CN111763177A - 一种喹唑啉类化合物的合成及其抗三阴性乳腺癌作用 - Google Patents
一种喹唑啉类化合物的合成及其抗三阴性乳腺癌作用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Description
技术领域
本发明公开一种抗肿瘤化合物以及在肿瘤治疗中的应用,属于抗肿瘤药学技术领域。
背景技术
乳腺癌是临床上女性常见的高发恶性肿瘤之一,全球每年约170万女性被确诊为乳腺癌,导致50万患者死亡。三阴性乳腺癌是指雌激素受体,孕激素受体和人表皮生长因子受体2均为阴性的乳腺癌,占所有乳腺癌病理类型的15-20%左右,具有特殊的生物学行为和临床病理特征,与其他亚型乳腺癌相比具有细胞分化差、侵袭性病程、远端转移高等特点,因此预后较差,早期复发风险高、五年生存率极低。
目前临床上常用的三阴性乳腺癌治疗手段仍然是手术和常规的全身细胞毒化学治疗,含蒽环和紫杉烷类药物的方案在已广泛应用于术后辅助治疗,但是密集型和高剂量的化疗会产生巨大的毒性,且肿瘤复发或转移后往往缺乏有效的药物,治疗效果并不理想,预后依然很差。随着药物化学、药理学等学科的发展,抗肿瘤小分子药物也在不断被发现和报道。
本发明公开一种抗肿瘤化合物,对人三阴性乳腺癌细胞MDA-MB-231和MDA-MB-468具有较好的抑制作用,对于开发抗三阴性乳腺癌药物和治疗乳腺癌具有重要意义。
发明内容
本发明涉及一种抗肿瘤化合物的制备,及其抗肿瘤药物中的应用。
本发明提供一种具有肿瘤抑制作用的喹唑酮类化合物,该化合物能够有效抑制人三阴性乳腺癌细胞MDA-MB-231和MDA-MB-468。
本发明提供所述的喹唑酮类化合物在药学上可接受的盐。
本发明提供所述喹唑酮类化合物的制备方法。
本发明提供所述喹唑酮类化合物的应用。
附图说明
图1抗肿瘤化合物(1μM浓度下)对MDA-MB-231和MDA-MB-468细胞的抑制率。
具体实施方式
本发明的上述目的通过以下技术方案实现:
制备中间体I,2-氨基-6-甲基苯甲酸(4.0mmol)中加入羧基活化剂HOBT(1.0mmol),偶联剂EDCI(1.0mmol),碱N-甲基吗啉(4.0mmol),溶于THF(5mL)中,最后加入氢氧化铵(5.0mmol)进行缩合,常温搅拌12小时,反应完毕后,加入20mL水溶液,乙酸乙酯萃取,并在减压下蒸发萃取液。以乙酸乙酯/石油醚(1∶15-1∶1)为洗脱剂,通过硅胶层析纯化得到产物中间体1,收率为74%。
制备化合物1,将中间体1(0.61mmol)分别与3-氯-4-甲酰基苯甲酸(0.61mmol)溶于DMAc(8mL)中,并加入亚硫酸氢钠(0.74mmol),PTSA(0.15mmol)。将反应混合物在120℃下搅拌16小时。向反应中加入水(60ml),过滤收集沉淀的固体,通过硅胶色谱法(二氯甲烷/甲醇=100∶1-1∶1)纯化该固体,得到化合物1,产率为60%。
反应式为:
化合物1,白色固体粉末,产率60%。1H NMR(400MHz,DMSO-d6),δ(ppm):13.21(1H,brs),11.58(1H,s),8.41(1H,d,J=8.6Hz),8.38(1H,d,J=8.2Hz),7.94(1H,d,J=1.3Hz),7.73(1H,dd,J=8.5Hz,1.4Hz),7.69(1H,d,J=7.8Hz),2.87(3H,s);13C NMR(100MHz,DMSO-d6),δ(ppm):167.3,162.3,141.8,136.9,136.8,135.3,132.7,132.4,131.8,124.8,124.7,122.6,121.8,121.7,117.0,24.1;[M+H]+:m/z 315.7259。
实验证明,采用MTT法测试了化合物1对人三阴性乳腺癌细胞MDA-MB-231和MDA-MB-468的抑制作用,化合物1对上述两种三阴性乳腺癌细胞均有抑制作用(图1)。
本发明涉及的化合物能抑制三阴性乳腺癌细胞增殖,用于三阴性乳腺癌的治疗。
Claims (5)
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CN112409268A (zh) * | 2020-12-03 | 2021-02-26 | 西南交通大学 | 靶向Fam20C抑制剂的制备及其抗三阴性乳腺癌作用 |
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US20060178386A1 (en) * | 2005-02-10 | 2006-08-10 | Saleem Ahmad | Dihydroquinazolinones as 5HT modulators |
WO2008157500A1 (en) * | 2007-06-17 | 2008-12-24 | Kalypsys, Inc. | Aminoquinazoline cannabinoid receptor modulators for treatment of disease |
US20130281398A1 (en) * | 2012-04-19 | 2013-10-24 | Rvx Therapeutics Inc. | Treatment of diseases by epigenetic regulation |
CN109265463A (zh) * | 2018-12-18 | 2019-01-25 | 上海肇钰医药科技有限公司 | 作为parp抑制剂的吡唑并喹唑啉酮衍生物及其用途 |
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Patent Citations (4)
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US20060178386A1 (en) * | 2005-02-10 | 2006-08-10 | Saleem Ahmad | Dihydroquinazolinones as 5HT modulators |
WO2008157500A1 (en) * | 2007-06-17 | 2008-12-24 | Kalypsys, Inc. | Aminoquinazoline cannabinoid receptor modulators for treatment of disease |
US20130281398A1 (en) * | 2012-04-19 | 2013-10-24 | Rvx Therapeutics Inc. | Treatment of diseases by epigenetic regulation |
CN109265463A (zh) * | 2018-12-18 | 2019-01-25 | 上海肇钰医药科技有限公司 | 作为parp抑制剂的吡唑并喹唑啉酮衍生物及其用途 |
Non-Patent Citations (1)
Title |
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VINAY SONAWANE等: ""Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112409268A (zh) * | 2020-12-03 | 2021-02-26 | 西南交通大学 | 靶向Fam20C抑制剂的制备及其抗三阴性乳腺癌作用 |
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