Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the most widely used therapeutics against pain, fever, and inflammation; additionally, antitumor properties are reported. NSAIDs reduce the synthesis of prostaglandins by inhibiting the cyclooxygenase (COX) isoforms COX‐1 and COX‐2. As nonselective inhibition is associated with off‐target effects, strategies to achieve selectivity for the clinically preferred isoform COX‐2 are of high interest. The modification of NSAIDs using carborane clusters as phenyl mimetics is reported to alter the selectivity profile through size exclusion. Inspired by these findings, isonimesulide and its carborane derivatives are prepared. The biological screening shows that the carborane containing compounds exhibit a stronger antitumor potential compared to nimesulide and isonimesulide. Furthermore, the replacement of the phenyl ring of isonimesulide with a carborane moiety resulted in a shift of the COX activity from nonactive to COX‐active compounds.

The cylcooxygenase isoforms COX‐1 and COX‐2 are involved in the production of prostaglandins in physiological and pathological processes. The overexpression of COX‐2 under inflammatory conditions, its role in cancer and neurodegenerative diseases necessitates the need to develop and improve nonsteroidal anti‐inflammatory drugs. These mainly unselective COX inhibitors, e.g. aspirin, are used to reduce the symptoms of inflammation. To reduce unwanted side effects connected with unselective inhibition, the development of novel COX‐2 selective inhibitors is a major goal. Herein, the synthesis, characterization and in vitro biological evaluation of eight flurbiprofen‐ and celecoxib‐based carborane analogs are described. Carboranes as hydrophobic surrogates are suitable substituents that can contribute to a selectivity increase toward COX‐2 due to size exclusion. The inhibitory efficacy for COX‐1 and COX‐2 of the four ortho‐ and four nido‐carborane derivatives has been tested. The nido compounds are much more potent than their closo‐carborane analogs. The celecoxib‐based nido‐carborane compound 10 shows an IC₅₀(COX‐2) value in the sub‐μM range and slight selectivity for COX‐2. This is in contrast to its ortho‐carborane counterpart 9, which shows an inhibition preference for COX‐1. While none of these carborane derivatives outperforms their organic analogs, the flurbiprofen‐based nido‐carborane derivatives 14a and 14b surpass the known carborane‐based flurbiprofen analogs.

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with a severe stromal reaction mediated by pancreatic stellate cells (PSCs), leading to increased resistance to chemotherapy and radiotherapy. Following a repurposing concept, this preclinical study investigates the potential of approved drugs, known to be modulators of cellular copper transport, in combination with cisplatin for therapeutic approaches in PDAC. Two major strategies were pursued: (i) inhibiting copper transporters ATP7A and B with tranilast (TR) and omeprazole (OM) to block the cellular copper and, potentially, also cisplatin efflux, and (ii) using the chelator elesclomol (ES) to elevate intracellular copper and cisplatin levels. Human cell lines PanC-1 (PDAC), HPaSteC (PSC), and their co-culture, as well as the hepatocellular carcinoma cell line HepG2 as a reference model, were used. In addition to an analysis of the expression of copper transport proteins, the dynamics of cellular copper uptake and transport were monitored using a [⁶⁴Cu]CuCl₂ radiotracer approach. In vitro, all drugs enhanced cellular copper uptake and/or reduced copper efflux. Moreover, all drugs contributed to the enhanced cellular anticancer activity of cisplatin, with ES being the most effective compound. The results suggest that the targeted modulation of copper transport mechanisms may offer novel adjuvant approaches for the treatment of PDAC.

