,J=8.9Hz),6.41(1H,d,J=2.9Hz),6.26(1H,d,J=15.9Hz),6.01(1H,d,J=2.3Hz),5.46(1H,t,J=10.1Hz),5.47-5.43(1H,m),4.50(1H,d,J=10.1Hz),4.25(1H,ddd,J=10.6,6.7和1.7Hz),3.85(3H,s),3.29(1H,br d,J=11.3Hz),3.14(1H,ddd,J=12.8,6,4和3.2Hz),2.80(1H,dd,J=13.4和4.9Hz),2.69(1H,dd,J=13.4和10.6Hz),2.54(1H,d,J=13.4Hz),1.88(3H,d,J=1.4Hz).
DETD-27(方法A):(1H-NMR,400MHz,CDCl3)σ7.67(1H,d,J=16.0Hz),7.41(2H,d,J=8.0Hz),7.20(2H,d,J=8.0Hz),6.93(1H,s),6.41(1H,d,J=2.9Hz),6.34(1H,d,J=16.0Hz),6.00(1H,d,J=2.3Hz),5.46(1H,t,J=10.0Hz),5.48-5.43(1H,m),4.50(1H,d,J=10.0Hz),4.25(1H,ddd,J=10.6,6.7和1.7Hz),3.29(1H,dd,J=13.2和2.0Hz),3.14(1H,ddd,J=12.7,6.3和3.2Hz),2.80(1H,dd,J=13.4和4.8Hz),2.69(1H,dd,J=13.4和10.7Hz),2.54(1H,d,J=13.4Hz),2.38(3H,s),1.88(3H,d,J=1.4Hz).
DETD-28(方法A):(1H-NMR,400MHz,CDCl3)σ7.65(1H,d,J=15.8Hz),7.45(2H,d,J=8.6Hz),7.37(2H,d,J=8.6Hz),6.93(1H,s),6.41(1H,d,J=3.1Hz),6.37(1H,d,J=16.0Hz),5.98(1H,d,J=2.1Hz),5.46(1H,t,J=10.1Hz),5.48-5.43(1H,m),4.50(1H,d,J=10.0Hz),4.25(1H,ddd,J=10.7,6.6和1.6Hz),3.29(1H,br d,J=11.2Hz),3.14(1H,ddd,J=12.7,6.4和3.2Hz),2.80(1H,dd,J=13.4和4.9Hz),2.69(1H,dd,J=13.4和10.7Hz),2.54(1H,d,J=13.4Hz),2.38(3H,s),1.88(3H,d,J=1.4Hz).
DETD-29(方法A):(1H-NMR,400MHz,在CDCl3中的3%CD3OD)σ7.51(1H,s),7.43(1H,d,J=16.0Hz),6.96(1H,br s),6.65(1H,d,J=3.1Hz),6.52-6.48(1H,m),6.41(1H,d,J=3.1Hz),6.28(1H,d,J=16.0Hz),6.01(1H,d,J=2.5Hz),5.50-5.41(2H,m),5.48-5.44(1H,m),4.50(1H,d,J=10.1Hz),4.24(1H,dd,J=10.5和6.4Hz),3.27(1H,d,J=12.8Hz),3.19-3.10(1H,m),2.80(1H,dd,J=13.7和5.0Hz),2.70(1H,dd,J=12.8和11.0Hz),2.55(1H,d,J=13.7Hz),1.88(3H,s).
DETD-30(方法A):(1H-NMR,400MHz,CDCl3)σ7.81(1H,dd,J=3.8和1.2Hz),7.60(1H,dd,J=5.0和1.2Hz),7.14(1H,dd,J=5.0和3.8Hz),6.94(1H,br s),6.41(1H,d,J=3.1Hz),6.08(1H,d,J=2.5Hz),5.51(1H,t,J=10.1Hz),5.48-5.44(1H,m),4.55(1H,br d,J=10.0Hz),4.26(1H,ddd,J=10.7,6.5和1.6Hz),3.30(1H,br d,J=13.2Hz),3.23(1H,ddd,J=12.8,6.4和3.1Hz),2.80(1H,dd,J=13.5和4.9Hz),2.71(1H,dd,J=13.1和10.7Hz),2.54(1H,d,J=13.5Hz),1.90(3H,d,J=1.4Hz).
DETD-31(方法A):(1H-NMR,400MHz,CDCl3)σ8.04-7.99(2H,m),7.63-7.58(1H,m),7.48(1H,d,J=8.0Hz),7.46(1H,d,J=7.4Hz),6.95(1H,br s),6.36(1H,d,J=3.3Hz),5.97(1H,d,J=2.7Hz),5.60(1H,t,J=10.0Hz),5.48-5.44(1H,m),4.55(1H,br d,J=10.0Hz),4.26(1H,ddd,J=10.5,6.5和1.6Hz),3.35-3.22(2H,m),2.80(1H,dd,J=13.5和4.9Hz),2.72(1H,dd,J=13.3和10.7Hz),2.53(1H,d,J=13.3Hz),1.92(3H,d,J=1.4Hz).
DETD-32(方法B):(1H-NMR,400MHz,CDCl3)σ7.96(2H,d,J=8.0Hz),6.97-6.92(3H,m),6.35(1H,d,J=2.9Hz),5.96(1H,d,J=2.3Hz),5.58(1H,t,J=10.0Hz),5.48-5.43(1H,m),4.55(1H,d,J=10.0Hz),4.29(1H,dd,J=9.4和7.1Hz),3.31(1H,d,J=12.7Hz),3.28-3.18(1H,m),2.80(1H,dd,J=13.5和4.9Hz),2.72(1H,dd,J=12.9和10.7Hz),2.54(1H,d,J=13.5Hz),1.91(3H,br s).
DETD-33(方法B):(1H-NMR,400MHz,CDCl3)σ7.89(2H,d,J=8.2Hz),7.26(2H,d,J=8.0Hz),6.94(1H,s),6.35(1H,d,J=3.1Hz),5.96(1H,d,J=2.7Hz),5.58(1H,t,J=10.0Hz),5.49-5.43(1H,m),4.55(1H,d,J=10.0Hz),4.29(1H,ddd,J=10.6,6.7,和1.6Hz),3.36-3.27(1H,m),3.24(1H,ddd,J=12.8,6.4,和3.1Hz),2.80(1H,dd,J=13.6和4.8Hz),2.72(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.5Hz),2.42(3H,s),1.91(3H,d,J=1.4Hz).
DETD-34(方法B):(1H-NMR,400MHz,CDCl3)σ7.86(2H,d,J=8.6Hz),7.62(2H,d,J=8.4Hz),6.94(1H,s),6.35(1H,d,J=2.9Hz),5.89(1H,d,J=2.7Hz),5.59(1H,t,J=10.1Hz),5.48-5.44(1H,m),4.54(1H,d,J=10.1Hz),4.29(1H,dd,J=9.5和6.7Hz),3.31(1H,br d,J=13.5Hz),3.28-3.20(1H,m),2.81(1H,dd,J=13.5和4.7Hz),2.72(1H,dd,J=13.1和10.9Hz),2.53(1H,d,J=13.3Hz),1.91(3H,d,J=1.0Hz).
DETD-35(方法A):(1H-NMR,400MHz,CDCl3)σ7.91-7.84(2H,m),7.81(1H,d,J=8.0Hz),7.51(1H,d,J=9.6Hz),7.53-7.50(1H,m),7.44(1H,t,J=8.0Hz),7.37(1H,d,J=6.4Hz),6.85(1H,s),5.88(1H,d,J=3.1Hz),5.44-5.38(1H,m),5.20(1H,t,J=10.0Hz),5.06(1H,d,J=2.7Hz),4.33(1H,d,J=10.0Hz),4.13-4.00(1H,m),4.07(2H,d,J=10.8Hz),3.18(1H,br d,J=12.9Hz),2.93-2.86(1H,m),2.77(1H,dd,J=13.4和4.8Hz),2.55(1H,dd,J=12.9和10.8Hz),2.50(1H,d,J=13.4Hz),1.81(3H,d,J=1.0Hz).
DETD-36(方法B):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.44(1H,d,J=3.1Hz),6.04(1H,d,J=2.7Hz),5.49-5.41(1H,m),5.31(1H,t,J=10.0Hz),4.46(1H,d,J=10.0Hz),4.24-4.15(1H,m),3.26(1H,br d,J=11.7Hz),3.14-3.03(1H,m),2.78(1H,dd,J=13.5和4.7Hz),2.66(1H,dd,J=13.1和10.7Hz),2.54(1H,d,J=13.5Hz),1.81(3H,d,J=1.4Hz),1.64-1.52(1H,m),1.05-0.86(4H,m).
