CN115466250A - 6-氨基己酰色氨酸苄酯修饰的氧代恶唑烷,其合成,活性和应用 - Google Patents
6-氨基己酰色氨酸苄酯修饰的氧代恶唑烷,其合成,活性和应用 Download PDFInfo
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- CN115466250A CN115466250A CN202110656424.3A CN202110656424A CN115466250A CN 115466250 A CN115466250 A CN 115466250A CN 202110656424 A CN202110656424 A CN 202110656424A CN 115466250 A CN115466250 A CN 115466250A
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Abstract
Description
技术领域
本发明涉及一种(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷,涉及它的制备方法,涉及它对尿激酶型纤溶酶原激活物的抑制作用,涉及它的抗血栓活性,进一步涉及它对肿瘤转移的抑制作用。因而本发明涉及它在制备抗血栓药物和抗肿瘤转移药物中的应用。本发明属于生物医药领域。
背景技术
恶性肿瘤的特征是转移。肿瘤细胞浸润,迁移及增殖在人类肿瘤发展并向恶性转变的过程中起重要作用。尤其在肿瘤转移过程中,肿瘤细胞浸润,迁移及增殖起重要作用。肿瘤转移严重影响患者对健康和正常生活的期待。恶性肿瘤生长时,通常出现转移。有些患者在恶性肿瘤的早期就出现了微转移。这种状况使得常规的治疗方法不再有效。在恶性肿瘤相关的死亡病例中,90%以上患者的死因是肿瘤转移。大多数前列腺癌患者也死于转移。对于恶性肿瘤来说,肺癌是最具侵略性的人类癌症之一。例如通常只有10%-15%的肺癌晚期患者能存活5年。而在过去的30年里这种困难局面仍无显著改善。在很多临床病例中,肺癌在被诊断之前已经转移到周围组织。肿瘤转移,尤其是肿瘤向肺转移是肿瘤患者最大的死亡风险。在首次确诊的结肠癌患者中,出现肝转移的比例大约25%。在结肠癌患者晚期出现肝转移的比例为40-50%。那些肝转移患者若不治疗,那么平均存活率会降低到6-12个月,5年存活率只有9%。乳腺癌患者发生脑膜转移的比例为12-35%。在众多转移途径中,淋巴管是最普遍的路径。发生率超过60%。至今,仍然没有抗肿瘤转移的药物用于临床。
巨噬细胞是穿透肿瘤的最丰富的免疫细胞。肿瘤相关的巨噬细胞(TAM)可以促进肿瘤细胞粘附,迁移和侵袭,因而对癌转移有重要影响。肿瘤相关的巨噬细胞促进肿瘤细胞粘附,迁移和侵袭的部分机制涉及由癌细胞表达的白细胞介素-1α(IL-1α)能够募集环氧化酶-2(COX2)表达的巨噬细胞。反过来,募集的巨噬细胞又促进肿瘤细胞粘附,迁移和侵袭,进一步推进肿瘤转移进程。另一个与肿瘤转移相关的物质是纤溶系统重要调节因子u-PA。在多种癌症转移中都发现了u-PA过量表达的现象,抑制u-PA的活性或抑制u-PA的表达。这意味着,抑制u-PA的活性或抑制u-PA的表达就能抑制肿瘤转移。
上述知识说明,能够进入白细胞介素-1α和环氧化酶-2活性口袋的化合物将有能力抑制巨噬细胞募集,因而有能力抑制癌转移。能够进入u-PA活性口袋的化合物将有能力抑制u-PA表达,因而有能力抑制癌转移。此外,抑制u-PA表达可阻断纤溶酶原转化并影响血栓。
