Abstract
The novel 1,2,3-triazolyl-appended N- and O-heterocycles containing amidine 4–11 and amidoxime 12–22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC50 values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6, 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.
Highlights
Nitrogen- and oxygen-containing heterocyclic compounds may be found in pharmaceuticals, natural products, dyes, organic materials, and in biologically active molecules [1,2]
Since nucleic acids are a major target for a large number of antievaluations of novel indole, quinoline and coumarin‐based aromatic amidines 1–11 and cancer drugs, one of our aims was to investigate the binding of small molecules to DNA
Alkynyl derivatives of benzonitrile (1a and 1b), indole (1c and 1d), quinoline (1e–1g) and coumarin (1h and 1i) were synthesized by alkylation with propargyl bromide in the presence of a base
Summary
Nitrogen- and oxygen-containing heterocyclic compounds may be found in pharmaceuticals, natural products, dyes, organic materials, and in biologically active molecules [1,2]. The design of bioactive molecules is primarily focused on novel N-heterocycles, due to their ease of synthesis and possible mimicking of physiological molecules, O-heterocycles have provided potent molecules with a lesser risk of toxicity [2,3] These compounds were found to act via various targets such as protein kinases, histone deacetylases, topoisomerase I and II, carbonic anhydrase, aromatase, sulfatase, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) receptors, monocarboxylate transporters, DNA polynucleotide, tubulin/microtubule system [1,4,5,6,7,8,9,10,11,12,13,14]. Orderhistone to obnew hybrids potent anticancer activity [11]
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