CN111285900B - 基于紫檀芪和香荚兰乙酮的偶联分子dcz0847类化合物、其制备方法及用途 - Google Patents
基于紫檀芪和香荚兰乙酮的偶联分子dcz0847类化合物、其制备方法及用途 Download PDFInfo
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Abstract
本发明公开了一种抗肿瘤化合物DCZ0847及其制备方法和应用，所述化合物结构式如下所示。本发明还提供了所述化合物的制备方法，该方法具有步骤简单、得率高的优点。细胞实验显示，化合物DCZ0847对多发性骨髓瘤、淋巴瘤、甲状腺癌、肺癌、膀胱癌、胃癌、结肠癌细胞、食管癌和骨肉瘤具有很强的杀伤活性，可通过抑制肿瘤细胞的增殖，达到预防和治疗肿瘤的目的。DCZ0847单用或与硼替佐米联用能够有效抑制体内多发性骨髓瘤细胞生长。因此，本发明的DCZ0847小分子化合物，副作用相对较少，在抗肿瘤药物领域具有很好的应用前景。本发明不仅为抗肿瘤提供了新的治疗药物，也为克服肿瘤的耐药性提供了新途径。
Description
技术领域
本发明涉及生物医药技术领域，具体地说，是一种新型抗肿瘤化合物DCZ0847及其制备方法和应用。
背景技术
恶性肿瘤作为全球较大的公共卫生问题之一，极大地危害人类的健康，并成为新世纪人类的第一杀手。恶性肿瘤已不再只是发达工业国家的严重疾病，发展中国家面临着更大的疾病负担。恶性肿瘤包括实体瘤(如肺癌、结直肠癌、肝癌、胃癌等)和血液肿瘤(如骨髓瘤、淋巴瘤等)，两者疾病的发生发展和治疗方式有着较为显著的不同，胃癌、膀胱癌、甲状腺癌、肺癌、结肠癌、骨肉瘤是较为常见的肿瘤类型。
化学药物作为治疗肿瘤的重要手段之一，在近三十年已经有了巨大的发展和进步，得到了一大批具有不同作用机制的临床抗肿瘤药物。但抗肿瘤药存在许多不良反应，比如脱发，呕吐，快速产生耐药性等等，这些都导致化学药物无法达到预期的治疗效果。因此，新的抗肿瘤药物的研究与开发是目前药学领域的热点和难点问题之一。发明人前期发表了多项抗肿瘤化合物相关专利，如发明专利CN201810132882.5，公开一种抗肿瘤化合物2-(4-(吡啶-4-亚甲基)苯基)-4,4a,5,5a,6,6a-六氢-4,6-乙桥环丙烯并[f]异吲哚-1,3(2H,3aH)-二酮，该化合物对多发性骨髓瘤细胞及其他肿瘤细胞(包括人淋巴瘤、肺癌、前列腺癌和结直肠癌)具有杀伤活性。发明专利CN201610094005.4，公开了一种抗肿瘤化合物7-((4-(吡啶-4-亚甲基)苯基)氨基甲酰基)三环[3.2.2.02,4]壬-8-烯-6-甲酸，该化合物可显著抑制多发性骨髓瘤和淋巴瘤。这些已经公开的化合物对血液肿瘤(如骨髓瘤、淋巴瘤等)具有较强的杀伤活性，然而对于实体瘤(如膀胱癌、肺癌、结直肠癌、甲状腺癌、胃癌、骨肉瘤等)杀伤活性不强。
发明内容
本发明的第一个目的是针对现有技术中的不足，提供一种抗肿瘤的化合物及其制备方法和应用。
在本发明的第一方面，提供了一种抗肿瘤化合物(DCZ0847)，其化学结构式为：
在本发明的第二方面，提供了所述化合物DCZ0847的晶型、药学上可接受的无机酸盐或有机酸盐、水合物、溶剂合物或前药。
在本发明的第三方面，提供了一种药物组合物，所述药物组合物含有药学上可接受的赋形剂或载体，以及所述化合物DCZ0847或所述化合物DCZ0847的晶型、药学上可接受的无机酸盐或有机酸盐、水合物、溶剂合物或前药。
在本发明的第四方面，提供了所述化合物DCZ0847的制备方法，包括以下步骤：