在分析了白细胞介素-1α和环氧化酶-2和u-PA活性口袋形态之后,发明人设计了(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷。利用分子对接技术,发明人将该化合物与白细胞介素-1α及环氧化酶-2及u-PA对接。发现(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷可很好地进入白细胞介素-1α和环氧化酶-2和u-PA的活性口袋(此处省略分子对接图)。这些理论研究使发明人认识到,(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷可抑制癌转移及动脉血栓。根据这种认识,发明人完成了后面的实验研究。
发明内容
本发明的第一个内容提供了下式结构的新化合物(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷。
本发明的第二个内容是提供上式的(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷的制备方法,该方法包括:
1)氨基正己酸在甲醇和二氯亚砜溶液中合成氨基正己酸甲酯(1);
2)用二环己基碳二亚胺为缩合剂,1-羟基苯并三氮唑为催化剂将Cbz-Thr与化合物1缩合得到Cbz-Thr-氨基正己酸甲酯(2);
3)化合物2经皂化和环合制备5S-甲基-4S-甲酰(6-基氨基己酸)-2-氧代恶唑烷(3);
4)用二环己基碳二亚胺为缩合剂,1-羟基苯并三氮唑为催化剂将化合物3与色氨酸苄酯缩合制备(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷(4)。
本发明的第三个内容是评价化合物4对u-PA转化纤溶酶原的抑制作用。
本发明的第四个内容是评价化合物4对肿瘤转移的抑制作用。
本发明的第五个内容是评价化合物4的溶栓和抗栓作用。
附图说明
图1.(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷的合成路线:(i)甲醇,二氯亚砜;(ii)二环己基碳二亚胺,1-羟基苯并三氮唑,无水四氢呋喃;(iii)甲醇,NaOH(4N);(iv)二环己基碳二亚胺,1-羟基苯并三氮唑,无水乙腈。
图2.(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷的电泳图。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备6-氨基己酸甲酯(1)
冰浴下向38mL甲醇中缓慢滴加9.9mL二氯亚砜,活化30分钟后向反应液中加5.00g(38.2mmol)6-氨基己酸。TLC(二氯甲烷/甲醇,10/1)监测反应进程,6-氨基己酸消失后将反应液减压浓缩,残留物加50mL甲醇,再减压浓缩。该操作重复两次。残留物用无水乙醚洗,倾去乙醚,得6.45g(100%)标题化合物,为无色固体。ESI-MS(m/e):168[M+H]+。
实施例2制备Cbz-Thr-6-氨基己酸甲酯(2)
冰浴下将2.19g(8.7mmol)Cbz-Thr用50mL无水四氢呋喃溶解,向得到的溶液中加1.11g(8.2mmol)1-羟基苯并三氮唑。冰浴下将1.98g(9.6mmol)二环己基碳二亚胺用20mL无水四氢呋喃溶解。将两种溶液混合,通过搅拌活化30分钟。之后,向活化过的反应液加0.79g(8.2mmol)6-氨基己酸甲酯,用N-甲基吗啉将反应液pH调至8,撤去冰浴,TLC(二氯甲烷/甲醇,40/1)监测反应进程,直至6-氨基己酸甲酯消失。将反应液过滤,滤液减压浓缩,将得到的黄色油状物加100mL乙酸乙酯溶解,然后依次用饱和NaHCO3水溶液洗(50mL×3),饱和NaCl水溶液洗(50mL×3),饱和KHSO4水溶液洗(50mL×3),饱和NaCl水溶液洗(50mL×3),饱和NaHCO3水溶液洗(50mL×3),饱和NaCl水溶液洗(50mL×3)。将乙酸乙酯相用无水Na2SO4干燥12小时,过滤,滤液减压浓缩。得到的淡黄色油状物经柱层析纯化(二氯甲烷/甲醇,40/1),得到2.89g(93%)标题化合物,为无色固体。ESI-MS(m/e):370[M+H]+。
