Biological activity and DNA binding studies of 2-substituted benzimidazo[1,2-a]quinolines bearing different amino side chains

Abstract

describes the synthesis and biological activity of 2-substituted benzimidazo[1,2-a]quinolines substituted with different amino side chains on the quinoline nucleus prepared by microwave assisted amination. The majority of compounds were newly synthesized and active at submicromolar IC 50 concentrations, while the alkylamino substituents, either acyclic or cyclic, increased antitumor activities in comparison with previously published nitro and amino substituted benzimidazo [1,2-a]quinolines. The compound with the longest tertiary amino side chain ( 16) was the least active. A series of additional experiments, including DNA binding propensities, topoisomerases I and II inhibition, inhibition of recombinant green fluorescent protein in a cell-free translation system, cell cycle perturbances and cellular localization, was performed to shed more light on the mechanisms of action of the most active compounds. The DNA intercalation activity correlates with anti-proliferative effect. Several DNA intercalators (11, 20 and 21) also evidence some sequence selective DNA binding.However, only N,N-dimethylaminopropyl analogue 11 was unequivocally demonstrated to be a strong DNA-binder and intercalative agent, which efficiently targets DNA in the cells, while the activity of compound 10, with a bulky i-butylamino side chain, points to its potential antimitotic activity.

Enhancement of antiproliferative activity by phototautomerization of anthrylphenols

“…Similar results were obtained previously with the cross-linking agent, cisplatin. 49 The irradiation of compound 1 led to a certain inhibition of EGFP expression, but compared to the control, irradiated DNA, this inhibition was not statistically significant, pointing to its lower alkylating potential (Fig. 8).…”

“…49 This system can produce high levels of recombinant proteins if supplemented with an appropriate expression plasmid, T7 RNA polymerase for transcription, and other necessary components for translation, such as amino acids. Briefly, 500 ng of pEGFP-C1 plasmid (Clontech, USA) was incubated with water or the tested compound (at 100 µM concentration) and was irradiated at 350 nm for 5 min, or kept in dark at 24°C.…”

“…49,55,56 If tumor cells were transfected with a prealkylated plasmid coding for a reporter protein GFP with N-methylquinolinium quinone methide, the significant suppression of GFP protein expression was detected. This inhibition was correlated with the amount of DNA adducts formed, i.e.…”

“…54 Moreover, if a prealkylated DNA was also used as a template for coupled transcription and translation, the significant inhibition of reporter protein expression occurs. 49,53 Therefore, to further examine whether the enhancement of tumor cells' growth inhibition is a consequence of DNA alkylation/damage by photogenerated QMs, which is produced by the irradiation of 1, we assessed the expression of Enhanced Green Fluorescence protein (EGFP) in a cell free environment using a high-capacity T7 promoter driven in vitro translation system. The samples of DNA encoding the EGFP gene were incubated with compound 1 (100 µM) and psoralen and subsequently irradiated at 350 nm for 5 min or kept in dark.…”

New [4]helicene derivatives: Synthesis, characterization and photophysical properties

“…1) have excellent fluorescence features [13][14], which make them promising candidates for several important applications in modern electronic and optoelectronic devices. [4]helicene 3 is the smallest PAH that has showed biological activities such as carcinogenic [15], mutagenic [16] and antiproliferative activity [17]. 3,4-dihydrodiol 4 and the corresponding diolepoxide 5 (Fig.…”