DETD-37(方法B):(1H-NMR,400MHz,CDCl3)σ6.92(1H,s),6.43(1H,dd,J=3.1和0.8Hz),6.00(1H,dd,J=2.7和0.8Hz),5.46-5.41(1H,m),5.24(1H,t,J=10.0Hz),4.42(1H,d,J=10.0Hz),4.18(1H,ddd,J=10.7,6.4和1.6Hz),3.26(1H,dd,J=13.1和2.2Hz),3.10-3.02(1H,m),2.79(1H,dd,J=13.5和4.9Hz),2.74-2.66(1H,m),2.65(1H,dd,J=13.1和10.6Hz),2.54(1H,d,J=13.1Hz),1.84(3H,d,J=1.6Hz),1.93-1.84(1H,m),1.80-1.63(4H,m),1.63-1.55(2H,m).
DETD-38(方法B):(1H-NMR,400MHz,CDCl3)σ6.91(1H,s),6.43(1H,dd,J=2.9和0.8Hz),5.98(1H,dd,J=2.5和0.8Hz),5.46-5.41(1H,m),5.25(1H,t,J=10.0Hz),4.40(1H,d,J=10.0Hz),4.18(1H,ddd,J=10.7,6.4和1.6Hz),3.30-3.22(1H,m),3.06(1H,ddd,J=13.1,6.4和3.0Hz),2.78(1H,dd,J=13.5和4.7Hz),2.65(1H,dd,J=13.1和10.7Hz),2.53(1H,d,J=13.1Hz),2.32-2.21(1H,m),1.92-1.80(2H,m),1.83(3H,d,J=1.4Hz),1.80-1.71(2H,m),1.49-1.18(6H,m).
DETD-39(方法A):(1H-NMR,400MHz,CDCl3)σ7.66(1H,d,J=15.9Hz),7.32(1H,t,J=8.0Hz),7.11(1H,d,J=7.8Hz),7.05-7.01(1H,m),6.96(1H,dd,J=8.0和2.5Hz),6.93(1H,br s),6.41(1H,d,J=2.9Hz),6.38(1H,d,J=15.9Hz),6.00(1H,d,J=2.9Hz),5.45(1H,t,J=10.1Hz),4.50(1H,d,J=10.1Hz),4.25(1H,ddd,J=10.5,6.6和1.6Hz),3.84(3H,s),3.29(1H,br d,J=13.0Hz),3.19-3.11(1H,m),2.80(1H,dd,J=13.3和4.9Hz),2.69(1H,dd,J=13.3和10.5Hz),2.54(1H,d,J=13.3Hz),1.89(3H,d,J=1.2Hz).
DETD-40(方法A):(1H-NMR,400MHz,CDCl3)σ7.70(1H,d,J=7.8Hz),7.58(1H,d,J=8.4Hz),7.56(1H,s),7.49(1H,dd,J=8.4和7.8Hz),7.34(1H,t,J=7.8Hz),6.95(1H,s),6.43(1H,d,J=3.1Hz),6.20(1H,d,J=2.7Hz),5.58(1H,t,J=10.1Hz),5.49-5.44(1H,m),4.59(1H,d,J=10.1Hz),4.33-4.24(1H,m),3.36-3.24(2H,m),2.82(1H,dd,J=13.5和4.9Hz),2.72(1H,dd,J=13.1和10.7Hz),2.56(1H,d,J=13.5Hz),1.93(3H,br s).
DETD-41(方法A):(1H-NMR,400MHz,CDCl3)σ8.07(1H,s),7.89(1H,d,J=7.8Hz),7.87(1H,d,J=7.8Hz),7.50(1H,dt,J=7.8和1.2Hz),7.42(1H,dt,J=7.8和1.2Hz),6.96(1H,s),6.43(1H,d,J=3.1Hz),6.14(1H,d,J=2.5Hz),5.56(1H,t,J=10.0Hz),5.49-5.44(1H,m),4.58(1H,d,J=10.0Hz),4.27(1H,ddd,J=10.7,6.4和1.5Hz),3.35-3.23(2H,m),2.82(1H,dd,J=13.7和4.9Hz),2.72(1H,dd,J=13.1和10.7Hz),2.56(1H,d,J=13.5Hz),1.92(3H,d,J=1.4Hz).
DETD-42(方法A):(1H-NMR,400MHz,CDCl3)σ7.79(1H,d,J=15.7Hz),7.41(1H,d,J=5.1Hz),7.27(1H,d,J=5.1Hz),7.07(1H,dd,J=5.1和3.7Hz),6.93(1H,br s),6.41(1H,d,J=3.1Hz),6.18(1H,d,J=15.7Hz),5.99(1H,t,J=2.7Hz),5.45(1H,t,J=10.0Hz),5.47-5.42(1H,m),4.48(1H,d,J=10.0Hz),4.24(1H,dd,J=9.3和6.5Hz),3.27(1H,br d,J=13.3Hz),3.17-3.08(1H,m),2.80(1H,dd,J=13.5和5.0Hz),2.69(1H,dd,J=13.3和10.7Hz),2.54(1H,d,J=13.5Hz),1.87(3H,br s).
DETD-43(方法A):(1H-NMR,400MHz,CDCl3)σ7.36-7.26(3H,m),7.24-7.20(2H,m),6.90(1H,br s),6.18(1H,d,J=2.9Hz),5.47(1H,t,J=2.4Hz),5.44-5.40(1H,m),5.24(1H,t,J=10.0Hz),4.40(1H,d,J=10.0Hz),4.14(1H,ddd,J=10.6,6.3和1.6Hz),3.65(1H,d,J=15.2Hz),3.60(1H,d,J=15.2Hz),3.23(1H,br d,J=13.1Hz),3.01(1H,ddd,J=12.8,6.3和3.0Hz),2.78(1H,dd,J=13.5和4.9Hz),2.62(1H,dd,J=13.1和10.7Hz),2.52(1H,d,J=13.5Hz),1.83(3H,d,J=1.5Hz).
DETD-44(方法A):(1H-NMR,400MHz,CDCl3)σ7.13(2H,d,J=8.5Hz),6.90(1H,brs),6.86(2H,d,J=8.5Hz),6.22(2H,d,J=3.1Hz),5.53(1H,t,J=2.4Hz),5.43(1H,t,J=2.4Hz),5.46-5.41(1H,m),5.24(1H,t,J=10.0Hz),4.40(1H,d,J=10.0Hz),4.18-4.11(1H,m),3.80(3H,s),3.58(1H,d,J=15.4Hz),3.53(1H,d,J=15.4Hz),3.23(1H,br d,J=13.1Hz),3.02(1H,ddd,J=12.6,6.3和3.1Hz),2.77(1H,dd,J=13.4和4.8Hz),2.63(1H,dd,J=13.1和10.7Hz),2.52(1H,d,J=13.4Hz),1.82(3H,br s).
DETD-45(方法A):(1H-NMR,400MHz,CDCl3)σ7.78(1H,d,J=10.2Hz),7.70(1H,d,J=8.0Hz),7.39(1H,t,J=8.0Hz),7.21(1H,d,J=7.0Hz),7.20-7.15(2H,m),6.86(1H,brs),5.90(1H,d,J=2.8Hz),5.44-5.39(1H,m),5.19(1H,t,J=10.0Hz),5.04(1H,d,J=2.8Hz),4.33(1H,d,J=10.0Hz),4.15-3.99(3H,m),3.93(3H,s),3.18(1H,br d,J=12.5Hz),2.94-2.85(1H,m),2.77(1H,dd,J=13.5和4.8Hz),2.62-2.46(2H,m),1.81(3H,brs).
DETD-46(方法A):(1H-NMR,400MHz,CDCl3)σ7.71(1H,d,J=8.4Hz),7.68(1H,d,J=9.1Hz),7.60(1H,br s),7.29(1H,d,J=8.4Hz),7.18-7.10(2H,m),6.89(1H,br s),6.09(1H,d,J=3.1Hz),5.46(1H,d,J=2.5Hz),5.45-5.40(1H,m),5.26(1H,t,J=10.0Hz),4.40(1H,d,J=10.0Hz),4.14(1H,dd,J=10.0和6.4Hz),3.92(3H,s),3.77(1H,d,J=15.1Hz),3.72(1H,d,J=15.1Hz),3.22(1H,d,J=13.1Hz),3.05-2.95(1H,m),2.77(1H,dd,J=13.3和4.8Hz),2.60(1H,dd,J=13.1和10.8Hz),2.51(1H,d,J=13.3Hz),1.83(3H,br s).
DETD-47(方法A):(1H-NMR,400MHz,CDCl3)σ7.67(1H,d,J=16.0Hz),7.48-7.42(2H,m),7.36(1H,s),7.30-7.25(1H,m),6.96(1H,s),6.42(1H,d,J=16.0Hz),6.42(1H,d,J=2.5Hz),5.99(1H,d,J=2.5Hz),5.49(1H,t,J=10.1Hz),5.47-5.48(1H,m),4.51(1H,d,J=10.8Hz),4.25(1H,dd,J=10.5和6.7Hz),3.28(1H,d,J=13.1Hz),3.18-3.14(1H,m),2.81(1H,dd,J=13.7和4.8Hz),2.71(1H,dd,J=13.1和10.5Hz),2.56(1H,d,J=13.7Hz),1.90(3H,s).
