Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo

Abstract

Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators—prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line—CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC50 values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.

Isonimesulide and Its Carborane Analogues as Isoform‐Selective COX Inhibitors and Antitumor Agents

“…Furthermore, the structural analogy of a rotating phenyl ring with the 3D icosahedral shape of carboranes made carboranes a great tool for structural modification of a wide range of chemicals, especially for drug design in medical chemistry. [ 28,44,46–48,55–60 ] Thus, carboranes are used as hydrophobic moieties for structural modification of commercially available drugs, [ 28,49,57–60 ] among them many commercial NSAIDs (Figure 2). [ 51,56,61–65 ]…”

2‐Carboranylquinazoline: The Path to an ABCG2 Inhibitor

“…However, carboranes have special properties that go beyond isosteric exchange. Due to their hydrophobicity, incorporation into biologically active molecules is advantageous to specifically address hydrophobic enzyme binding pockets or to increase cell penetration by passive transport [18] . Furthermore, it is assumed that the inorganic nature of the cluster slows down enzymatic degradation of the active compound, thus enhancing its effect or bypassing toxic degradation products [17,19] …”

“…Due to their hydrophobicity, incorporation into biologically active molecules is advantageous to specifically address hydrophobic enzyme binding pockets or to increase cell penetration by passive transport. [18] Furthermore, it is assumed that the inorganic nature of the cluster slows down enzymatic degradation of the active compound, thus enhancing its effect or bypassing toxic degradation products. [17,19] Herein, we present the investigation of modifying a 2phenylquinazolin-4-amine by replacement of the phenyl ring with a carborane moiety, based on its recently published regioisomer QCa, [15] followed by studying the cytotoxicity, human ABCG2 inhibition and the reversal of hABCG2-mediated MXN resistance in an ABCG2-overexpressing cell line.…”

Carborane‐Based Tebufelone Analogs and Their Biological Evaluation In Vitro

“…An approach to obtain selective and potent carborane‐based 5‐LO inhibitors as analogs of Rev‐5901 resulted in decreased inhibitory activity toward 5‐LO [50] . However, the quinoline‐containing analog, CarbZDChin, showed increased cytotoxicity on colon carcinoma in vitro and in vivo [51] . We have recently reported the first carborane‐based dual COX‐2/5‐LO inhibitors that are derived from RWJ‐63556 showing excellent inhibitory potential toward COX‐2 and 5‐LO, accompanied by high anticancer activity on the A357 melanoma cell line [52] …”

“…[50] However, the quinoline-containing analog, CarbZDChin, showed increased cytotoxicity on colon carcinoma in vitro and in vivo. [51] We have recently reported the first carborane-based dual COX-2/5-LO inhibitors that are derived from RWJ-63556 showing excellent inhibitory potential toward COX-2 and 5-LO, accompanied by high anticancer activity on the A357 melanoma cell line. [52] Herein, we report the synthesis of eight carborane-containing tebufelone analogs, their inhibitory potential toward COX-1, COX-2, and 5-LO, as well as their cytotoxicity on five human cancer cell lines.…”