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 carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.
Highlights
The widespread use of COX-2-selective inhibitors revealed an increased risk for cardiovascular adverse effects in long-term therapy[16,17]
It has been shown that the incorporation of a carboranyl moiety in place of a phenyl ring in scaffolds of established NSAIDs can lead to compounds with improved activity[33,34,35,36,37], against COX, and against other targets, such as transthyretin and aldo/keto reductase 1A138,39
Metabolic transformation of rofecoxib occurs at the unsubstituted phenyl ring[40], and a carborane cluster was introduced instead at the 3-position of the butenolide ring of rofecoxib (Fig. 2). o-Carborane was selected because it can be transformed into a nido cluster
Summary
The widespread use of COX-2-selective inhibitors revealed an increased risk for cardiovascular adverse effects in long-term therapy[16,17]. It is known that substituents at the para position of the second phenyl ring in rofecoxib contribute to the COX-2 selectivity of the inhibitor and its analogues[41,42].
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