DETD-48(方法A):(1H-NMR,400MHz,CDCl3)σ7.77(1H,s),7.72(1H,d,J=16.2Hz),7.66(1H,d,J=7.8Hz),7.54(1H,t,J=7.8Hz),6.95(1H,s),6.47(1H,d,J=16.2Hz),6.43(1H,d,J=2.8Hz),6.00(1H,d,J=2.8Hz),5.48(1H,t,J=10.0Hz),5.48-5.45(1H,m),4.51(1H,d,J=10.0Hz),4.26(1H,ddd,J=10.5,6.8和2.0Hz),3.30(1H,dd,J=13.2和2.0Hz),3.19-3.12(1H,m),2.82(1H,dd,J=13.7和4.8Hz),2.70(1H,dd,J=13.2和10.5Hz),2.55(1H,d,J=13.3Hz),1.89(3H,d,J=1.4Hz).
DETD-49(方法A):(1H-NMR,400MHz,CDCl3)σ7.64(1H,d,J=15.6Hz),7.11(1H,dd,J=8.3和1.8Hz),7.03(1H,d,J=1.8Hz),6.94(1H,s),6.88(1H,d,J=8.3Hz),6.42(1H,d,J=2.6Hz),6.26(1H,d,J=15.6Hz),6.02(1H,d,J=2.6Hz),5.48(1H,t,J=10.1Hz),5.48-5.45(1H,m),4.50(1H,d,J=10.1Hz),4.26(1H,ddd,J=10.5,6.6和1.8Hz),3.93(3H,s),3.92(3H,s),J=1.3Hz),3.29(1H,dd,J=13.3和1.8Hz),3.18-3.10(1H,m),2.81(1H,dd,J=13.3和5.0Hz),2.70(1H,dd,J=13.3和10.5Hz),2.54(1H,d,J=13.3Hz),1.89(3H,d,J=1.4Hz).
DETD-50(方法A):(1H-NMR,400MHz,CDCl3)σ7.66(1H,d,J=16.0Hz),7.30(1H,t,J=7.7Hz),7.10(1H,d,J=7.7Hz),7.04-7.02(1H,m),6.97-6.93(1H,m),6.94(1H,s),6.421H,d,J=3.0Hz),6.37(1H,d,J=16.0Hz),6.00(1H,d,J=3.0Hz),5.46(1H,t,J=10.1Hz),5.45-5.44(1H,m),4.50(1H,d,J=10.1Hz),4.25(1H,ddd,J=10.8,6.8和1.4Hz),4.06(2H,q,J=7.0Hz),3.29(1H,dd,J=13.3和2.1Hz),3.15(1H,ddd,12,8,6.9和3.5Hz),2.81(1H,dd,J=13.3和4.8Hz),2.70(1H,dd,J=13.3和10.8Hz),2.55(1H,d,J=13.3Hz),1.89(3H,d,J=1.4Hz),1.43(3H,t,J=7.0Hz).
DETD-51(方法A):(1H-NMR,400MHz,CDCl3)σ7.98(1H,d,J=7.8Hz),7.90-7.85(1H,m),7.75(1H,d,J=7.8Hz),7.54(1H,dt,J=6.8和1.3Hz),7.50(1H,dt,J=6.8和1.3Hz),7.38(1H,t,J=6.8Hz),7.31(1H,d,J=6.8Hz),6.87(1H,s),6.19(1H,d,J=2.8Hz),5.65(1H,d,J=2.8Hz),5.43(1H,dd,J=4.6和1.8Hz),5.26(1H,t,J=10.1Hz),4.30(1H,d,J=10.1Hz),4.15(1H,ddd,J=10.5,6.4和1.4Hz),3.40(2H,t,J=7.8Hz),3.26-3.19(1H,m),2.98-2.92(1H,m),2.82-2.73(3H,m),2.61(1H,dd,J=13.3和10.8Hz),2.50(1H,d,J=13.8Hz),1.85(3H,d,J=1.4Hz).
DETD-52(方法A):(1H-NMR,400MHz,CDCl3)σ8.84(1H,dd,J=4.1和1.8Hz),8.16(1H,dd,J=8.3和1.4Hz),7.79(1H,dd,J=8.3和1.4Hz),7.62(1H,d,J=6.7Hz),7.51(1H,dd,J=8.3和6.7Hz),7.42(1H,dd,J=8.3和4.1Hz),6.89(1H,br s),6.25(1H,d,J=2.7Hz),5.95(1H,d,J=2.7Hz),5.43(1H,dd,J=4.8和2.1Hz),5.28(1H,t,J=10.1Hz),4.43(1H,d,J=10.1Hz),4.36(1H,d,J=15.6Hz),4.17(1H,ddd,J=10.8,6.7和1.5Hz),4.10(1H,d,J=15.6Hz),3.24(1H,dd,J=13.1和2.1Hz),3.04(1H,ddd,J=13.1,6.7和3.3Hz),2.78(1H,dd,J=13.2和4.8Hz),2.63(1H,dd,J=13.1和10.8Hz),2.53(1H,d,J=13.2Hz),1.80(3H,d,J=1.4Hz).
DETD-53(方法A):(1H-NMR,400MHz,CDCl3)σ7.70(1H,d,J=8.7Hz),7.69(1H,d,J=8.7Hz),7.57(1H,br s),7.29(1H,dd,J=8.7和1.8Hz),7.16(1H,dd,J=8.7和2.5Hz),7.12(1H,d,J=2.3Hz),6.80(1H,br s),6.26(1H,d,J=2.8Hz),5.69(1H,d,J=2.5Hz),5.40-5.35(1H,m),5.23(1H,t,J=10.0Hz),4.21(1H,d,J=10.0Hz),4.18-4.11(1H,m),3.94(3H,s),3.84(1H,q,J=7.0Hz),3.21(1H,br d,J=13.3Hz),2.95(1H,ddd,J=13.3,6.5和3.1Hz),2.75(1H,dd,J=13.7和4.6Hz),2.57(1H,dd,J=13.3和10.7Hz),2.41(1H,d,J=13.3Hz),1.85(3H,d,J=1.4Hz),1.55(3H,d,J=7.0Hz).
DETD-54(方法A):(1H-NMR,400MHz,CDCl3)σ7.71(1H,d,J=8.3Hz),7.68(1H,d,J=9.0Hz),7.61(1H,br s),7.31-7.26(1H,m),7.16(1H,dd,J=9.0和2.3Hz),7.12(1H,d,J=2.3Hz),6.80(1H,br s),5.56(1H,d,J=2.7Hz),5.47-5.42(1H,m),5.20(1H,t,J=10.1Hz),4.78(1H,d,J=2.7Hz),4.41(1H,d,J=10.1Hz),4.12-4.05(1H,m),3.94(3H,s),3.77(1H,q,J=7.0Hz),3.24-3.16(1H,m),2.94(1H,ddd,J=12.8,6.1和3.1Hz),2.81(1H,dd,J=13.3和4.6Hz),2.63-2.52(2H,m),1.86(3H,d,J=1.4Hz),1.54(3H,d,J=7.0Hz).
DETD-55(方法A):(1H-NMR,400MHz,CDCl3)σ8.25和8.02(1H,d,J=8.7Hz,3:5),7.90-7.82(3H,m),7.68和7.64(1H,d,J=6.9Hz,5:3),7.54-7.36(6H,m),6.81和6.70(1H,br s,3:5),6.01(5/8H,d,J=2.7Hz),5.43-5.25(27/8H,m),5.13和5.11(1H,t,J=10.1Hz,3:5),4.30(3/8H,d,J=2.7Hz),4.26-4.20(5/8H,m),4.09-4.01(1H,m),3.91(5/8H,d,J=10.1Hz),3.17-3.12(3/8H,m),3.11和3.08(3H,s,5:3),2.84-2.68(2H,m),2.54-2.25(2H,m),1.95和1.92(3H,s,5:3),1.85和1.83(3H,d,J=1.4Hz,3:5).
DETD-56(方法A):(1H-NMR,400MHz,CDCl3)σ7.87-7.80(4H,m),7.55-7.49(2H,m),7.42(1H,dd,J=8.5和1.4Hz),6.81(1H,br s),6.22(1H,d,J=3.2Hz),5.78(1H,d,J=2.7Hz),5.40-5.35(1H,m),5.28(1H,t,J=10.1Hz),4.92(1H,s),4.24(1H,d,J=10.1Hz),4.17-4.10(1H,m),3.43(3H,s),3.20(1H,dd,J=13.3和1.8Hz),3.03(1H,ddd,J=12.9,6.5和3.2Hz),2.72(1H,dd,J=13.3和4.7Hz),2.58(1H,dd,J=12.9和10.8Hz),2.38(1H,d,J=13.3Hz),1.81(1H,d,J=1.4Hz).