The significant side effects associated with platinum-based anticancer agents have driven the continuous pursuit of novel, non-platinum-based metal compounds. Ruthenium-based organometallic compounds have emerged as promising alternatives, owing to their distinctive and adaptable biochemical properties. The research efforts are focused on the development of ruthenacarborane-based anticancer drugs. The combination of ruthenium(II) complexes, recognized for their inherent anticancer potential, with carboranes, boron-rich clusters possessing unique chemical and physical characteristics, and NSAIDs, known to inhibit COX, an enzyme overexpressed in tumors, offers a novel approach for cancer therapy. Consequently, combining these three moieties into a single molecule represents a compelling strategy to develop drugs with a dual mode of action. Herein, we report the synthesis of a series of ruthenacarborane-(η⁶-p-cymene)–NSAID conjugates (4a, 4b, 5b, and 6b) by linking NSAIDs (flurbiprofen, fenoprofen, and ibuprofen) to ruthenacarborane complexes using methylene and ethylene spacers, while maintaining the integrity of the sensitive ester groups present in the system. The synthesized conjugates were thoroughly characterized using multinuclear (¹H, ¹¹B, and ¹³C) NMR spectroscopy. Notably, the conjugates demonstrated low COX inhibition and no cytotoxic potential against different cancer cell lines, probably due to oxidative deactivation confirmed by cyclic voltammetry (CV). This indicates that the conjugation of this type of ruthenacarborane with NSAIDs does not result in novel anticancer drugs.

Cyclooxygenase‐2 (COX‐2) and 5‐lipoxygenase (5‐LO) are key enzymes in prostanoid and leukotriene signaling and are overexpressed in various cancers, correlating with malignancy and metastasis. This renders them promising molecular targets for radiotracer development. In this study, isomeric closo ‐dicarbadodecaborane(12)‐based dual COX‐2/5‐LO inhibitors ( 1 and 2 ) served as scaffolds for iodine‐123‐labeling. Iodinated derivatives 3 and 4 inhibited 5‐LO more potently than COX‐2 in vitro ( IC ₅₀ 0.62 µM and 41.3 µM ( 3 ); 0.54 µM and 67.7 µM ( 4 )). Radioiodination yielded 39%–71% of [ ¹²³ I]3 and [ ¹²³ I]4 ; and the formulations were stabilized with antioxidants. Cellular uptake of [ ¹²³ I]3 and [ ¹²³ I]4 was evaluated in human cells with distinct COX‐2 and 5‐LO expression: U87 glioblastoma, HT‐29 colorectal carcinoma cells, THP‐1 monocytes (MC) and macrophages. Consistent with the observed inhibitory potency, the uptake of the radiotracers proved to be independent of COX‐2 expression. In contrast, it was influenced by 5‐LO expression in tumor but not inflammatory cells. Single‐photon emission computed tomography imaging in tumor xenograft mouse models revealed no tumor retention of [ ¹²³ I]3 and [ ¹²³ I]4 due to rapid metabolism via radiodeiodination. Despite successful radiosynthesis and in vitro evaluation of iodine‐123‐labeled COX‐2/5‐LO inhibitors, improved inhibitory activity and stability are required for development of suitable radiotracers.

Dicarbadodecaboranes (12) (carboranes) are versatile molecular building blocks with unique properties, which allow the expansion of classical medicinal-chemical space. To enable single-photon emission computed tomography (SPECT) imaging of cyclooxygenase-2 (COX-2), we investigated the feasibility of introducing iodine-123 into nido-indoborin 1, a nido-carborane analog of indomethacin with potent and selective cyclooxygenase-2 inhibitory activity. An electrophilic iodination strategy afforded two regioisomers, 2a and 2b, bearing the iodine at the carborane cluster. Compared to nido-indoborin, a reduced COX-2 inhibition potency and selectivity were observed, with 2b exhibiting the more favorable inhibition profile. Radiosynthesis of [¹²³I]2b was achieved by N-chlorosuccinimide–mediated electrophilic substitution of 1, and conditions were optimized, leading to an isolated radiochemical yield of 4%. While the radiotracer displayed high stability in phosphate buffer, ester hydrolysis was observed in human plasma and murine liver microsomes with no significant deiodination in vitro. Cell uptake studies indicated partial COX-2–dependent accumulation but also revealed substantial non-specific uptake and unexpected enhancement of radiotracer uptake in the presence of carborane-based blocking agents. In vivo pilot imaging studies in mice bearing U87 xenografts showed renal and hepatobiliary clearance without measurable tumor accumulation but evidence of deiodination over time. Overall, iodination was feasible, but the resulting compounds lacked the required COX-2-selective tumor accumulation for further radiotracer development.