Synthesis, anti-proliferative activity, and toxicity of C4(C5) substituted N,N′-bis(arylmethyl)imidazolium salts

Abstract

The syntheses and characterization of C 4 and C 5 substituted N,N'bis(arylmethyl)imidazolium salts with hydrophilic or lipophilic substituents on the imidazole ring are reported. A structure-activity relationship study revealed that the lipophilicity of groups at the C 4 and C 5 positions plays a crucial role in modulating the efficacy against select non-small cell lung cancer cell lines tested. Compounds 11-17 were determined to be the most active against the panel of cell lines studied. Compounds 11 and 12 were examined by the National Cancer Institute's Developmental Therapeutic Program where they were tested against the NCI-60 human cancer cell line panel in a one-dose and five-dose assay. Compound 11 had high activity against the nine lung cancer lines tested while 12 had cytotoxic effects against 59 of the 60 cell lines. Compound 11 was also studied in a murine model to determine its in vivo toxicity.

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

“…[5,6] The highly lipophilic N,N ′-bis(naphthylmethyl)imidazolium salt 1 exhibited high anti-proliferative activity against several NSCLC cell lines (Figure 2). It was shown that the in vitro anti-tumor activity of 1 was strongly correlated to the two naphthylmethyl substituents at the N 1 and N 3 positions of the imidazole ring.…”

Synthesis, characterization, and in vitro SAR evaluation of N,N′-bis(arylmethyl)-C2-alkyl substituted imidazolium salts

“…12 In particular, naphthylmethyl-substituted imidazolium salts, such as IS29 with a proton at the C 2 position, were shown to have high anti-proliferative effects against non-small cell lung cancer (NSCLC) (Figure 2). 13–16 However, the clinical use of IS29 was limited by poor water solubility. The quinoline motif is structurally similar to a naphthalene substituent but has a nitrogen heteroatom to increase the hydrogen bonding capabilities and increase aqueous solubility, which has been shown previously by our group.…”

“…The quinoline motif is structurally similar to a naphthalene substituent but has a nitrogen heteroatom to increase the hydrogen bonding capabilities and increase aqueous solubility, which has been shown previously by our group. 13,15,16 Also, the nitrogen atom could potentially be protonated to further increase the solubility if necessary. 17 Therefore, the historical quinoline motif and the novel, highly-active naphthylmethyl-based imidazolium salt could be combined to produce potent chemotherapeutics with high aqueous solubility.…”

“…In a separate attempt to increase aqueous solubility, compounds 3, 4-Br, 4-Cl , and 5–7 , with a quinolylmethyl substituent at the N 1 position and a naphthylmethyl substituent at the N 3 position, were synthesized by procedures developed in the Youngs’ lab 13,15,19–21 and evaluated for their anti-cancer properties. The nitrogen heteroatom of the quinoline moiety increases the hydrophilicity of the compound; whereas the naphthalene ring helps to maintain the high anti-cancer activity.…”

“…The anti-cancer properties of 1–3, 4-Br, 4-Cl , and 5–12 against several NSCLC cell lines (NCI-H460, NCI-H1975, HCC827, and A549) were evaluated by the MTT assay, as done previously by our group, 13,15,16 to create a SAR of C 2 substituted imidazolium salts with a highly lipophilic substituent (naphthylmethyl) or a more hydrophilic substituent (quinolylmethyl) at the N 1 and/or N 3 positions (Table 1). Briefly, cells were grown to confluency and plated in 96-well plates at 5,000–7,000 cells per well depending on the cell line.…”