DETD-57(方法A):(1H-NMR,400MHz,CDCl3)σ7.90-7.81(4H,m),7.58-7.50(2H,m),7.46(1H,dd,J=8.5和1.6Hz),6.87(1H,br s),5.70(1H,d,J=3.2Hz),5.45-5.40(1H,m),5.27(1H,t,J=10.1Hz),5.03(1H,d,J=2.3Hz),4.86(1H,s),4.36(1H,d,J=10.1Hz),4.15-4.07(1H,m),3.37(3H,s),3.20(1H,br d,J=12.8Hz),3.03-2.95(1H,m),2.76(1H,dd,J=13.3和4.8Hz),2.59(1H,dd,J=12.8和10.8Hz),2.48(1H,d,J=13.3Hz),1.84(1H,d,J=1.4Hz).
DETD-58(方法A):(1H-NMR,400MHz,CDCl3)σ7.90-7.85(1H,m),7.68-7.64(1H,m),7.44-7.36(2H,m),7.32(1H,s),6.89(1H,br s),6.07(1H,d,J=2.7Hz),5.45-5.41(1H,m),5.37(1H,d,J=2.3Hz),5.26(1H,t,J=10.1Hz),4.37(1H,d,J=10.1Hz),4.16-4.08(1H,m),3.88(2H,s),3.24-3.17(1H,m),2.97(1H,ddd,J=13.0,6.0和3.2Hz),2.78(1H,dd,J=13.3和4.7Hz),2.60(1H,d,J=13.0Hz),2.51(1H,d,J=13.3Hz),1.84(1H,d,J=1.4Hz).
DETD-59(方法A):(1H-NMR,400MHz,CDCl3)σ7.59(1H,s),7.47(2H,t,J=8.7Hz),7.34-7.28(1H,m),7.25(1H,m),6.90(1H,br s),6.22(1H,d,J=3.2Hz),5.65(1H,d,J=2.3Hz),5.45-5.41(1H,m),5.30(1H,t,J=10.1Hz),4.39(1H,d,J=10.1Hz),4.20-4.09(1H,m),3.70(2H,s),3.22(1H,br d,J=12.8Hz),3.02(1H,ddd,J=12.8,6.4和3.2Hz),2.79(1H,dd,J=13.3和4.7Hz),2.63(1H,dd,J=13.3和10.7Hz),2.51(1H,d,J=13.3Hz),1.84(1H,d,J=1.4Hz).
DETD-60(方法A):(1H-NMR,400MHz,CDCl3)σ7.65(1H,d,J=15.6Hz),7.46(2H,d,J=8.7Hz),6.94(1H,br s),6.89(2H,d,J=8.7Hz),6.41(1H,d,J=2.5Hz),6.25(1H,d,J=15.6Hz),6.01(1H,d,J=2.5Hz),5.46(1H,t,J=10.1Hz),5.48-5.42(1H,m),4.50(1H,d,J=9.6和6.5Hz),4.07(2H,q,J=6.9Hz),3.28(1H,br d,J=11.9z),3.19-3.10(1H,m),2.80(1H,dd,J=13.3和5.0Hz),2.69(1H,dd,J=13.3和10.3Hz),2.54(1H,d,J=13.3Hz),1.89(1H,br s),1.43(3H,t,J=6.9Hz).
DETD-61(方法A):(1H-NMR,400MHz,CDCl3)σ7.60(1H,d,J=16.0Hz),7.06-6.97(2H,m),6.94(1H,br s),6.82(1H,d,J=7.7Hz),6.41(1H,d,J=3.2Hz),6.21(1H,d,J=16.0Hz),6.02(2H,s),6.00(1H,d,J=2.7Hz),5.45(1H,t,J=10.1Hz),5.49-5.43(1H,m),4.50(1H,d,J=10.1Hz),4.28-4.22(1H,m),3.28(1H,br d,J=11.6Hz),3.02(1H,ddd,J=13.0,6.4和3.2Hz),2.80(1H,dd,J=13.3和4.8Hz),2.69(1H,dd,J=13.0和10.7Hz),2.54(1H,d,J=13.3Hz),1.88(1H,d,J=1.4Hz).
DETD-62(方法C):(1H-NMR,400MHz,CDCl3)σ7.96-7.91(1H,m),7.91-7.85(1H,m),7.80(1H,d,J=8.3Hz),7.57-7.47(2H,m),7.43(1H,dd,J=8.3和6.9Hz),7.37(1H,d,J=6.9Hz),7.03(1H,br s),6.20(1H,d,J=3.4Hz),5.84(1H,d,J=16.0Hz),5.45(1H,d,J=3.4Hz),5.27(1H,dd,J=16.0和9.6Hz),5.24-5.17(1H,m),4.44-4.35(1H,m),3.99(2H,s),3.57-3.48(1H,m),3.21(1H,br d,J=13.0Hz),2.83(1H,t,J=12.2Hz),2.56(1H,dd,J=14.6和6.4Hz),2.32(1H,d,J=14.6Hz),2.51(1H,d,J=13.0Hz),1.71(1H,s).
合成的DETD-3至DETD-61的所有侧链结构以及DETD-62的结构在表2和6中总结并列出。
表2
细胞培养
在制造商推荐的介质(补充有10%热灭活的胎牛血清、100单位/mL青霉素以及100μg/mL链霉素)中,37℃下在湿化的5%CO2恒温箱中培养由ATCC(马纳萨斯(Manassas),弗吉尼亚州(VA))获得的小鼠巨噬细胞RAW 264.7,人正常上皮细胞系M10和黑素细胞,包括小鼠B16-F10(N-RAS突变)、人MeWo(B-RAF和N-RAS两者的野生型)、人A375和A2058(B-RAFV600E突变)的黑色素瘤细胞系,以及人SK-Mel-2(N-RAS突变),包括小鼠TS/A(ER+),人MDA-MB-231(ER-,Her2-,PR-)、人MCF-7(ER+,Her2-),人SKBR3(ER-,Her2+),人BT474(ER+,Her2+)的乳腺癌细胞系、脑癌细胞系U-87MG,结肠癌细胞系HCT-116,肾癌细胞系A498,肺癌细胞系PC6,淋巴瘤细胞系U937,神经上皮瘤细胞系SK-N-MC,胃癌细胞系KATOIII和子宫癌细胞系NES-SA。
获得性耐维罗非尼黑色素瘤细胞A375-R产自A375亲本细胞并在与A375细胞相同的条件下生长。
细胞活力试验
将正常细胞或癌细胞(2×103至1×104个细胞/孔)接种在96孔板中过夜,并用不同的化合物处理24小时至72小时。通过基于MTT的比色分析法测定细胞生长。将仅用溶媒(0.5%DMSO)处理的测试细胞的活力定义为100%活力。使用以下公式计算用DETD处理后细胞的存活率:活细胞数(%)=OD570(处理过的细胞培养物)/OD570(溶媒对照)×100。
Boyden小室试验
为了测试DET、DETD-35以及PTX的抗迁移以及抗侵袭效果,进行Boyden小室试验。向小室(6.5mm直径,8mm孔径;Costar,剑桥(Cambridge),马萨诸塞州,美国)的下孔添加10%胎牛血清(FBS)作为化学引诱物并填充包含溶媒(DMSO,0.05%)、DET(2.5μM和4μM)、DETD-35(1.25μM和2.5μM)、或PTX(2.5μM和4μM)的DMEM培养介质。将MDA-MB-231细胞放置在具有含0.1%FBS的介质的上室(每个插入5×104个细胞)。37℃下在5%CO2气氛中培养24小时后,使用棉签从膜的上表面刮除未迁移的细胞,而留在孔中的迁移的细胞被固定并用DAPI溶液(4,6-二脒基-2-苯基吲哚,1μg/ml)染色。通过倒立式荧光显微镜以20×原始的放大率在三个区域中计数迁移的细胞。为了检测化合物的抗侵袭效果,用基底膜基质预涂8-μm的过滤器(每个过滤器30μg)并在37℃下培养2小时,接着进行上述迁移试验的程序。
化合物-药物联合试验
