CN107737346A - 一种甲啶铂与葫芦[n]脲的包合物 - Google Patents
一种甲啶铂与葫芦[n]脲的包合物 Download PDFInfo
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- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 title claims abstract description 50
- 229950005566 picoplatin Drugs 0.000 title claims abstract description 50
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 239000004202 carbamide Substances 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 230000000694 effects Effects 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 201000005296 lung carcinoma Diseases 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- -1 JM473 Chemical compound 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种甲啶铂与葫芦[n]脲的包合物,属于制药技术领域。本发明所述甲啶铂与葫芦[n]脲的包合物采用如下方法制备得到:在25~45℃下边搅拌边向溶有葫芦[n]脲的水溶液中加入甲啶铂,继续避光搅拌24~72h后,滤去不溶物,减压蒸干溶剂即得甲啶铂与葫芦[n]脲的包合物;其中,葫芦[n]脲为葫芦[7]脲。葫芦[7]脲与甲啶铂产生包合作用,大大提升甲啶铂的水溶性,减少其毒副作用;本发明提供的方法制得的包合物水溶性好、稳定性好,且减少其毒副作用。同时,其制备方法简单、条件温和和易于操作,可用于甲啶铂新制剂的开发,具有重要的实用价值。
Description
技术领域
本发明涉及一种甲啶铂与葫芦[n]脲包合物,属于制药技术领域。
背景技术
甲啶铂(Picoplatin),JM473,AMD473,ZD0473等,化学名称为顺式-二氯-氨,(2-甲基吡啶)合铂(Ⅱ)(结构式及氢谱上质子的标注如式Ⅱ所示)是继顺铂、卡铂与奥沙利铂之后的新一代铂族金属抗肿瘤药物,目前已在全球范围内开展Ⅱ/Ⅲ期临床研究,有耐药能力强等优点。
人体内复杂的生理环境决定了很多药物在到达作用部位前的体内运转过程中会发生分解或降解,因而降低药物的治疗效果,随之而来出现各种毒副作用。研究显示目前处于临床Ⅲ期试验甲啶铂,其毒副作用主要为恶心、呕吐,其水溶性差,生物利用度低,在人体复杂的环境中,甲啶铂在未到达作用癌细胞时,极易被分解代谢,因此,如何降低甲啶铂的毒副作用成为亟待解决的问题。
发明内容
本发明的目的在于提供一种甲啶铂与葫芦[n]脲的包合物,采用如下方法制备得到:在25~45℃下边搅拌边向溶有葫芦[n]脲的水溶液中加入甲啶铂,继续避光搅拌24~72h后,滤去不溶物,减压蒸干溶剂即得甲啶铂与葫芦[n]脲的包合物;葫芦[n]脲为葫芦[7]脲,其结构式如式Ⅰ所示:
优选的,本发明所述甲啶铂与葫芦[n]脲的摩尔比为2:1。
本发明所述葫芦[7]脲为市售产品。
本发明的有益效果:本发明包合物的制备方法简便易行,条件温和,适合工业化生产。合成的包合物安全性高、稳定性好、溶解性好,可有效克服甲啶铂本身水溶性差和生物利用度低的缺点。
附图说明
图1是葫芦[7]脲及甲啶铂与二者包合物1H-NMR的比较示意图。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此。
实施例1
本实施例所述甲啶铂与葫芦[7]脲的包合物,采用如下方法制备得到:在25℃下边搅拌边向溶有葫芦[7]脲的水溶液中加入甲啶铂,继续避光搅拌24h后,滤去不溶物,减压蒸干溶剂即得甲啶铂与葫芦[7]脲的包合物Ⅰ;其中,甲啶铂与葫芦[7]脲的摩尔比为2:1,其一维核磁谱图如图1所示。
由图1为实施例1一维核磁谱图(A为 CB[7]、B为甲啶铂、C为 甲啶铂@CB[7]包合物)对比可以看出,CB[7]的三个质子峰化学位移在δ 4.21,5.49,5.66 ppm,它与在甲啶铂的质子峰化学位移在 δ 7.0-9.0 ppm和 δ 3.2 ppm有明显的区别;甲啶铂与CB[7]形成包合物后,甲啶铂的化学位移明显向高场移动了约0.7ppm,由此可以确定已成功制备甲啶铂@CB[7]的包合物。
实施例2
