Carboranyl Analogues of Celecoxib with Potent Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines
Carboranyl Analogues of Celecoxib with Potent Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines
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DOI：
10.1002/cmdc.201800685
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发表时间：
2019-02-05
期刊：
影响因子：
3.4
通讯作者：
Hey-Hawkins, Evamarie
中科院分区：
文献类型：
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作者：
Buzharevski, Antonio;Paskas, Svetlana;Hey-Hawkins, Evamarie
非甾体抗炎药（NSAIDs）是治疗炎症性疾病最常见的方法。它们的广泛使用有助于揭示它们作为药物的其他作用方式，例如对各种癌症的深远影响。塞来昔布已被证明是这类药物中具有细胞抑制活性的重要成员。另一方面，高度动态的药物设计领域正在不断寻找修改已知结构的新方法，以获得更强效和更少有害的药物。一个非常有趣的发展是碳硼烷在药理活性结构中的应用，主要是作为苯基模拟物。本文报道了三种含碳硼烷的cox -2选择性非甾体抗炎药塞来昔布衍生物的合成。这些新化合物被证明对各种黑色素瘤和结直肠癌细胞系具有良好的细胞抑制潜力。用最有效的塞来昔布类似物3b（4-[5-（1,7-二碳-近十二硼基）-3-三氟甲基- 1h -吡唑-1-酰基]-1-甲基磺酰基苯）治疗后，发现增殖抑制伴随caspase非依赖性凋亡细胞死亡是细胞活力下降的主要原因。
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common way of treating inflammatory disorders. Their widespread use helped reveal their other modes of action as pharmaceuticals, such as a profound effect on various cancers. Celecoxib has proven to be a very prominent member of this group with cytostatic activities. On the other hand, the highly dynamic field of drug design is constantly searching for new ways of modifying known structures to obtain more powerful and less harmful drugs. A very interesting development is the implementation of carboranes in pharmacologically active structures, mostly as phenyl mimetics. Herein we report the synthesis of three carborane-containing derivatives of the COX-2-selective NSAID celecoxib. The new compounds proved to have promising cytostatic potential against various melanoma and colorectal adenocarcinoma cell lines. Inhibited proliferation accompanied by caspase-independent apoptotic cell death was found to be the main cause of decreased cell viability upon treatment with the most efficient celecoxib analogue, 3 b (4-[5-(1,7-dicarba-closo-dodecaboranyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-1-methylsulfonylbenzene).