1)三氯氧磷溶于二氯甲烷，加入化合物1和三乙胺的二氯甲烷溶液，搅拌反应完全；2)反应液加入N-甲基哌嗪3和三乙胺的二氯甲烷溶液，搅拌反应完全；3)反应液加入化合物2、N,N-二甲胺基吡啶和三乙胺的二氯甲烷溶液，搅拌反应完全；4)加入水稀释，萃取，分离，水洗，饱和氯化钠洗，干燥，蒸干，硅胶柱分离，无色油状液体，加过量盐酸乙醚溶解混匀，蒸干，既得目标化合物。
在本发明的第五方面，提供了所述化合物DCZ0847，或所述化合物DCZ0847的晶型、药学上可接受的无机酸盐或有机酸盐、水合物、溶剂合物或前药的用途。
作为一个优选例，提供了所述化合物DCZ0847，或所述化合物DCZ0847的晶型、药学上可接受的无机酸盐或有机酸盐、水合物、溶剂合物或前药在制备药物中的应用，所述药物用于抗肿瘤。所述肿瘤为甲状腺癌、肺癌、膀胱癌、胃癌、结肠癌细胞、食管癌或骨肉瘤，但不仅限于此。
作为一个优选例，提供了所述化合物DCZ0847，或所述化合物DCZ0847的晶型、药学上可接受的无机酸盐或有机酸盐、水合物、溶剂合物或前药在制备试剂中的应用，所述试剂用于抑制肿瘤细胞的增殖。所述肿瘤为多发性骨髓瘤、淋巴瘤、甲状腺癌、肺癌、膀胱癌、胃癌、结肠癌细胞、食管癌和骨肉瘤，但不仅限于此。
在本发明的第六方面，提供了治疗多发性骨髓瘤药物组合物，包含化合物DCZ0847和硼替佐米，所述的DCZ0847和硼替佐米质量比为10:1。用于抑制肿瘤细胞的增殖，所述的肿瘤为多发性骨髓瘤。
本发明优点在于：
1、本发明合成了一种新型抗肿瘤化合物DCZ0847。
2、本发明的化合物DCZ0847合成方法步骤简单，得率高。
3、本发明证实了化合物DCZ0847具有很强的抗肿瘤活性，尤其对甲状腺癌、肺癌、膀胱癌、胃癌、结肠癌细胞、食管癌、骨肉瘤等实体瘤以及多发性骨髓瘤、淋巴瘤等血液系统恶性肿瘤杀伤活性很强。
附图说明
附图1为本发明化合物结构示意图。
附图2-8为本发明化合物DCZ0847对甲状腺癌(TPC-1细胞)、肺癌(A549细胞)、膀胱癌(T24细胞)、胃癌(SGC-7901细胞)、结肠癌细胞(HCT116细胞)、食管癌细胞(EC109细胞)、骨肉瘤细胞(U20S细胞)的抑制曲线。图中横坐标为化合物浓度(μM)，纵坐标为相对存活率(％)。
附图9-10为本发明化合物DCZ0847针对多发性骨髓瘤的动物实验结果。其中：图9DCZ0847抑制裸鼠多发性骨髓瘤的生长。图10DCZ0847与硼替佐米联用抑制裸鼠多发性骨髓瘤的生长。
具体实施方式
本文中，“前药”是指一个试剂在体内转化为原型药。前药通常是有用的，因为在某种情况下，它们可能比原型药容易给药。前药通常是药的前体，接下来的给药和吸收被转化为活性物质，或通过一些过程变为活性更强的种类，如通过代谢途径转化。一些前药具有的化学基团使其活性较低和/或对比原型药的溶解性或一些其它性质有所改变。一旦前药的化学基团被去除和/或对其修饰，得到活性药。
所述药物组合物可以是固体形式或是液体形式，其剂型可以是片剂、分散片、含片、口崩片、缓释片、胶囊剂、软胶囊剂、滴丸、颗粒剂、注射剂、粉针剂或气雾剂等。当本发明化合物用于上述用途时，可与一种或多种药学上可接受的载体或赋形剂混合，如溶剂、稀释剂等，而且可以用如下形式口服给药：片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液(含有如约0.05-5％悬浮剂)、糖浆(含有如约10-50％糖)、和酏剂(含有约20-50％乙醇)，或以外用方式给药：软膏剂、凝胶、含药胶布等，或者以无菌可注射溶液或悬浮液形式(在等渗介质中含有约0.05-5％悬浮剂)进行非肠胃给药。例如，这些药物制剂可含有与载体混合的约0.01-99％，更佳地约为0.1-90％(重量)的活性成分。