Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells

Abstract

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...

Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue

“…Taken together, compound 5 provides a good toxicity profile for possible follow-up in vivo studies. In contrast, the carborane-analogues of the COX-2 selective inhibitors, celecoxib and rofecoxib, showed increased toxicity in the low micromolar range towards several cancer cell lines (A375, B16, B16–F10, and HCT116) [ 65 , 66 ]. This underlines that the site for introducing a carborane moiety has to be chosen carefully.…”

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…COX-2 is involved in carcinogenesis, and increasing studies have been conducted on the potential cytotoxic properties of COX-2 selective inhibitors. 226 , 227 , 228 , 229 The incorporation of carborane units into the established anti-inflammatory drugs improved their metabolic stability. 226 Hey-Hawkins and co-workers designed and synthesized several carborane-containing rofecoxib derivatives ( 49 , Figure 6 I), and these compounds showed superior selectivity against melanoma and colon cancer cells in comparison with normal cells.…”

Preparing (Metalla)carboranes for Nanomedicine

“…It is particularly striking that the term “toxicity” is practically exclusively used to indicate the ability of the (metalla)carborane‐based drug, with or without carrier, to promote cell death in the tumour cell line or tissue examined (acute toxicity), and is solely evaluated in terms of half‐maximal inhibitory concentration (IC 50 ). A handful of examples exist, where IC 50 values were calculated for (metalla)carborane and borate compounds against model cell cultures for immune response, based on simple in vitro colorimetric assays, which will be briefly discussed below [51,52,203a,b] . But to the best of our knowledge, no specific investigations on the immune response upon (metalla)carborane‐based treatment, with or without encapsulation in a carrier system, have been reported.…”