Synthesis, anti-proliferative activity, SAR study, and preliminary in vivo toxicity study of substituted N,N′-bis(arylmethyl)benzimidazolium salts against a panel of non-small cell lung cancer cell lines

Abstract

A series of N,N′-bis(arylmethyl)benzimidazolium salts have been synthesized and evaluated for their in vitro anti-cancer activity against select non-small cell lung cancer cell lines to create a structure activity relationship profile. The results indicate that hydrophobic substituents on the salts increase the overall anti-proliferative activity. Our data confirms that naphthylmethyl substituents at the nitrogen atoms (N1(N3)) and highly lipophilic substituents at the carbon atoms (C2 and C5(C6)) can generate benzimidazolium salts with anti-proliferative activity that is comparable to that of cisplatin. The National Cancer Institute’s Developmental Therapeutics Program tested 1, 3–5, 10, 11, 13–18, 20–25, and 28–30 in their 60 human tumor cell line screen. Results were supportive of data observed in our lab. Compounds with hydrophobic substituents have higher anti-cancer activity than compounds with hydrophilic substituents.

Recent Developments in the Medicinal Applications of Silver-NHC Complexes and Imidazolium Salts

“…Authors attribute this to the release of silver. This further establishes the importance of the relationship between lipophilicity and cytotoxicity, as demonstrated in previous studies [ 95 , 96 , 97 , 98 ].…”

Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N′bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC

“…Although it has been shown that the quinolylmethyl substituent at the N 1 or N 3 position could be used to increase solubility and not severely alter anti-cancer activity, 11–13 the highest anti-cancer activities were observed with the most lipophilic compounds containing two naphthylmethyl substituents. Therefore, molecular excipients such as cyclodextrins (CD), which have been used to improve drug solubility and the bioavailability of such compounds, 14 were considered to aid in solubilizing highly lipophilic and highly active compounds.…”

Synthesis, characterization, and biological activity of a triphenylphosphonium-containing imidazolium salt against select bladder cancer cell lines

“…Therefore the aqueous solubility achieved by the substitution of imidazolium salts with a TPP moiety was desirable. The biscationic nature of TPP1 has considerably enhanced the water solubility to 8 mg/mL as compared to previously reported systems such as starting material 1, which has a solubility of <1 mg/mL [46]. While the aqueous solubility is helpful for aiding in the process of TPP1 delivery, it is important to balance that with sufficient lipophilicity to diffuse across the cell membrane.…”

“…The synthesis outlined in Scheme 1 shows the synthetic strategy used to produce the triphenylphosphonium (TPP)-substituted benzimidazolium salt (TPP1). 2-(3hydroxypropyl)-1,3-bis(naphthalen-2-ylmethyl)benzimidazolium bromide (1) was synthesized, using a previously published procedure [46]. To transform the alcohol to a TPP substituent, compound 1 was reacted with thionyl bromide to form the alkyl halide.…”

“…In addition, imidazolium salts have been of great interest for their biological activity [36][37][38][39][40][41][42][43]. The focus of the Youngs' group has been the anticancer potential of imidazolium salts and their extensive structure activity relationships [44][45][46][47][48]. Furthermore, some imidazolium salts have been shown to induce apoptosis and disrupt the MMP of lung cancer cells [48].…”