[(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), an organometallic derivative of the irreversible cyclooxygenase-1/2 (COX-1/2) inhibitor acetylsalicylic acid (ASS), demonstrated high growth-inhibitory potential against various tumor cell lines and inhibition of both COX isoenzymes. With the objective of increasing the selectivity for COX-2, we introduced a chlorine substituent in position 3, 4, 5, or 6 of the ASS moiety, respectively. Increased COX-2 selectivity is desirable as this isoenzyme is predominantly related to the development of cancer and abnormal tissue growth. The new compounds were investigated in comprehensive cellular biological assays to identify the impact of the chlorine substitution at the complex on COX-1/2 inhibition, antiproliferative activity, apoptosis, metabolic activity, cell-based COX inhibition, and cellular uptake. Chlorination distinctly reduced the effects at isolated COX-1 (about 25% inhibition at 10 μM; Co-ASS: 82.7%), while those at COX-2 remained almost unchanged (about 65% inhibition at 10 μM; Co-ASS: 78.5%). In cellular systems, with exception of the 6-Cl derivative, all compounds showed notable antitumor activity in COX-1/2 expressing tumor cells (HT-29 (IC₅₀ = 1.5–2.7 μM), MDA-MB-231 (IC₅₀ = 5.2–8.0 μM)), but were distinctly less active in the COX-1/2-negative MCF-7 breast cancer cell line (IC₅₀ = 15.2–22.9 μM). All complexes possess high selectivity for tumor cells, because they did not influence the growth of the non-tumorigenic, human bone marrow stromal cell line HS-5. These findings clearly demonstrate that the interference with the COX-1/2 cascade contributes to the mode of anticancer action of the cobalt alkyne complexes.

中文翻译：

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乙酰水杨酸衍生的氯化钴炔烃复合物作为新的特异性抗肿瘤药†

[（丙-2-炔基）-2-乙酰氧基苯甲酸酯]二钴六羰基（Co-ASS）是不可逆的环加氧酶-1/2（COX-1 / 2）抑制剂乙酰水杨酸（ASS）的有机金属衍生物，具有高度的生长抑制作用对各种肿瘤细胞系的潜在潜能以及对两种COX同工酶的抑制作用。为了提高对COX-2的选择性，我们分别在ASS部分的3、4、5或6位引入了一个氯取代基。由于这种同工酶主要与癌症的发展和组织异常生长有关，因此提高COX-2选择性是可取的。在全面的细胞生物学分析中研究了这些新化合物，以确定复合物中的氯取代对COX-1 / 2抑制，抗增殖活性，细胞凋亡，代谢活性，基于细胞的COX抑制的影响，和细胞吸收。氯化作用明显降低了对分离的COX-1的影响（在10μM时抑制约25％； Co-ASS：82.7％），而对COX-2的作用几乎保持不变（在10μM时抑制约65％； Co-ASS：78.5） ％）。在细胞系统中，除6-Cl衍生物外，所有化合物均在表达COX-1 / 2的肿瘤细胞中表现出显着的抗肿瘤活性（HT-29（IC₅₀ = 1.5–2.7μM），MDA-MB-231（IC ₅₀ = 5.2–8.0μM）），但在COX-1 / 2阴性MCF-7乳腺癌细胞系中的活性明显较低（IC ₅₀ = 15.2 –22.9μM）。所有复合物都对肿瘤细胞具有高选择性，因为它们不影响非致瘤性人骨髓基质细胞系HS-5的生长。这些发现清楚地表明，对COX-1 / 2级联的干扰有助于钴炔烃复合物的抗癌作用模式。