CN107235947A - 一类5，7‑双羟基‑6，8‑双(1‑甲基哌嗪)‑4h‑色烯‑4‑酮类新型化合物及其抗肿瘤用途 - Google Patents

一类5，7‑双羟基‑6，8‑双(1‑甲基哌嗪)‑4h‑色烯‑4‑酮类新型化合物及其抗肿瘤用途 Download PDF

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CN107235947A
CN107235947A CN201710541722.1A CN201710541722A CN107235947A CN 107235947 A CN107235947 A CN 107235947A CN 201710541722 A CN201710541722 A CN 201710541722A CN 107235947 A CN107235947 A CN 107235947A
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pairs
compound
chromenes
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hydroxyl
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CN107235947B (zh
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俞军
杨翊柠
林森森
陈森清
张元颖
朱明�
吕敏
张晓梅
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Jiangsu Cancer Hospital
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Jiangsu Cancer Hospital
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明新发现了一类5，7‑双羟基‑6，8‑双(1‑甲基哌嗪)‑4H‑色烯‑4‑酮类化合物，体外筛选表明该类化合物对多种胃癌细胞(BGC‑823、MGC‑803)具有较强的抑制作用，随后生长抑制实验证明该类化合物可抑制胃癌细胞(BGC‑823、MGC‑803)的体外增殖。该类新型化合物可应用为抗肿瘤药物。

Description

一类5，7-双羟基-6，8-双(1-甲基哌嗪)-4H-色烯-4-酮类新型 化合物及其抗肿瘤用途
技术领域
本发明发现一类5，7-双羟基-6，8-双(1-甲基哌嗪)-4H-色烯-4-酮类新型化合物，该类化合物可抑制胃癌细胞的体外增殖。本发明发现该类化合物在制备抗肿瘤药物中的应用，属于医药技术领域。
背景技术
本发明通过对化合物库的筛选，发现了一类5，7-双羟基-6，8-双(1-甲基哌嗪)-4H-色烯-4-酮类新型化合物，该类化合物可以显著抑制胃癌细胞的体外增殖。
发明内容
本发明在体外细胞水平上寻找先导化合物，发现了一类5，7-双羟基-6，8-双(1-甲基哌嗪)-4H-色烯-4-酮类结构新颖的化合物，并细胞学实验证实了该类化合物可抑制肿瘤细胞的体外增殖。本发明可为抗肿瘤药物的开发提供先导化合物。
本发明的技术方案为：首先在细胞水平上进行初筛、复筛，发现一类体外可抑制肿瘤细胞的化合物；随后，以MTT实验和克隆形成实验证实其抑制胃癌细胞增殖的作用。
附图说明
图1：1号样品抑制两种胃癌细胞体外生长的柱状图(n＝3)；
图2：1号样品抑制两种胃癌细胞的克隆形成实验(代表图)；
图3：1号样品克隆形成实验的统计图(n＝3)。
具体实施方式：
以下结合附图说明
1.MTT实验
(1)取处于指数生长期状态良好的人胃癌细胞一瓶，消化后计数，取180μl细胞悬液接种于96孔板上，2-4×103个/孔，置恒温CO2培养箱中培养24小时。
(2)第二天换入新鲜的培养液(含10％血清)，加入不同浓度的受试样品，继续培养72小时。
(3)将MTT试剂加入96孔板中，20μl/孔，培养箱中反应4小时。
(4)吸去上清液，加入DMSO，150μl/孔，平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸光值，并计算细胞抑制。
2.克隆形成实验
取对数生长期的胃癌细胞，消化后计数1000个，加入3.5cm细胞培养皿中，贴壁过夜；第二天换新鲜培养基2ml，加入不同浓度的受试药物，放入恒温CO2培养箱连续培养7天。姬姆萨染色，解剖显微镜下计数含50个细胞以上的集落。
实验结果
1.筛选得到的该类化合物结构通式如下：
化合物 R1 R2 R3
1 F A A
2 F B B
3 F C C
4 F D D
5 F E E
6 F F F
7 F K K
8 F L L
9 E A A
10 G A A
11 H A A
12 I A A
13 I B B
14 J A A
15 K A A
16 L A A
其中，
A：-H；
B：-CH2-CH3；
C：-O-CH3；
D：-CH2OH；
2.10μg/ml的样品对胃癌细胞的抑制率(72h，％)如下：
3.样品对胃癌细胞的抑制及IC50值(72h)
根据初筛结果，选择效果最好的1号样品进行复筛，作出样品抑制胃癌细胞生长的柱状图(图1)。1号样品对胃癌BGC-823和MGC-803细胞的IC50值分别为11.27±0.67μM和7.31±0.53μM。
4.样品抑制胃癌细胞的体外增殖
研究1号样品对BGC-823以及MGC-803两种细胞体外增殖的抑制作用。分别设高(5μM)、中(3μM)、低(1μM)三组剂量，给予BGC-823以及MGC-803细胞，恒温CO2培养箱连续培养7天。实验结束后以姬姆萨染色，解剖显微镜下观察细胞集落的形成状况。结果见图2，统计结果见图3。可见，1号样品对两种胃癌细胞的集落形成均具有明显的抑制作用，并呈现显著的剂量依赖性。

Claims (2)

1.一类5，7-双羟基-6，8-双(1-甲基哌嗪)-4H-色烯-4-酮类新型化合物，其结构如通式(I)所示：
其中：
R1代表C4-C7的环烷基、取代环烷基、芳基或取代芳基，所述取代基为烷基、链烯基、烷氧基、卤代烷基、卤素、硝基、羟基、羟烷基、氨基、烷氨基。
R2、R3代表C2-C6的烷基、烷氧基、卤代烷基、环烷基、取代环烷基、芳基或取代芳基，所述取代基为烷基、卤素、硝基、羟基、羟烷基、氨基、烷氨基。
2.权利要求1所述的化合物在抗肿瘤药中的应用。
CN201710541722.1A 2017-06-29 2017-06-29 一类5，7-双羟基-6，8-双(1-甲基哌嗪)-4h-色烯-4-酮类新型化合物及其抗肿瘤用途 Active CN107235947B (zh)

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CN113549044A (zh) * 2021-07-23 2021-10-26 中国药科大学 8-氮杂环取代色酮类衍生物及其制备方法与制药用途

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WO1997042949A1 (en) * 1996-05-10 1997-11-20 Bristol-Myers Squibb Company 2-thio or 2-oxo flavopiridol analogs

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113549044A (zh) * 2021-07-23 2021-10-26 中国药科大学 8-氮杂环取代色酮类衍生物及其制备方法与制药用途
CN113549044B (zh) * 2021-07-23 2024-01-23 中国药科大学 8-氮杂环取代色酮类衍生物及其制备方法与制药用途

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