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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Fluorination as tool to improve bioanalytical sensitivity and COX-2-selective antitumor activity of cobalt alkyne complexes
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Fluorination as tool to improve bioanalytical sensitivity and COX-2-selective antitumor activity of cobalt alkyne complexes

机译：氟化作为提高生物分析敏感性和Cox-2选择性抗肿瘤活性的工具

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摘要

The cobalt alkyne complex [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) is an auspicious lead, which exhibits its anticancer activity mainly by inhibition of both cyclooxygenases (COX-1 and COX-2). Since COX-2 participates in carcinogenesis, a selective inhibition of that isoenzyme is aimed. To study if fluorination increases the COX-2/COX-1 inhibition ratio of the lead, substitution was respectively performed in the positions 3, 4, 5, and 6 of the aromatic moiety. The complexes 3/4/5F-Co-ASS and to a much lower extent also 6F-Co-ASS showed cytotoxic, antimetabolic, and apoptotic effects in COX-1/2-positive HT-29 and MDA-MB-231 cells and remarkably less activity in the COX-1/2-negative MCF-7 cell line. The metabolic activity in MCF-7 cells was even unaffected up to a concentration of 40 mu M. With exception of 6F-Co-ASS, the complexes strongly reduced the PGE(2) synthesis in HT-29 cells and all complexes inhibited COX-2 more effectively than COX-1 in an assay at isolated enzymes. These findings point to an interference in the COX cascade as part of the mode of antitumor action. The limited cellular effects of 6F-Co-ASS are related to its poor uptake as determined by HR CS AAS/MAS. Moreover, the cellular uptake studies confirm fluorination as beneficial tool for bioanalytical labeling. The higher quantification of fluorine by HR CS MAS makes this method about 5-fold more sensitive than HR CS AAS measuring cobalt. As a further positive result, 3/4/5/6-Co-ASS demonstrated high selectivity to tumor cells due to lack of antimetabolic activity against the non-tumorigenic bone marrow stromal cell line HS-5.
机译：钴炔醇[（prop-2-炔基）-2-乙酰氧基苯甲酸酯]二钴至丙基羰基（CO-ASS）是一种令人愉快的铅，其主要通过抑制环氧氢酶（COX-1和COX-2）来表现出抗癌活性。由于COX-2参与致癌作用，因此针对该同工酶的选择性抑制。为了研究氟化可以增加铅的COX-2 / COX-1抑制比，分别在芳族部分的位置3,4,5和6中进行取代。复合物3/4 / 5F-CO-AS和更低的程度也也是6F-CO-ASS表明COX-1/2阳性HT-29和MDA-MB-231细胞中的细胞毒性，抗体和凋亡作用和凋亡作用在Cox-1/2阴性MCF-7细胞系中具有显着较少的活性。 MCF-7细胞中的代谢活性甚至不受40μm的浓度。除了6F-Co-ass的外，复合物在HT-29细胞中强烈降低了PGE（2）合成，并且所有复合物抑制了Cox- 2在分离的酶的测定中比COX-1更有效。这些发现点指向Cox级联的干扰作为抗询问动作模式的一部分。 6F-Co-As的有限细胞效应与其通过HR CS AAS / MAS确定的差的摄取有关。此外，细胞吸收研究证实氟化作为生物分析标记的有益工具。 HR CS MAS的氟量较高的氟使得该方法比HR CS AAS测量钴比HR CS AAS更敏感。作为进一步的阳性结果，由于针对非致荷骨髓基质细胞系HS-5缺乏抗抗药物活性，3 / 4/5 / 6-CO-AS对肿瘤细胞表现出高选择性。

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