适合的给药途径包括但不限于口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指代是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的疗效。药学上可接受的载体部分例子有糖(如葡萄糖、蔗糖、乳糖等)，淀粉(如玉米淀粉、马铃薯淀粉等)，纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)，明胶，滑石粉，固体润滑剂(如硬脂酸钠、硬脂酸镁)，硫酸钙，植物油(如豆油、芝麻油、花生油、橄榄油等)，多元醇(如丙二醇、甘油、甘露醇、山梨醇等)，乳化剂(如吐温类)、润湿剂(如十二烷基磺酸钠)，着色剂，调味剂，稳定剂，抗氧化剂，防腐剂，无热原水等。
下面结合具体实施方式，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1 化合物DCZ0847的制备
合成反应路线如下：
具体制备方法为：三氯氧磷(0.50mL,5.5mmol)溶于二氯甲烷(60mL)，氮气保护，冰浴降温，逐滴加入化合物1(1.28g,5.0mmol)和三乙胺(0.85mL,6.0mmol)的二氯甲烷(15mL)溶液，搅拌反应2小时，取样监测反应完全。反应液再次冰浴降温，然后加入N-甲基哌嗪3(0.55mL,5.0mmol)和三乙胺(0.85mL,6.0mmol)的二氯甲烷(10mL)溶液，搅拌反应5小时，取样监测反应完全。反应液再次冰浴降温，逐滴加入化合物2(830mg,5.0mmol)、N,N-二甲胺基吡啶(122mg,1.0mmol)和三乙胺(0.85mL,6.0mmol)的二氯甲烷(10mL)溶液，搅拌反应10小时，取样监测反应完全。加入水稀释，二氯甲烷萃取反应液，分离有机相，水洗，饱和氯化钠洗，无水硫酸钠干燥，减压蒸干，残余物经硅胶柱分离(PE/EA＝1:1；CH2Cl2/MeOH＝20:1)，得到无色油状液体，加过量盐酸乙醚溶解混匀，减压蒸干，得白色固体产物DCZ0847(2.3g,产率77％)。
4-乙酰基-2-甲氧基苯基(4-(3,5-二甲氧基苯乙烯基)苯基)(4-甲基哌嗪-1-基)膦酸酯盐酸盐(4-acetyl-2-methoxyphenyl(4-(3,5-dimethoxystyryl)phenyl)(4-methylpiperazin-1-yl)phosphonate hydrochloride)：
1H NMR(400MHz,Chloroform-d)δ7.61(dd,J＝2.0,1.1Hz,1H),7.57–7.42(m,4H),7.28–7.25(m,2H),7.03(q,J＝16.3Hz,2H),6.68(d,J＝2.3Hz,2H),6.42(t,J＝2.2Hz,1H),3.94(s,3H),3.85(s,6H),3.44–3.29(m,4H),2.61(s,3H),2.33(s,4H),2.26(s,3H).13C NMR(125MHz,Chloroform-d)δ196.39,160.50,138.65,134.11,133.68,128.20,127.54,127.25,121.75,120.57,120.54,120.09,120.05,110.99,104.05,99.55,76.73,55.58,54.89,54.34,54.29,45.87,44.17,25.99.HRMS(ESI)calcd for C30H36N2O7P 567.2255[M+H]+,found 567.2258[M+H]+.
