Journal
ARCHIV DER PHARMAZIE
Volume 355, Issue 2, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ardp.202100408
Keywords
acetylsalicylic acid; anticancer; cobalt-alkyne complex; cyclooxygenase; methyl substituent
Funding
- Osterreichische Forschungsforderungsgesellschaft [West Austrian BioNMR 858017]
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The methylated cobalt-alkyne complexes with enhanced selectivity for COX-2 showed superior cytotoxicity towards COX-positive colon carcinoma cells compared to cisplatin, indicating their potential as alternative antitumor agents.
Derivatives of the cytotoxic cyclooxygenase (COX) inhibitor [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) with a methyl group in the 3, 4, 5, or 6 position of the acetylsalicylic acid (ASS) scaffold were synthesized with the aim to achieve enhanced selectivity for COX-2. From this modification, a higher specificity for COX-2-expressing tumors is expected, preventing COX-1-mediated side effects. The cobalt-alkyne complexes were tested for their COX-inhibitory and antiproliferative properties as well as their cellular uptake. Methylation reduced the effects at the isolated COX-1, whereas those at the isolated COX-2 remained nearly constant compared to Co-ASS. In cellular systems, the new compounds showed superior cytotoxicity toward the COX-positive HT-29 colon carcinoma cells than cisplatin. The reduced growth-inhibitory potency in T-24 cells, which express distinctly fewer COX enzymes (COX-1/COX-2 = 50/1) than HT-29 cells (COX-1/COX-2 = 50/50), and the only marginal activity in COX-negative MCF-7 breast cancer cells point to an interference in the arachidonic acid cascade through COX-2 inhibition as part of the mode of action, especially as the cellular uptake was even higher in MCF-7 cells than in T-24 cells. These findings clearly demonstrate that the methylated cobalt-alkyne complexes possess promising potential for further development as reasonable alternatives to the limited platinum-based antitumor agents.
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