实施例3制备5S-甲基-2-恶唑烷酮-4S-甲酰基氨基正己酸(3)
冰浴下用10mL甲醇将3.3g(8.6mmol)化合物2溶解。向溶液中滴加4N NaOH溶液,将反应液的pH调至13,TLC(二氯甲烷/甲醇,10/1)监测反应进程,直至化合物2消失。反应混合物用饱和NaHSO4溶液调pH至2,减压浓缩,残留物用100mL无水乙腈溶解,滤去无机盐,滤液减压浓缩,得1.74g(79%)标题化合物,为淡黄色油状物。ESI-MS(m/e):257[M-H]-;1HNMR(300MHz,DMSO-d6):δ/ppm=12.062(s,1H),8.144(s,1H),7.867(s,1H),4.404(m,1H),3.791(d,J=5.1Hz,1H),3.099(q,J=6.3Hz,2H),2.220(t,J=7.2Hz,2H),1.539(dd,J1=7.5Hz,J2=7.2Hz,2H),1.438(dd,J1=7.2Hz,J2=7.8Hz,2H),1.359(d,J=6.3Hz,3H),1.299(dd,J1=6.6Hz,J2=7.8Hz,2H)。
实施例4制备(4S,5S)-5-甲基-4-[甲酰-(6-基氨己酰-Trp-OBzl)]-2-氧代恶唑烷(4)
冰浴下0.73g(2.8mmol)化合物3用50mL无水四氢呋喃溶解,向得到的溶液中加0.32g(2.4mmol)1-羟基苯并三氮唑。冰浴下0.58g(2.8mmol)二环己基碳二亚胺用30mL无水四氢呋喃溶解。两种溶液混合,通过搅拌活化30分钟。之后,加入0.78g(2.4mmol)Trp-OBzl,用N-甲基吗啉将反应液pH调至8,撤去冰浴,TLC(二氯甲烷/甲醇,20/1)监测化合物3消失。反应液过滤,滤液减压浓缩,残留物用50mL乙酸乙酯溶解,然后依次用饱和NaHCO3水溶液洗(50mL×3),饱和NaCl水溶液洗(50mL×3),饱和KHSO4水溶液洗(50mL×3),饱和NaCl水溶液洗(50mL×3),饱和NaHCO3水溶液洗(50mL×3),饱和NaCl水溶液洗(50mL×3)。将乙酸乙酯相用无水Na2SO4干燥12小时,过滤,滤液减压浓缩。得到的淡黄色油状物经柱层析纯化(二氯甲烷/甲醇,40/1),得到0.57g(45%)标题化合物,为淡黄色固体。FT-MS(m/e):569.2183[M+Cl]-,理论值569.2195。1HNMR(300MHz,DMSO-d6):δ/ppm=10.858(s,1H),8.293(d,J=7.2Hz,1H),8.001(m,1H),7.849(s,1H),7.510(d,J=7.8Hz,1H),7.363(m,2H),7.325(m,2H),7.203(m,2H),7.178(m,1H),7.130(m,1H),7.075(m,1H),5.758(s,1H),5.043(q,J=4.5Hz,2H),4.566(q,J=6.3Hz,1H),4.412(q,J=5.1Hz,1H),3.795(dd,J1=4.5Hz,J2=0.6Hz,1H),3.156(m,1H),3.088(m,2H),2.106(t,J=6.9Hz,2H),1.455(m,2H),1.404(m,3H),1.358(m,2H)。
实施例5测定化合物4对u-PA激活纤溶酶原的抑制作用
1)本发明的化合物4用含0.5%DMSO的生理盐水配制成所需浓度;
2)实验用的蛋白为牛血纤维溶酶原(10U/支);