实施例2 对肿瘤细胞的杀伤活性
1.实验材料
(1)细胞株：人多发性骨髓瘤细胞(OCI-MY5、ARP-1、NCI-H929)、淋巴瘤(NUDUL-1、OCI-LY8、TMD8、DB和SUDHL-4细胞)、甲状腺癌(TPC-1细胞)、肺癌(A549细胞)、膀胱癌(T24细胞)、胃癌(SGC-7901细胞)、结肠癌(HCT116细胞)、食管癌(EC109细胞)、骨肉瘤(U20S细胞)购自美国ATCC，本实验室传代保存。
(2)主要试剂：1640培养基(美国Gibco公司)，DMEM培养基(美国Gibco公司),胎牛血清(美国Gibco公司)，DCZ0847，硼替佐米(美国Sigma公司)，Cell Counting Kit-8试剂盒(CCK8，日本株式会社同仁化学研究所)。
(3)主要仪器：二氧化碳培养箱(美国Thermo Forma公司)，全自动酶标仪(Bio-TEK，Elx800)。
2.实验方法
(1)细胞培养
结肠癌(HCT116细胞)、肺癌(A549细胞)、食管癌(EC109细胞)、骨肉瘤(U20S细胞)，培养于DMEM培养基(含10％胎牛血清)。人多发性骨髓瘤细胞(OCI-MY5、ARP-1、NCI-H929)，淋巴瘤(NUDUL-1、OCI-LY8、TMD8、DB和SUDHL-4细胞)、胃癌(SGC-7901细胞)、膀胱癌(T24细胞)、甲状腺癌(TPC-1细胞)细胞培养于1640培养基(含10％胎牛血清)。
(2)CCK8试剂盒测定对各细胞的毒性
取甲状腺癌(TPC-1细胞)、肺癌(A549细胞)、膀胱癌(T24细胞)、胃癌(SGC-7901细胞)、结肠癌(HCT116细胞)、食管癌(EC109细胞)、骨肉瘤(U20S细胞)、人多发性骨髓瘤细胞(OCI-MY5、ARP-1、NCI-H929)，淋巴瘤(NUDUL-1和SUDHL-4细胞)的单细胞悬液，计数后调整细胞浓度至2×105个/mL。取96孔培养板每孔加入95μL上述细胞悬液，然后加不同浓度的用培养基配制的药物5μL，对照组加入相应体积的培养基，每组设置3个平行孔。连续培养48h，培养结束前2h，每孔加入CCK8试剂10μL，于CO2孵箱中继续培养。2h后自动酶标仪检测450nm各孔OD值。计算细胞存活率与抑制率：细胞存活率(％)＝(实验孔OD均值/对照孔OD均值)×100％。细胞抑制率(％)＝100％-细胞存活率(％)。拟合函数求出抑制细胞生长达50％时的药物浓度(IC50)。实验重复三次。
3.实验结果
以上结果说明该类化合物能够广泛抑制各种肿瘤细胞的活性。附图2-8为本发明化合物DCZ0847对甲状腺癌(TPC-1细胞)、肺癌(A549细胞)、膀胱癌(T24细胞)、胃癌(SGC-7901细胞)、结肠癌细胞(HCT116细胞)、食管癌细胞(EC109细胞)、骨肉瘤细胞(U20S细胞)的抑制曲线。图中横坐标为化合物浓度(μM)，纵坐标为相对存活率(％)。
实施例3 针对多发性骨髓瘤的动物实验
1.实验材料
(1)细胞株：人多发性骨髓瘤细胞(ARP-1细胞)(美国ATCC，本实验室传代保存)，培养于1640培养基(含10％胎牛血清)。
(2)实验动物：雄性BALB/C裸鼠(5-6周，购自北京维通利华实验动物技术有限公司)，置于SPF级环境中饲养(上海第十人民医院中心实验室动物房)。
2.实验方法
(1)细胞培养具体参见测试例1。
(2)动物实验
将含2.5×106个ARP-1细胞悬浮于100μL预冷的磷酸盐缓冲盐(PBS)中并注射到裸鼠右腋窝皮下，当瘤子长成并可测量时，随机分至对照组和DCZ0847治疗组。DCZ0847治疗组裸鼠腹腔注射DCZ0847(10mg/kg，溶于1％DMSO和生理盐水，每周3次)，对照组裸鼠注射相同体积的溶剂(200μL，1％DMSO和生理盐水)。每两天称量小鼠体重，并测量肿瘤的长和宽，计算肿瘤体积(肿瘤体积＝(长×宽2)×0.5)。给药3周后处死老鼠并取肿瘤拍照。
3.实验结果
结果如图9所示，结果说明DCZ0847能够有效抑制裸鼠多发性骨髓瘤的生长。
实施例4 DCZ0847与硼替佐米联用能够有效抑制裸鼠体内多发性骨髓瘤的生长
1.实验材料
(1)细胞株：人多发性骨髓瘤细胞(ARP-1细胞)(美国ATCC，本实验室传代保存)，培养于1640培养基(含10％胎牛血清)。
(2)实验动物：雄性BALB/C裸鼠(5-6周，购自北京维通利华实验动物技术有限公司)，置于SPF级环境中饲养(上海第十人民医院中心实验室动物房)。
2.实验方法
(1)细胞培养具体参见测试例1。
(2)动物实验