在DETD和PLX4032或DETD和PTX的指定浓度范围内测定DETD与PLX4032之间或DETD与PTX之间的协同作用。简单地说,将细胞(1.5×103至5×103个细胞/孔)接种在96孔板中,并用化合物或药物单独或联合处理24小时至72小时。通过MTT比色法测量细胞增殖。使用等效应图分析法(Isobologram analysis)和Chou-Talalay法测定化合物药物联合的效果。通过协同治疗指数(CI)测定DETD和PLX4032或PTX的相互作用,并且用CompuSyn软件生成CI图。将两种化合物的联合效果归类如下:CI=1表示相加效果,CI<1表示协同作用,以及CI>1表示拮抗作用。
延时显微镜分析
用25μg/mL的纤连蛋白涂布12孔细胞培养板1小时,接着接种在含10%血清的DMEM中的5×104MDA-MB-231细胞。接种后12小时,在配备有带有相衬光学器件的环境舱的倒立式共聚焦显微镜(LSM 510META)上进行延时显微镜实验(每30分钟拍下图像)。使用Metamorph软件(Molecular Devices)的目标跟踪应用,将每30分钟两个连续图像之间12个继发的细胞质心的位移的平均值评价为细胞迁移速度。总共记录24小时内的细胞轨迹。在延时成像/视频录制的开始添加溶媒(DMSO,0.05%)、DET(2.5μM,4μM以及10μM)、以及DETD-35(1.25μM,2.5μM,4μM)进行处理的情况下完成这些试验。
蛋白质印迹分析
从之前所述的测试细胞制备总的细胞蛋白。通过Bradford法(Bio-Rad)测定蛋白浓度。用5%至20%梯度SDS-PAGE溶解蛋白样品之后进行免疫印迹。ERK1/2和GAPDH的第一抗体来自圣克鲁兹生物技术公司(Santa Cruz Biotechnology)(圣克鲁兹(Santa Cruz),加利福尼亚州,美国)以及MEK、phospho-ERK1/2和phospho-MEK来自细胞信号技术公司(Cell Signaling Technology)(丹弗斯(Danvers),马萨诸塞州,美国)。使用合适的辣根过氧化物酶标记的第二抗体。通过使用增强化学发光(Amersham)暴露于化学发光光膜(BioMax公司;柯达公司)使对特异性抗体反应的蛋白条带得到显现。
一氧化氮(NO)产生的检测
用化合物处理巨噬细胞(2×105个细胞/孔,在96孔板中)1小时,接着在培养介质中在存在或不存在100ng/μL LPS的情况下进一步培养24小时。通过格里斯(Griess)反应法测定细胞培养介质中的亚硝酸盐的水平。与格里斯分析法平行,使用基于MTT的比色分析法测定巨噬细胞的细胞活力。
谷胱甘肽生物合成阻滞剂与DET和DETD-35对癌细胞增殖的协同作用
测定谷胱甘肽生物合成阻滞剂(丁胱亚磺酰亚胺(BSO)和柳氮磺胺吡啶)与DET或DETD-35的协同效应。简单地说,将细胞(5×103个细胞/孔)接种在96孔板中,并且用BSO以100μM、45μM、18μM、7.2μM、2.8μM、1.15μM、461nM、184nM、74nM和29nM的浓度,以及柳氮磺胺吡啶以62.75μM、25.10μM、10μM、4μM、1.6μM、642nM、257nM、102nM、41nM和16.4nM的浓度处理30小时,接着在培养介质中加入12μM DET或3μM DETD-35再处理细胞24小时。通过MTT比色法测定细胞增殖。
动物
雌性NOD/SCID小鼠(NOD.CB17-Prkdcscid/IcrCrlBltw)和SCID小鼠(CB17-Prkdcscid/IcrCrlBltw)由Laboratory Animal Core Facility(BioLASCO台湾有限公司)提供并且向其提供自由的标准的实验室饲料以及蒸馏水并在22±2℃下以12小时光/暗周期饲养。所有实验方案均得到中国台湾中央研究院机构动物使用与管理委员会(Institutional Animal Care and Utilization Committee)(IACUC)的批准。
NOD/SCID小鼠中乳腺肿瘤生长的抑制
使用带有MDA-MB-231癌细胞的NOD/SCID小鼠(6周大)研究乳腺肿瘤对DET类似物(DETD-35)的反应。于0天向小鼠的乳腺脂肪垫区域注射在100μL(9.1mg/mL)基质胶(基底膜基质,无酚红)中的5×106MDA-MB-231细胞。使肿瘤在小鼠中生长7天,接着将动物随机分为三个组(n=5,每组):假手术组(sham)、肿瘤(溶媒)对照组以及10mg/kg DETD-35治疗组。每三天腹腔(i.v.)注射DETD-35。在第71天通过颈椎脱位法处死试验小鼠,并收集肿瘤以及使用卡尺并通过公式V=(L×W2)/2计算来测定体积(V),其中L为肿瘤的长度以及W为肿瘤的宽度。
在SCID小鼠中MDA-MB-231细胞肺转移的抑制
将雌性小鼠(5周大,平均体重19.59±1.26g)分为8个组:PTX组(5mg/kg紫杉醇)、DETD-35-2组(2mg/kg DETD-35)、DETD-35-10组(10mg/kg DETD-35)、PTX-5+DETD-35-2组(对于总共11剂量的紫杉醇(PTX)和10剂量的DETD-35,交替施用5mg/kg紫杉醇和2mg/kgDETD-35)、肿瘤(溶媒)组(5%DMSO)以及假手术组(5%DMSO)。预-DETD-35-10组是于0天静脉注射1×106MDA-MB-231肿瘤细胞之前每两天施用10mg/kg DETD-35共3剂量次的小鼠。从第一天开始每三天腹腔注射所有其他药物或化合物。在实验结束时(第71天),通过颈椎脱位法处死试验小鼠。除掉肺、肝、肾、和脾器官,记录重量并计算器官指数(%器官重量/体重)。对试验小鼠肺上的肿瘤集落数进行计数。
体内黑色素瘤异种移植模型
将A375和A375-R黑色素瘤细胞(3×106)皮下注射入六周大的NOD/SCID小鼠的侧腹。接种后一周,随机选取小鼠为治疗组(n=8每组)并开始治疗。使用公式a×b2×0.5每三天记录小鼠的体重和肿瘤体积,其中a和b表示较大和较小肿瘤直径。
两阶段皮肤癌变模型
将六周大的雌性FVB/N小鼠的背部皮肤剃毛并用局部施加DMBA(25μg在100μL丙酮中)来处理。DMBA处理后一周,每周两次用12-O-十四酰佛波醇-13-乙酸酯(TPA)(4μg在100μL丙酮中)局部处理相同的皮肤区域。对该区域定期刮毛并且每周评估两次肿瘤形成,并将肿瘤定义为最小直径为1mm的凸起损伤。
结果
DET和新合成的DETD对乳腺癌细胞增殖的抑制效果
从母体化合物DET衍生出60种DETD并检测它们的抗乳腺癌细胞活性。表3示出通过MTT比色法a分析的DET和DETD分别对小鼠乳癌细胞TS/A(ER+,Her2-)、人类乳腺癌细胞MCF-7(ER+,Her2-)、MDA-MB-231(ER-,Her2-,PR-)以及正常乳腺细胞M10的增殖24小时处理的IC50值(50%细胞增殖抑制)。分别在2.3μM和5.0μM测定DET对于TS/A和MCF-7细胞的IC50,观察到其对于MDA-MB-231细胞作用非常小,IC50=14.0μM。在60种检测的DETD当中,对TS/A细胞、MCF-7细胞以及MDA-MB-231细胞的50%增殖抑制比DET活性好的前三种DETD分别为DETD-39(0.8μM)、-26(1.5μM)、和-35(1.7μM),DETD-6(1.6μM)、-39(2.1μM)、和-7(2.3μM),以及DETD-39(1.9μM)、-34(2.2μM)、和-35(3.5μM)。DETD-6、-26以及-39还对正常乳腺上皮M10细胞显示一些毒性。
表3
a:细胞用化合物处理24小时,并且表中的数值为每种化合物对细胞活力的50%抑制浓度(IC50μM)。
“-”:在高至7.5–10μM的实测浓度下没有检测到IC50。
DET和DETD-35抑制MDA-MB-231细胞迁移和侵袭
使用Boyden小室试验研究DET和DETD-35对MDA-MB-231细胞迁移和侵袭活性的影响,并且PTX为参考对照。图1A显示在处理24小时后DET(2.5μM和4μM),DETD-35(1.25μM和2.5μM)以及PTX(2.5μM和4μM)以浓度相关方式显著抑制细胞迁移。与溶媒对照组相比,高浓度的DET、DETD-35以及PTX极大地减少77%、84%以及88%的细胞迁移,而低浓度的DET、DETD-35以及PTX分别抑制16%、10%以及87%的细胞迁移(P<0.05)。Trans-well侵袭试验进一步揭示DET和DETD-35抑制MDA-MB-231细胞穿过薄基质胶基质的侵袭。高浓度的DET、DETD-35以及PTX显著抑制76%、80%以及90%的细胞侵袭,而低浓度的抗侵袭作用分别为57%、64.6%以及85%(P<0.05)(图1B)。这些数据提示DET及其衍生物DETD-35降低癌细胞迁移以及侵袭基底膜屏障的能力。