3)向5μL尿激酶溶液(500U/mL)中加20μL生理盐水或化合物4,37℃孵育15分钟;加5μL牛血纤维溶酶原溶液,37℃孵育15分钟;加5μLSDS-PAGE蛋白上样缓冲液(5×),混匀,100℃变性5分钟,于-20℃冷却,在10%SDS-PAGE凝胶电泳上分离,纤溶酶原组不加尿激酶溶液和化合物4;用垂直式电泳槽装置,拔去BeyoGelTMSDS-PAGE预制胶上的样品梳,将处理后的5μL样品加入样品池中,加5μL蛋白分子量标准品作对照;电泳槽内槽加满1×电泳缓冲液,外槽电泳液加至没过电极,连接电泳仪电源,负极在上,正极在下,打开电泳仪电源,设置浓缩胶电压80V,时间为30分钟,分离胶电压120V,电泳至溴酚蓝行至电泳槽下端停止(约50分钟);用剥胶铲将胶从双层玻璃板中取出,置培养皿中,加考马斯亮蓝染色液染色,于摇床(60RPM)室温染色10分钟;从考马斯亮蓝染色液中取出胶,加100mL脱色液,于摇床室温脱色8小时后将胶用成像系统扫描,观察实验结果;图2的电泳图表明,化合物4有效地抑制u-PA对纤溶酶原的激活作用。
实施例6评价化合物4的抗肿瘤转移活性
1)实验动物
雄性C57BL/6小鼠(20±2g),购自北京维通利华实验动物技术有限公司。Arg-Gly-Asp-Ser(RGDS)和化合物4的剂量分别为20μmol/kg/天和0.5μmol/kg/天,阴性对照为羧甲基纤维素钠溶液(0.5%CMCNa)。它们均通过腹腔注射给药。
2)实验操作
Lewis小鼠肺癌LLC细胞购自ATCC,按单层细胞培养方法自行传递培养。选用含10%经灭活的胎牛血清DMEM(包含青霉素和链霉素)培养基。按照贴壁细胞培养方法每天传代一次,富集细胞至所需数量。预先将PBS缓冲液,胰蛋白酶-EDTA消化液、细胞需要的DMEM于37℃预热30分钟。待细胞生长状态良好,透明度大,内颗粒少,无空泡,胞膜清晰,培养液上清液清澈透明,无悬浮细胞和碎片并处于对数生长期,细胞生长至铺满瓶底面积80%时去除原细胞培养液,加1mLPBS缓冲液清洗残留培养基3次,弃缓冲液,加1mL胰蛋白酶-EDTA消化液置于孵箱中消化。在显微镜下观察细胞形态,如果大部分由不规则形状变为规则圆形颗粒并有小部分从瓶壁脱落飘起,则加1mL培养基终止消化。沿瓶壁反复用力吹打细胞使其脱壁分散于液体中,将液体转移至灭菌的15mL离心管中1368g离心3分钟,弃上清液,用4℃生理盐水调整细胞浓度至2×107个/mL,台盼蓝染色计数表明活细胞数>95%。取近交系C57BL/6雄性小鼠,左手固定小鼠,用75%乙醇消毒小鼠右前肢腋窝皮肤,右手持1mL无菌注射器于小鼠腋部皮下注射Lewis小鼠肺癌细胞悬液(0.2mL/只)。接种后10天可见有实体瘤组织形成。第17-20天小鼠长出直径约2-3mm的实体瘤,即为瘤源小鼠。
将Lewis肺癌荷瘤小鼠用乙醚麻醉,脱颈椎处死,用75%乙醇浸泡消毒10分钟,在超净工作台上剥离瘤体,在无菌平皿中剪碎,置于玻璃组织匀浆器内按瘤块重(g)/生理盐水体积(mL)为1/3的比例用预冷至4℃的生理盐水轻轻研磨,制成的细胞悬液过200目细胞筛制成单细胞悬液。用生理盐水调整细胞浓度为2×107个/mL,台盼蓝染色计数表明活细胞数>95%。取近交系C57BL/6雄性小鼠,左手固定小鼠,用75%乙醇消毒小鼠右前肢腋窝皮肤,右手持1mL无菌注射器于小鼠腋部皮下注射Lewis小鼠肺癌细胞悬液(0.2mL/只)。自接种肿瘤后当天起,每日对荷瘤小鼠进行观察,待小鼠腋下实体瘤长至黄豆粒大小时重新分组,保证每组小鼠肿瘤状态基本一致后开始给药,每天给药1次(0.1ml/10g),连续给药10天。期间每隔1天用游标卡尺测定一次小鼠腋下肿瘤体积。第10天用乙醚将小鼠麻醉,脱颈椎处死,取小鼠肺及肿瘤。快速数肺部的瘤结。瘤结数以均值±SD个表示,经单因素方差分析进行组间统计学比较。
3)实验结果
在小鼠Lewis肺癌转移模型评价化合物4抑制癌转移活性。结果列入表1。数据显示,RGDS抑制癌向肺转移的活性显著强于CMCNa,化合物4抑制癌向肺转移的活性显著强于RGDS。可见,本发明有突出的技术效果。
表1化合物4抑制肿瘤转移的活性
a)与CMC-Na比P<0.01;b)与CMC-Na比P<0.01,与RGDS比P<0.05;n=9。
实施例7评价化合物4的抗血栓活性
作为u-PA的抑制剂,化合物4可能具有溶栓活性及抗血栓活性。本发明首先评价了化合物4的溶栓活性,结果表明化合物4没有溶栓活性(此处不列负面结果)。于是,本发明采用以下方法评价化合物4的抗血栓活性。
