Synthesis and Biological Evaluation of Aza-Crown Ether–Squaramide Conjugates as Anion/Cation Symporters

Abstract

Aim: Anion/cation symport across cellular membranes may lead to cell apoptosis and be developed as a strategy for new anticancer drug discovery. Methodology: Four aza-crown ether–squaramide conjugates were synthesized and characterized. Their anion recognition, anion/cation symport, cytotoxicity and probable mechanism of action were investigated in details. Conclusion: These conjugates are able to form ion-pairing complexes with chloride anions and facilitate the transmembrane transport of anions via an anion/cation symport process. They can disrupt the cellular homeostasis of chloride anions and sodium cations and induce the basification of acidic organelles in live cells. These conjugates exhibit moderate cytotoxicity toward the tested cancer cells and trigger cell apoptosis by mediating the influx of chloride anions and sodium cations into live cells.

Heterocyclic Crown Ethers with Potential Biological and Pharmacological Properties: From Synthesis to Applications

“…This crowded Scheme 5 presents the formation of compounds (8)(9)(10)(11) [55]. As reported earlier, an important structure 1,10-diaza-18-crown-6 was used as a starting material for the synthesis of compounds 2,2 -(1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)diethanamine (2) and 2-(16-ethyl-1,4,10,13-tetraoxa-7,16-diazacyclo-octadecan-7yl)ethaneamine ( 5) [56].…”

Recent Advances in Bioactive Artificial Ionophores

“…Chen and colleagues developed a series of 1,3-bis (benzimidazol-2-yl)benzene (m-Bimbe) derivatives (52)(53) as transmembrane anionophores which exhibit anticancer activity (Figure 15A). [54] The 5-nitrated derivatives bearing trifluoromethyl (53 b) and the ones bearing nitro (53 c) at the benzimidazoloyl subunits were the most cytotoxic carriers among other derivatives tested against a few select cancerous and normal cells.…”

“…Recently anion/cation symporters consisting of aza‐crown ether‐squaramide conjugates were reported by Chen and co‐workers. [53] The most efficient transporter bearing 3,5‐bis(trifluoromethyl)phenyl substituents 51 exhibited moderate cytotoxicity and could basify the acidic organelles, unsettling ionic homeostasis towards the HeLa cells and triggered cancer cell death via apoptosis (Figure 14 I–J).…”

Synthesis and biological activity of squaramido-tethered bisbenzimidazoles as synthetic anion transporters

“…In these aspects, squaramides and (benz)imidazoles represent two classes of ideal structural skeletons for the construction of superior anion transporters. 22–40 This may be ascribed to their unique features, including ready availability, high stability and strong capability to complex anions mainly via hydrogen-bonding interactions. Some simple squaramides, such as trifluoromethylphenyl derivatives have been found to efficiently facilitate the transport of chloride anions across phospholipid bilayers.…”