对于抑制乳腺癌细胞移动,DETD-35显示比DET更优的效果
使用延时显微镜研究和对比DET和DETD-35对MDA-MB-231细胞移动的效果。监测和分析24小时内在不同的处理条件下迁移的MDA-MB-231细胞的轨迹。观察到溶媒对照细胞以连续运动的方式(0-24小时)活跃地移动并具有强健的膜突出,在24小时内的时间点捕捉到总体细胞增殖(图2A)。如图2B所示,在溶媒对照中观察到从原始面积的最显著的细胞扩散面积,而在用2.5μM DET处理12小时的细胞中观察到由移动受限导致的相对小面积,而在用4μM和10μM DET,或1.25μM、2.5μM和4μM DETD-35处理的细胞中观察到更加减小的细胞轨迹。与溶媒对照细胞和用2.5μM DET处理的细胞相比,在用1.25μM、2.5μM和4μM的DETD-35处理的,或用4μM和10μM的更高浓度的DET处理的细胞中,平均移动速度降低,移动的抑制变得更加显著(图2C)。用2.5μM、4μM、10μM的DET(144μm vs.15μmvs.9μm),或用1.25μM、2.5μM和4μM的DETD-35(70μm vs.23μm vs.3μm)处理的细胞迁移距离比对照(186μM)的细胞迁移距离显著更短(图2D)。这些结果表明DETD-35(一种新合成的倍半萜烯内酯)在抑制MDA-MB-231细胞移动方面显示比DET有力的和更好的生物活性。
DETD-35降低NOD/SCID小鼠中原位乳腺肿瘤的肿瘤生长
评价DETD-35在带有MDA-MB-231癌细胞的异种移植NOD/SCID小鼠中的治疗效力。相比对照组,56天DETD-35(10mg/kg,腹腔)治疗组中肿瘤生长显著延迟(P<0.05)(图3A),而不影响小鼠体重(图3B)。与肿瘤对照组相比,治疗组中在第71天时肿瘤体积减小1.8倍(1268mm3vs.712mm3)(图3C)。计算肺、肝、肾和脾的器官指数(器官重量/体重,%)。肿瘤对照组的肾指数高于假手术组和DETD-35治疗组(图3D)。
DETD-35有力抑制MDA-MB-231细胞的肺转移
将DETD-35对异种移植小鼠中三阴性乳腺癌肿瘤MDA-MB-231的肺转移的预处理和后处理效果与参考化疗药物PTX进行比较。在预处理的预-DETD-35-10组中,小鼠肺中肿瘤灶的数目与肿瘤对照组相比显著减少83%,而用DETD-35-10与PTX-5后处理的抑制效果分别为50%和62%。DETD-35-2治疗没有统计学上的显著效果,肺转移抑制为9%。PTX-5+DETD-35-2交替治疗组与单独治疗相比极大地降低71%的肺肿瘤灶(P<0.05,图4A)。DETD-35-2治疗组的体重比其他组稍低,但没有统计学差异(数据未示出)。肺、肝、肾和脾的器官指数在所有试验动物中无显著性差异(图4B)。
DETD-35或DETD-39与PTX之间对MDA-MB-231细胞的协同作用
为了研究DETD-35和DETD-39是否与PTX对MDA-MB-231细胞活性有协同作用,进行使用MTT试剂的抗增殖试验以得到每个化合物的IC60值。PTX、DETD-35和DETD-39对MDA-MB-231细胞的IC60分别为23.8nM、3.32μM以及3.79μM(图5A)。固定浓度的DETD-35或DETD-39(1μM)与升高浓度的PTX(0nM,2nM,5nM,10nM,15nM,20nM和25nM)的联合处理显示比PXT单独处理更好的癌细胞增殖抑制(图5B)。基于IC60值,使用在0μM至4μM范围内的DETD-35或DETD-39和0nM至25nM的PTX用于化合物-药物联合研究。采用经典等效应图分析法和Chou-Talalay法来研究化合物和药物的协同效应。使用CalcuSyn软件(2.0版,Biosoft)计算协同治疗指数(CI)并表达为CI vs.Fa(影响比例)。CI<1表示协同作用;CI=1表示相加效果;以及CI>1表示拮抗作用。DETD-35或DETD-39与PTX联合协同作用来抑制MDA-MB-231细胞的生长(图5C-D)。
DET和DETD-35增强谷胱甘肽合成阻滞剂对MDA-MB-231细胞的抗增殖作用
我们已观察到由DET诱导的瞬态ROS产生是引发导致癌细胞死亡的级联反应的上游因子之一。γ-谷氨酰半胱氨酸合成酶抑制剂“丁胱亚磺酰亚胺(BSO)”以及半胱氨酸/谷氨酸转运体(xCT)抑制剂“柳氮磺胺吡啶”已知它们的功能是减弱谷胱甘肽介导的抗氧化防御并且被选择用于联合药物效应研究。研究了DET或其类似物(DETD-35)与BSO或柳氮磺胺吡啶之间的协同作用。如果该协同作用存在,其将/可能在防止耐药和/或提高用于治疗癌症的DET/DETD35以及II期药物BSO或临床药柳氮磺胺吡啶的敏感性方面具有巨大的潜力。
BSO和柳氮磺胺吡啶在指定范围的浓度下没有显示对MDA-MB-231细胞的任何细胞毒性,而DET和DETD-35可以敏化两种药的效果。在用BSO或柳氮磺胺吡啶预处理MDA-MB-231细胞30小时后,用固定浓度的DET(12μM)和DETD-35(3μM)处理24小时的细胞的活力可从大致70%和90%进一步降低至1%或检测不到(图6A-B)。观察到0.5μM、3μM以及更高浓度的BSO与DET或DETD-35的协同效应(图6A)。类似地,还观察到25μM、62μM以及更高浓度的柳氮磺胺吡啶与DET或DETD-35的协同效应(图6B)。这个新发现显示与临床药物柳氮磺胺吡啶或II期药物BSO联合使用的DET和DETD-35能够敏化两种化合物药物对抑制三阴性乳腺癌细胞活性的效力。
DET和新合成的DETD对黑色素瘤细胞增殖的抑制效果
几种基因参与黑色素瘤的发展和病理学;具体地,V-raf鼠科肉瘤病毒致病基因同源体B1(B-RAF)突变的发生占恶性黑色素瘤的大约50%-60%,而神经母细胞瘤RAS病毒致病基因同源体(N-RAS)突变的发生占恶性黑色素瘤的约30%。使用包括B16-F10、MeWo、A375、A2058、HTB-68和黑素细胞的一系列野生型或突变型黑色素瘤细胞系来研究亲本植物化合物DET和新合成的DETD的抗黑色素瘤细胞增殖活性。表4显示24小时处理后通过MTT比色法分析的DET及其衍生物(DETD)抑制不同的黑色素瘤细胞系、正常黑素细胞、巨噬细胞增殖的IC50值,以及RAW 264.7细胞a中LPS-诱导的一氧化氮(NO)的产生。不同的细胞系显示对DET和DETD不同的敏感性。DET对B16-F10和A375的IC50为约6μM,但DET在高至10μM的检测浓度下对其他黑色素瘤细胞型没有显示可检测的活性。在检测的60种DETD(DETD-1至DETD-62)当中,DETD-6、-28、-30、-33、-34、-35、-39、-45、-53、-54、-55、56、-58、-60、以及-61能够抑制所有类型的黑色素瘤细胞系,IC50值在1.6~9.9μM之内。DETD-35(IC50=2.5~6.0μM)以及DETD-39(IC50=1.6~3.5μM)显示最有力的抗黑色素瘤细胞增殖效果,但是DETD-39还对正常人黑素细胞显示一些毒性,IC50为9μM。
表4
a:细胞用化合物处理24小时,并且表中的数值为每种化合物对细胞活力的50%抑制浓度(IC50μM)。
b:小鼠细胞系;c:人细胞系
“-”:在高至10μM的实测浓度下IC50没被检测到。
DETD-35与PLX4032对A375黑色素瘤细胞的协同作用
为了研究DETD-35与PLX4032对A375黑色素瘤细胞是否显示协同作用,我们使用MTT试剂进行抗增殖试验来获得每种化合物的IC50。PLX4032和DETD-35对A375细胞的IC50分别为0.07μM和0.85μM(图7A-B)。基于每种化合物的IC50,我们将DETD-35的浓度固定为0.1μM至1μM,PLX4032的浓度固定为10nM至100nM用于化合物-药物联合研究。如上所述通过协同治疗指数(CI)分析来定量协同效应。DETD-35与PLX4032联合产生协同作用从而抑制A375黑色素瘤细胞的生长(图7C-D)。
