The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms.

5‐Lipoxygenase converts arachidonic acid into leukotrienes, which are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. Herein we report the syntheses of several carborane‐based inhibitors of the 5‐lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity toward several melanoma and colon cancer cell lines. For the colon cancer cell line HCT116, the co‐inhibition of heat shock protein 90 was observed.

The role of autophagy in cancer is often complex, ranging from tumor-promoting to -suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo-[3-(η 6 -p-cymene)-1-(quinolin-8-yl-acetate)-3,1,2-RuC 2 B 9 H 10 ](4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor-promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy-prone glioblastomas. [a] Dr. . Results from flow cytometric and fluorescence microscopy analysis, and wound healing assay of MCF-7 cells incubated (72 h) with 3 and 4 at 20 μM. (A) CFSE staining (left panel) and wound healing assay (right panel); (B) AnnV/PI double staining; (C) DAPI-stained cells observed under fluorescence microscope (magnification X200). Arrows indicate apoptotic cells; (D) ApoStat staining; (E) AO staining. Experiments were run in triplicate. One representative example per each experiment is shown. For each staining protocol, the respective control (untreated cells) is also shown. (FL1, green channel; FL2, orange channel; FL3, dark red channel).

Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue.

Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. furthermore, it was shown that the carboranemodified derivatives of rofecoxib showed different modes of action that were dependent on the cell type. Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics for the treatment of pain and inflammation 1. Their molecular target is the enzyme cyclooxygenase (COX), which catalyzes the dioxygenation/cyclization of arachidonic acid to form prostaglandin H2 (PGH2), which is further metabolized to prostaglandins (PGs), which in turn act as mediators of inflammation 2. The enzyme occurs as two isoforms: a constitutive one, namely COX-1, producing a basic level of PGs, and an inducible one, namely COX-2, activated by inflammatory stimuli 3. COX-2 expression is also upregulated in multiple human cancers 4,5. There is a substantial body of evidence that genetic deletion or pharmacological inhibition of COX-2 abrogates tumorigenesis 6-11. Thus, NSAIDs, in particular COX-2-selective inhibitors, have garnered attention as potential cytostatic drugs. For example, rofecoxib was shown to exhibit excellent potential as a cytotoxic agent 8,12-15. In addition to inhibition of COX, it was demonstrated that the cytotoxic activity of NSAIDs also involves the inhibition of other cellular targets. Unfortunately, the widespread use of COX-2-selective inhibitors revealed an increased risk for cardiovascular adverse effects in long-term therapy 16,17. This prompted research into the development of COX-2-selective inhibitors with improved cardiovascular safety profiles. One promising approach is the incorporation of nitric oxide (NO)-releasing moieties into the structures of COX inhibitors, given that NO has vasodilatory activity and inhibits platelet aggregation 18-22. Moreover, as NO plays an important role in the formation and progression of various cancers 23 , NO-releasing analogues of rofecoxib (Fig. 1) were evaluated for their cytotoxic potency. These compounds retained an inhibitory potential against COX-2 similar to that of rofecoxib but exhibited even higher cytotoxic activity 24,25. The highly dynamic field of drug design and synthesis is constantly in search of new pharmacophores. Recently, polyhedral heteroboranes, namely dicarba-closo-dodecaboranes (carboranes) 26 , have been increasingly studied as hydrophobic moieties 27,28. Carboranes are icosahedral clusters composed of ten BH and two CH vertices; different positions of the CH vertices give rise to ortho (1,2-), meta (1,7-), and...