nido-carborane conjugates with ibuprofen, flurbiprofen and fenoprofen: synthesis, characterization, COX inhibition potential and anticancer activity

The search for novel anticancer drugs with reduced side effects and innovative therapeutic approaches remains a significant challenge. Non-steroidal anti-inflammatory drugs (NSAIDs), known to inhibit cyclooxygenase (COX) - an enzyme overexpressed in certain tumors - offer a promising avenue for cancer therapy. Additionally, icosahedral carboranes are emerging as a class of compounds with significant potential in drug design. Combining these two moieties into a single molecule presents a compelling strategy to develop drugs with dual mode of action and enhanced efficacy. Here, we report nido-carborane-NSAID conjugates, linking NSAIDs (ibuprofen, flurbiprofen or fenoprofen) to 7,8-dicarba-nido-undecaborate(-1) via methylene, ethylene or propylene spacers, which were prepared from their corresponding closo-carborane-NSAID conjugates. An efficient method for converting closo-carborane-NSAID conjugates to their corresponding nido derivatives is using CsF, without compromising the sensitive ester groups present in the system. The synthesized conjugates were thoroughly characterized using multinuclear (¹H, ¹¹B, and ¹³C) NMR spectroscopy. The nido-carborane conjugates demonstrated significantly enhanced COX inhibition potency compared to their closo-carborane counterparts, exhibiting a higher selectivity towards human COX-2. Furthermore, the nido-carborane conjugates with ibuprofen, flurbiprofen or fenoprofen incorporating propylene spacers 3b, 6b, and 9b, respectively, displayed the most potent activity against A549 lung cancer cells and in comparison to other tested molecules exhibited better selectivity towards malignant cells, as evidenced by selectivity index values. The main mechanism of action of these NSAID conjugates includes caspase dependent apoptosis synchronized by inhibited cell division and hyperproduction of superoxide anions, hydrogen peroxide and peroxynitrites.