DETD-35克服A375黑色素瘤细胞对PLX4032的获得性耐药
为研究DETD-35如何克服对BRAF抑制剂的获得性耐药的机理,我们生成了抗PLX4032的A375细胞系(命名为A375-R)。简单地说,将A375黑色素瘤细胞接种在T75板中并用升高浓度的PLX4032处理(20nM,50nM,100nM,250nM,500nM,1000nM,2000nM)经过大约2个月传代20代。我们成功地开发出获得性耐药细胞系A375-R,因为其与亲本细胞系相比对PLX4032超过100倍不敏感(IC50:8.3μM vs.0.07μM;图8A,左图),而DETD-35对A375和A375-R细胞活力显示的效果没有不同,其中DETD-35的IC50对两个细胞系均为0.8μM(图8A,右图)。此外,PLX4032抑制亲本A375细胞中的MAPK信号分子phospho-MEK和phospho-ERK而不抑制A375-R细胞中的MAPK信号分子phospho-MEK和phospho-ERK(图8B)。在用PLX4032处理的A375-R细胞中的MAP激酶的这些再活化进一步确认了抗性细胞系的成功生成。蛋白质印迹分析的结果显示DETD-35抑制A375-R细胞中MAP激酶的再活化(图8C)。DETD-35在与PLX40332联合处理时还抑制MAPK信号分子,提示DETD-35在克服对PLX4032的获得性耐药中的作用。
DETD对各种癌细胞系增殖的结构活性关系
基于DET和DETD对不同的乳腺癌和黑色素瘤细胞系的毒性结果,考虑到结构活性关系,在表5中我们选择DETD-6、-32、-35和-39用来评估它们对具有指定肿瘤源的其他癌型细胞系的抑制效果。除了有效地抑制乳腺癌和黑色素瘤细胞生长以外,四种检测的DETD还显示对脑、肺、淋巴瘤、神经上皮瘤、肾、前列腺、胃、结肠和子宫癌细胞增殖的良好的抑制。观察到DETD-35在不同的癌型中具有最好的抑制作用而对正常细胞系M10、黑素细胞和巨噬细胞没有检测到毒性(表3和4)。因此,DETD-35显示出被进一步开发成为抗癌药物的巨大潜力。DETD-6和-39还显示对不同癌型的活性,但它们还显示出对正常细胞的一些体外毒性。表5显示DET以及选择的DETD在抑制各种癌细胞型的活力中的50%抑制浓度(IC50,μM)。用化合物处理这些细胞24小时接着进行MTT比色分析。
表5
LPS-刺激的巨噬细胞中一氧化氮(NO)产生的抑制
来自革兰氏阴性细菌外膜的LPS可以诱导催化L-精氨酸的氧化脱氨以产生一氧化氮(NO)的诱生型一氧化氮合酶(iNOS)的mRNA或蛋白水平。一旦NO大量产生,其与超氧阴离子相互作用并产生高活性氧化剂导致细胞炎症,DNA、蛋白和组织损伤,癌变以及抗凋亡。我们在RAW264.7细胞体系中使用体外LPS刺激的炎症并通过测定LPS处理后24小时培养介质中亚硝酸盐的水平(与NO水平等价)来评价DET及其衍生物DETD对NO产生的影响。DET本身已是有力的NO抑制剂,其IC50为2.9μM。大多数DETD显示对巨噬细胞中LPS诱导的NO的抑制。效力最好的为DETD-35和DETD-39,IC50值下降2倍和3倍(1.5μM和1.0μM)。DETD-39还显示对正常鼠巨噬细胞RAW 264.7细胞的可检测的毒性,IC50为3.5μM(表4)。
DETD-35单独或与PLX4032联合抑制A375原位异种移植模型中的肿瘤生长
我们使用A375人黑色素瘤异种移植模型来评价DET、DETD-35、PLX4032以及化合物药物联合的体内生物效力。图9A显示体内研究的实验设计。作为单一化合物或药物治疗组,每天腹腔注射PLX4032,每两天腹腔注射DET和DETD-35。作为联合治疗,每两天注射PLX4032,同时每4天注射DET和DETD-35。发现与肿瘤对照组(100%)相比,DET(20mg/kg),DETD-35(20mg/kg)可以抑制肿瘤生长并且分别减少肿瘤质量47.5%和70.5%,与临床药物PLX4032(20mg/kg)等效(71.9%),P<0.001(方差分析)。交替服用DET(20mg/kg)或DETD-35(20mg/kg)和PLX4032(20mg/kg)来进行化合物-药物联合治疗,通过该治疗,DET或DETD-35和PLX4032治疗频率仅为单一化合物或单独药物服用的一半。所有的治疗没有显示对小鼠体重的下降作用(数据未示出)。这些结果显示与单一药剂治疗相似的肿瘤质量抑制效力(72.3%),表明DETD-35与PLX4032在小鼠中的协同作用(图9B-D)。
DETD-35克服小鼠异种移植模型中获得性PLX4032耐药
为研究DETD-35是否可以克服对BRAF抑制剂的获得性耐药,我们生成了如上所述的抗PLX4032的A375细胞系(命名为A375-R)。我们接着进行A375-R原位异种移植研究。图10A显示实验设计。服药途径和剂量与上述关于A375原位肿瘤生长的抑制的研究相同,除了在单一药物治疗中注射75mg/kg的PLX4032,并且在联合治疗中每两天注射单独的DET或DETD-35。我们观察到PLX4032不再显示出抗肿瘤活性,肿瘤生长率和大小与肿瘤对照组相似(对照组中100%vs.PLX4032治疗组中98%),如所预期的那样,细胞系对PLX4032产生抗性。DET(20mg/kg)或DETD-35(20mg/kg)单独可以抑制肿瘤生长并分别使肿瘤质量减少32%(P<0.01)和46.9%(P<0.001)。在治疗组当中,DETD-35和PLX4032的联合展示出对获得性PLX4032耐药黑色素瘤最有效的抗肿瘤生长活性(减少肿瘤质量65.3%,P<0.001),提示DETD-35能够敏化PLX4032的效果(图10B-D)。所有治疗没有显示对小鼠体重的下降作用(数据未示出)。这些结果提示DET和DETD-35单独或与PLX4032联合可以克服体内黑色素瘤的获得性PLX4032耐药。
DETD-35延迟小鼠中PLX4032-诱导的乳头状瘤形成的加速并降低总的乳头状瘤的数目
经常在皮肤鳞状细胞癌和角化棘皮瘤中观察到RAS基因突变,该突变可在用PLX4032治疗的患者中发展。我们使用DMBA/TPA-诱导的皮肤致癌小鼠模型来模仿由PLX4032引起的皮肤副作用从而评价DETD-35是否可以减小PLX4032的皮肤副作用。图11A图示该实验设计。在用DMBA处理小鼠的背部皮肤后一周,每周两次向该皮肤的相同区域施用TPA,同时每周两次分别向不同组的小鼠腹腔注射PLX4032(20mg/kg)、DET(10mg/kg)以及DETD-35(10mg/kg)。在DMBA-TPA处理的小鼠中乳头状瘤的形成在第6-7周之间开始,而PLX4032处理能够使DMBA-TPA治疗的小鼠的乳头状瘤的形成提早到从第3-4周开始。DET(10mg/kg)或DETD-35(10mg/kg)的服用能够延迟PLX4032-诱导的皮肤乳头状瘤形成的加速,还使小鼠中总的乳头状瘤的数目从25.6分别降低至11.7和4.8,并且它们的平均大小从77.6分别降低至26.3mm3和8.9mm3(图11B-D)。所有的治疗没有显示对小鼠体重的下降作用(数据未示出)。这些结果指示DET和DETD-35均能减小PLX4032的皮肤副作用,并且DETD-35在相同的剂量以及方案下优于DET。
表6
Claims (15)
1.一种式(I)的化合物
或其药学上可接受的盐,其中R1选自氢、-羰基(C1-C8)烷基(C1-C8)烷叉基、-羰基(C1-C8)烷基(C1-C8)烷叉基(C1-C8)烷基、-羰基(C1-C8)烷叉基(C6-C20)芳基、-羰基(C1-C8)烷叉基(C1-C8)烷氧基(C6-C20)芳基、-羰基(C1-C8)烷叉基、-羰基(C1-C8)卤代烷基、-羰基(C1-C8)烷基、-羰基(C1-C8)烷基OCO(C1-C8)烷基、-羰基(C1-C8)烷叉基(C1-C8)烷基(C1-C8)烷叉基、-羰基(C1-C8)链烷醇(C1-C8)烷基、-羰基(C1-C8)烷叉基(C1-C8)烷基(C6-C20)芳基、-羰基(C1-C8)烷叉基卤代(C6-C20)芳基、-羰基(C1-C8)烷叉基(C3-C8)杂芳基、-羰基(C6-C20)芳基、-羰基(C1-C8)烷氧基(C6-C20)芳基、-羰基(C1-C8)烷基(C6-C20)芳基、-羰基卤代(C6-C20)芳基、-羰基(C3-C8)环烷基、(C1-C8)烷叉基(C1-C8)卤代烷基(C6-C20)芳基,以及-羰基(C1-C8)烷基(C1-C8)烷氧基(C6-C20)芳基。