本实施例所述甲啶铂与葫芦[7]脲的包合物,采用如下方法制备得到:在45℃下边搅拌边向溶有葫芦[7]脲的水溶液中加入甲啶铂,继续避光搅拌50h后,滤去不溶物,减压蒸干溶剂即得甲啶铂与葫芦[7]脲的包合物Ⅱ;其中,甲啶铂与葫芦[7]脲的摩尔比为5:1。
实施例3
本实施例所述甲啶铂与葫芦[7]脲的包合物,采用如下方法制备得到:在30℃下边搅拌边向溶有葫芦[7]脲的水溶液中加入甲啶铂,继续避光搅拌72h后,滤去不溶物,减压蒸干溶剂即得甲啶铂与葫芦[7]脲的包合物Ⅲ;其中,甲啶铂与葫芦[7]脲的摩尔比为8:1。
包合物对人体癌细胞的体外抑制作用
选用3种典型的人体细胞株,包括A549人肺癌细胞株、HCT-116人结直肠癌细胞株、MCF-7人乳腺癌细胞。其中以甲啶铂作对照组,采用MTT实验测试实施例1~3所合成的葫芦[7]脲—甲啶铂包合物的体外抗肿瘤活性,取A549人肺癌细胞株、HCT-116人结直肠癌细胞、MCF-7人乳腺癌细胞悬液各180uL,铺在相应的96孔板中,在37℃,饱和湿度,5% CO2的培养箱中培养24小时使细胞完全贴壁;更换其中的150uL培养基后,再加入不同浓度的葫芦[7]脲—甲啶铂包合物20uL,继续培养48h;用MTT法分别测定OD值,并计算各个化合物的IC50值;上述实验平行操作三次后取均值。
表1 甲啶铂与葫芦[7]脲包合物在各癌细胞中的IC50值(μM)
比较甲啶铂和CB[7]包合物在A549人肺癌细胞株、HCT-116人结直肠癌细胞、MCF-7人乳腺癌细胞中的IC50值,分别采用了2:1、5:1、8:1的比例进行包合。由表1可以发现,包合物II和包合物Ⅲ的细胞毒性变化较小,对于A549 的细胞毒性明显降低;而包合物I,对于A549和HCT-116的细胞毒性都有一定的影响,特别是HCT-116的细胞毒性增加了约1.5倍;同时包合物也明显提高了甲啶铂的水溶性。因此,通过不同比例包合物的数据分析,包合物I较包合物II和包合物III更为理想。
Claims (2)
1.一种甲啶铂与葫芦[n]脲的包合物,其特征在于,采用如下方法制备得到:在25~45℃下边搅拌边向溶有葫芦[n]脲的水溶液中加入甲啶铂,继续避光搅拌24~72h后,滤去不溶物,减压蒸干溶剂即得甲啶铂与葫芦[n]脲的包合物;其中,甲啶铂与葫芦[n]脲的摩尔比为2:1~8:1,葫芦[n]脲为葫芦[7]脲,其结构式如式Ⅰ所示:
。
2.根据权利要求1所述甲啶铂与葫芦[n]脲的包合物,其特征在于:甲啶铂与葫芦[n]脲的摩尔比为2:1。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003024978A1 (en) * | 2001-09-18 | 2003-03-27 | Postech Foundation | Inclusion compound comprising cucurbituril derivatives as host molecule and pharmaceutical composition comprising the same |
CN1922187A (zh) * | 2004-01-15 | 2007-02-28 | 新南创新有限公司 | 由葫芦形联脲[7-12]部分包封的多核金属配合物 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003024978A1 (en) * | 2001-09-18 | 2003-03-27 | Postech Foundation | Inclusion compound comprising cucurbituril derivatives as host molecule and pharmaceutical composition comprising the same |
CN1922187A (zh) * | 2004-01-15 | 2007-02-28 | 新南创新有限公司 | 由葫芦形联脲[7-12]部分包封的多核金属配合物 |
Non-Patent Citations (2)
Title |
---|
ZABIOLLAH BOLBOLI NOJINI ET AL: "Preference prediction for the stable inclusion complex formation between cucurbit [n=5-7]urils with anticancer drugs based on platinum (II): Computational study", 《JOURNAL OF MOLECULAR LIQUIDS》 * |
高传柱等: "铂抗肿瘤药物-大环化合物给药体系的研究进展", 《药学学报》 * |
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