Carborane Conjugates with Ibuprofen, Fenoprofen and Flurbiprofen: Synthesis, Characterization, COX Inhibition Potential and In Vitro Activity

Abstract

The most effective anticancer drugs currently entail substantial and formidable side effects, and resistance of tumors to chemotherapeutic agents is a further challenge. Thus, the search for new anticancer drugs as well as novel therapeutic methods is still extremely important. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit COX (cyclooxygenase), overexpressed in some tumors. Carboranes are emerging as promising pharmacophores. We have therefore combined both moieties in a single molecule to design drugs with a dual mode of action and enhanced effectiveness. The NSAIDs ibuprofen, flurbiprofen, and fenoprofen were connected with 1,2-dicarba-closo-dodecaborane(12) via methylene, ethylene or propylene spacers. Three sets of carborane-NSAID conjugates were synthesized and analyzed through multinuclear (¹H, ¹¹B, and ¹³C) NMR spectroscopy. Conjugates with methylene spacers exhibited the most potent COX inhibition potential, particularly conjugates with flurbiprofen and fenoprofen, displaying higher selectivity towards COX-1. Furthermore, conjugates with methylene and ethylene spacers were more efficient in suppressing the growth of human cancer cell lines than their propylene counterparts. The carborane-flurbiprofen conjugate with an ethylene spacer was the most efficient and selective toward the COX-2-negative cell line HCT116. Its mode of action was basically cytostatic with minor contribution of apoptotic cell death and dominance of cells trapped in the division process.

Keywords: carboranes; drug conjugates; fenoprofen; flurbiprofen; ibuprofen.

Scheme 1

Conjugation of carborane derivatives closo‐1‐(CH₂) _n OH‐C₂B₁₀H₁₁ (n=1–3) with ibuprofen, flurbiprofen, and fenoprofen (1 equiv.) using HATU (2 equiv.) and DIPEA (3.8 equiv.) in DCM, rt, 48 h.

Figure 1

Conjugate 5 induced proliferative arrest of HCT116 cells. Cells were exposed to an IC₅₀ concentration of 5 (CV assay) for 72 h followed by Annexin V/propidium iodide (Ann/PI) (A), PI (B), carboxyfluoresceindiacetate succinimidyl ester (CFSE) (C) and dihydrorhodamine 123 (DHR123) (D) staining.