2.如权利要求1所述的化合物,其中R1为氢、-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-(4-甲氧基苯基)、-CO-(4-甲基苯基)、-CO-(4-溴苯基)、-CO-CH2-萘-1-基、-CO-环丙基、-CO-环戊基、-CO-环己基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、或-CO-CH2-(萘-1-基)(C-6差向异构体)。
3.如权利要求1所述的化合物,其选自以下化合物:
4.一种制备式(I)的化合物或其药学上可接受的盐的方法
其中R1选自氢、-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-(4-甲氧基苯基)、-CO-(4-甲基苯基)、-CO-(4-溴苯基)、-CO-CH2-萘-1-基、-CO-环丙基、-CO-环戊基、-CO-环己基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、以及-CO-CH2-(萘-1-基)(C-6差向异构体),所述方法包括以下步骤:
(5)使式(II)的化合物
与氢氧化钠水溶液反应以得到式(I)的化合物,
其中R1为氢;以及
(6)使其中R1为氢的式(I)的化合物与1-萘乙酸、偶氮二甲酸二乙酯(DEAD)以及三苯基膦(PPh3)反应以得到其中R1为-CO-CH2-(萘-1-基)的式(I)的化合物;或
(7)使其中R1为氢的式(I)的化合物与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCl)、二甲氨基吡啶(DMAP)以及式(III)的化合物
R2COOH
式(III)
反应,
其中R2选自-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-CH2-萘-1-基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、或-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、以及-CO-CH2-(萘-1-基),
以得到式(I)的化合物,
其中R1选自-CO-C(CH3)=CH2、-CO-(E)C(CH3)=CHCH2CH3、-CO-(E)CH=CH-苯基、-CO-(E)CH=CH-(3,4,5-三甲氧基)苯基、-CO-CH=C(CH3)2,-CO-CH(Cl)2、-CO-CH2-CH(CH3)2、-CO-CH2C(CH3)(CH2CH3)(OCOCH3)、-CO-(E)CH=C(CH3)CH(CH3)2、-CO-CH(CH3)CH2CH3、-CO-(E)CH=C(CH3)CH2CH2CH=C(CH3)2、-CO-CH(CH2CH3)2、-CO-CH3、-CO-CH2C(CH3)CH2CH3、-CO-C(CH2CH3)=CH2、-CO-C(CH3)(CH2)2CH3、-CO-C(CH2CH3)(CH2)3CH3、-CO-CH(CH3)(CH2)3CH3、-CO-CH2C(OH)((CH(CH3)2)2、-CO-(E)CH=CHCH3、-CO-(E)CH=CHCH2CH3、-CO-(E)CH=CH-(4-甲氧基苯基)、-CO-(E)CH=CH-(4-甲基苯基)、-CO-(E)CH=CH-(4-氯苯基)、-CO-(E)CH=CH(呋喃-2-基)、-CO-2-噻吩基、-CO-苯基、-CO-CH2-萘-1-基、-CO-(E)CH=CH(3-甲氧基苯基)、-CO-苯并呋喃-2-基、-CO-苯并噻吩-2-基、-CO-(E)CH=CH-(噻吩-2-基)、-CO-CH2-苯基、-CO-CH2-(4-甲氧基苯基)、-CO-CH2-(6-甲氧基萘-1-基)、-CO-CH2-(6-甲氧基萘-2-基)、-CO-(E)CH=CH-(3-三氟甲氧基苯基)、-CO-(E)CH=CH-(3-三氟甲基苯基)、-CO-(E)CH=CH-(3,4-二甲氧基苯基)、-CO-(E)CH=CH-(3-乙氧基苯基)、-CO-(CH2)2-(萘-1-基)、-CO-CH2-(喹啉-8-基)、-CO-CH(S-CH3)(6-甲氧基萘-2-基)、-CO-CH(R-CH3)(6-甲氧基萘-2-基)、-CO-C(CH3)(OCH3)-(萘-2-基)、-CO-CH(S-OCH3)-(萘-2-基)、-CO-CH(R-OCH3)-(萘-2-基)、-CO-CH2-(苯并噻吩-3-基)、-CO-CH2-(苯并呋喃-3-基)、-CO-(E)CH=CH-(4-乙氧基苯基)、-CO-(E)CH=CH-(1,3-苯并二噁烷-5-基)、以及-CO-CH2-(萘-1-基)(C-6差向异构体);或
(8)使其中R1为氢的式(I)的化合物与三乙胺和其中R3为-(4-甲氧基苯基)、-(4-甲基苯基)、-(4-溴苯基)、-环丙基、-环戊基、或环己基的式(IV)的化合物
R3COCl
式(IV)
反应以得到式(I)的化合物,其中R1为-CO-(4-甲氧基苯基)、-CO-(4-甲基苯基)、-CO-(4-溴苯基)、-CO-环丙基、-CO-环戊基、或-CO环己基。
5.一种组合物,其包含有效量的如权利要求1至3中任一项所述的化合物或其药学上可接受的盐;以及药学上可接受的稀释剂或载体。
6.治疗有效量的如权利要求1至3中任一项所述的化合物或其药学上可接受的盐在制造用于抑制患者癌细胞的增殖、迁移、移动、侵袭、生长和/或转移的药剂中的用途。
7.如权利要求6所述的用途,其中,所述癌选自乳腺癌、黑色素瘤、耐药性黑色素瘤、脑肿瘤、肺癌、淋巴瘤、神经上皮瘤、肾癌、前列腺癌、胃癌、结肠癌和子宫癌。
8.治疗有效量的如权利要求1至3中任一项所述的化合物或其药学上可接受的盐在制造用于增强另一种抗癌药物在治疗患者时对癌细胞的抗增殖效果的药剂中的用途。
9.如权利要求8所述的用途,其中,所述另一种抗癌药物选自PLX4032、丁胱亚磺酰亚胺、柳氮磺吡啶紫杉醇、多西他赛、顺铂、奥沙利铂、桦木酸、4-S-半胱胺基儿茶酚、4-S-半胱胺基苯酚、依维莫司、硼替佐米、卡铂、达卡巴嗪、塞来昔布、替莫唑胺、索拉菲尼、沙利度胺、来那度胺、丙戊酸、长春碱、甲磺酸伊马替尼、波生坦、apomine、三氧化二砷、卡莫司汀、兰布鲁唑、抗CTLA-4药物、抗PD-1药物、易普利姆玛、多柔比星、MEK抑制剂、卡培他滨、PARP抑制剂和他莫昔芬。
10.如权利要求8或9所述的用途,其中,所述药剂显示与所述另一种抗癌药物的协同作用。
11.治疗有效量的如权利要求1至3中任一项所述的化合物或其药学上可接受的盐在制造用于敏化和/或增强谷胱甘肽合成阻滞剂抑制患者中三阴性乳腺癌细胞活性的抗癌效果的药剂中的用途。
12.如权利要求11所述的用途,其中,所述谷胱甘肽合成阻滞剂为γ-谷氨酰半胱氨酸合成酶抑制剂或半胱氨酸/谷氨酸转运体抑制剂。
13.治疗有效量的如权利要求1至3中任一项所述的化合物或其药学上可接受的盐在制造用于治疗和/或预防患者的脂多糖刺激的炎性反应的药剂中的用途。
14.如权利要求13所述的用途,其中,所述脂多糖刺激的炎性反应与选自炎症性皮肤病、炎性肠病、过敏性肺病、哮喘、过敏性鼻炎、自身免疫性疾病、急性和慢性炎性疾病、干燥综合征、人免疫缺陷病毒感染和癌症的炎性疾病相关。
15.治疗有效量的如权利要求1至3中任一项所述的化合物或其药学上可接受的盐以及治疗有效量的选自PLX4032、丁胱亚磺酰亚胺、柳氮磺吡啶紫杉醇、多西他赛、顺铂、奥沙利铂、桦木酸、4-S-半胱胺基儿茶酚、4-S-半胱胺基苯酚、依维莫司、硼替佐米、卡铂、达卡巴嗪、塞来昔布、替莫唑胺、索拉菲尼、沙利度胺、来那度胺、丙戊酸、长春碱、甲磺酸伊马替尼、波生坦、apomine、三氧化二砷、卡莫司汀、兰布鲁唑、抗CTLA-4药物、抗PD-1药物、易普利姆玛、多柔比星、MEK抑制剂、卡培他滨、PARP抑制剂和他莫昔芬的另一种抗癌剂在制造用于抑制对其需要的患者的癌细胞的增殖、迁移、侵袭和/或转移的联合疗法的药剂中的用途。
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