1)将聚乙烯管拉成一端为斜口的细管,定长为10.0cm,分别为右颈静脉(管径较粗)及左颈动脉(管径较细)插管;中段聚乙烯管定长为8.0cm,血栓线压在颈动脉插管方向,插管前需在管中充满肝素。
2)将体重200±20g雄性大鼠大鼠在手术前适应环境并禁食一天。随机分为CMCNa组(0.3mL/100g,10只大鼠),阿司匹林组(167μmol/kg,10只大鼠),化合物4组(0.5μmol/kg,10只大鼠)。按照规定剂量给大鼠口服药物。给药30分钟后,大鼠腹腔注射20%乌拉坦溶液麻醉(7mL/kg),2分钟之后开始手术。手术中将大鼠仰卧位于固定板上,剪开颈部皮肤,分离右颈总动脉及左颈静脉,血管下压线,结扎远心端,在静脉靠远心端处剪一小口,将插管插入静脉端,注射肝素,而后取下注射肝素的注射器,系线固定,再用动脉夹夹住动脉近心端,在靠近远心端方向剪一小口,将动脉端结扎,系线固定后松开动脉夹,建立体外循环旁路。循环15分钟后先剪断静脉端观察血液循环是否正常,若正常从动脉端取出血栓线,在纸上沾干浮血后称重,以血栓重表示活性,经单因素方差分析,数据列入表2。表2的血栓重量表明,在167μmol/kg口服剂量下阿司匹林有效地抑制大鼠患动脉血栓症。在0.5μmol/kg口服剂量下化合物4治疗的大鼠的血栓重与阿司匹林治疗的大鼠的血栓重没有显著性差异。这个结果说明,本发明有突出技术效果。
表2化合物4的抗血栓活性
a)与CMC-Na比P<0.01;b)与CMC-Na比P<0.01,与阿司匹林组相比P>0.05;n=10。
Claims (4)
2.权利要求1所述结构的6-氨基己酰色氨酸苄酯修饰的氧代恶唑烷的制备方法,其特征在于,该方法包括以下步骤:
2.1.氨基正己酸在甲醇,二氯亚砜溶液中制备6-氨基己酸甲酯;
2.2.采用二环己基碳二亚胺为缩合剂,1-羟基苯并三氮唑为催化剂,将Cbz-Thr与6-氨基己酸甲酯缩合制备Cbz-Thr-6-氨基己酸甲酯;
2.3.Cbz-Thr-6-氨基己酸甲酯通过皂化环合制备6-氨基己酸修饰的氧代恶唑烷;
2.4.用二环己基碳二亚胺为缩合剂,1-羟基苯并三氮唑为催化剂,将6-氨基己酸修饰的氧代恶唑烷与Trp-OBzl缩合制备权利要求1的6-氨基己酰色氨酸苄酯修饰的氧代恶唑烷。
3.权利要求1所述结构的6-氨基己酰色氨酸苄酯修饰的氧代恶唑烷在制备抗血栓药物中的应用。
4.权利要求1所述结构的6-氨基己酰色氨酸苄酯修饰的氧代恶唑烷在制备抗癌转移药物中的应用。
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DE69304538T2 (de) * | 1992-06-03 | 1997-01-09 | Fuji Photo Film Co Ltd | Aminosäure-derivate und deren verwendung |
CN108929320A (zh) * | 2017-05-22 | 2018-12-04 | 首都医科大学 | 3r-吲哚甲基-6r-恶唑烷酮修饰的哌嗪-2,5-二酮,其合成,活性和应用 |
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DE69304538T2 (de) * | 1992-06-03 | 1997-01-09 | Fuji Photo Film Co Ltd | Aminosäure-derivate und deren verwendung |
CN108929320A (zh) * | 2017-05-22 | 2018-12-04 | 首都医科大学 | 3r-吲哚甲基-6r-恶唑烷酮修饰的哌嗪-2,5-二酮,其合成,活性和应用 |
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