将含2.5×106个ARP-1细胞悬浮于100μL预冷的PBS中并注射到裸鼠右腋窝皮下，当瘤子长成并可测量时，随机分为4组，分别为对照组、DCZ0847治疗组、硼替佐米治疗组及双药组。DCZ0847治疗组裸鼠腹腔注射DCZ0847(10mg/kg，溶于1％DMSO和生理盐水，每周3次)，硼替佐米治疗组裸鼠腹腔注射硼替佐米(1mg/kg，溶于1％DMSO和生理盐水,每周2次)，双药组裸鼠腹腔注射DCZ0847(10mg/kg)和硼替佐米(1mg/kg)，对照组裸鼠腹腔注射相同体积的溶剂(200μL，1％DMSO和生理盐水)。每两天称量小鼠体重，并测量肿瘤的长和宽，计算肿瘤体积(肿瘤体积＝(长×宽2)×0.5)。给药3周后处死老鼠并取肿瘤拍照。
3.实验结果
结果如图10所示，结果说明DCZ0847与硼替佐米联用能够有效抑制裸鼠多发性骨髓瘤的生长。
治疗多发性骨髓瘤药物组合物，所述组合物包含DCZ0847和硼替佐米，DCZ0847和硼替佐米质量比为10:1。所述的DCZ0847为10mg/kg，硼替佐米为1mg/kg。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (5)
1.一种抗肿瘤的化合物，其特征在于，所述肿瘤为多发性骨髓瘤、淋巴瘤、甲状腺癌、肺癌、膀胱癌、胃癌、结肠癌、食管癌或骨肉瘤；所述化合物的化学结构式如下：
2.权利要求1所述化合物的制备方法，其特征在于，包括以下步骤：
1）三氯氧磷溶于二氯甲烷，加入化合物1和三乙胺的二氯甲烷溶液，搅拌反应完全；2）反应液加入N-甲基哌嗪3和三乙胺的二氯甲烷溶液，搅拌反应完全；3）反应液加入化合物2、N,N-二甲胺基吡啶和三乙胺的二氯甲烷溶液，搅拌反应完全；4）加入水稀释，萃取，分离，水洗，饱和氯化钠洗，干燥，蒸干，硅胶柱分离，无色油状液体，加过量盐酸乙醚溶解混匀，蒸干，既得目标化合物。
3.权利要求1所述化合物在制备药物中的应用，其特征在于，所述药物用于抗肿瘤，所述肿瘤为多发性骨髓瘤、淋巴瘤、甲状腺癌、肺癌、膀胱癌、胃癌、结肠癌、食管癌和骨肉瘤。
4.一种治疗多发性骨髓瘤药物组合物，所述组合物包含权利要求1所述的化合物和硼替佐米，所述的化合物和硼替佐米质量比为 10:1 。
5.权利要求4所述组合物在制备用于抑制肿瘤细胞的增殖疾病药物中的应用，所述的肿瘤为多发性骨髓瘤。
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| CN107365265A (zh) * | 2016-05-12 | 2017-11-21 | 中国科学院上海药物研究所 | 夹竹桃麻素水溶性前药、其制备方法、药物组合物及用途 |
| CN109942630A (zh) * | 2019-02-28 | 2019-06-28 | 上海市第十人民医院 | 基于柳胺酚和紫檀芪的天然活性分子偶联化合物及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107365265A (zh) * | 2016-05-12 | 2017-11-21 | 中国科学院上海药物研究所 | 夹竹桃麻素水溶性前药、其制备方法、药物组合物及用途 |
| CN109942630A (zh) * | 2019-02-28 | 2019-06-28 | 上海市第十人民医院 | 基于柳胺酚和紫檀芪的天然活性分子偶联化合物及其用途 |
Non-Patent Citations (4)
| Title |
|---|
| A novel phosphoramide compound, DCZ0847, displays in vitro and in vivo anti-myeloma activity, alone or in combination with bortezomib;Gege Chen，et al.;《CANCER LETTERS》;20201231;第478卷;第45-55页 * |
| Drug‐like dietary vanilloids induce anticancer activity through proliferation inhibition and regulation of bcl‐related apoptotic proteins;Chun‐Wai Mai，et al.;《Phytotherapy Research.》;20181231;第32卷;第1108-1118页 * |
| Synthesis and Characterization of Phosphoramide Piperazine Analogues of Paeonol;Xu Li，et al.;《Phosphorus, Sulfur, and Silicon and the Related Elements》;20150309;第1-14页 * |
| 罗布麻宁治疗少弱精子症模型小鼠的作用机制;马宝良 等;《中华男科学杂志》;20160731;第22卷(第7期);第649-653页 * |
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