Synthesis, Evaluation of Cytotoxicity and Molecular Docking Studies of the 7-Acetamido Substituted 2-Aryl-5-bromo-3-trifluoroacetylindoles as Potential Inhibitors of Tubulin Polymerization

Abstract

The 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5a–h were prepared and evaluated for potential antigrowth effect in vitro against human lung cancer (A549) and cervical cancer (HeLa) cells and for the potential to inhibit tubulin polymerization. The corresponding intermediates, namely, the 3-unsubstituted 7-acetyl-2-aryl-5-bromoindole 2a–d and 7-acetamido-2-aryl-5-bromoindole 4a–d were included in the assays in order to correlate both structural variations and cytotoxicity. No cytotoxicity was observed for compounds 2a–d and their 3-trifluoroacetyl–substituted derivatives 5a–d against both cell lines. The 7-acetamido derivatives 4–d exhibited modest cytotoxicity against both cell lines. All of the 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5e–h were found to be more active against both cell lines when compared to the chemotherapeutic drug, Melphalan. The most active compound, 5g, induced programmed cell death (apoptosis) in a caspase-dependent manner for both A549 and HeLa cells. Compounds 5e–h were found to significantly inhibit tubulin polymerization against indole-3-carbinol and colchicine as reference standards. Molecular docking of 5g into the colchicine-binding site suggests that the compounds bind to tubulin by different type of interactions including pi-alkyl, amide-pi stacked and alkyl interactions as well as hydrogen bonding with the protein residues to elicit anticancer activity.

A Study of the Crystal Structure and Hydrogen Bonding of 3-Trifluoroacetyloxime Substituted 7-Acetamido-2-aryl-5-bromoindoles

“…The X-ray structure and the DFT optimized counterpart calculated by the B3LYP/6-311G basis set compare favourably and the optimized geometry reproduced the crystal structure parameters well. Since a strong hydrogen bond acceptor (e.g., acetyl, formyl or trifluoroacetyl group) at the C-3 position of the indole framework enhances anticancer activity [5,6], the presence of a dual hydrogen bond donating and accepting ketoxime moiety in this position makes compounds 3 suitable candidates for evaluation of biological activity as potential anticancer agents to correlate between structural variation and cytotoxicity. Molecular docking (in silico) could be used to predict the hypothetical protein-ligand binding mode against tubulin or other relevant examples of enzyme kinases to guide further structure activity relationship (SAR).…”

“…The low-and high-resolution mass spectra were recorded at an ionization potential of 70 eV using Waters Synapt G2 Quadrupole Time-of-flight mass spectrometer (Waters Corp., Milford, MA, USA). Compounds 1a-d were prepared as described in our previous investigation [6].…”

“…Structure-activity relationship (SAR) studies of the polysubstituted indoles revealed that an acetyl or formyl group on C-3 of the indole framework facilitates the interaction with biological receptors and therefore enhances anticancer activity [5]. We evaluated the 3-trifluoroacetyl-substituted 7-acetyl-and 7-acetamido-2-aryl-5-bromoindoles as well as their corresponding C-3 unsubstituted precursors for antigrowth properties against the A549 and HeLa cell lines and for their ability to inhibit tubulin polymerization [6]. Only the 3-trifluoroacetyl substituted 7-acetamido-2-aryl-3-bromoindoles were found to exhibit significant cytotoxicity against the two cancer cell lines and also to inhibit tubulin polymerization.…”

“…Only the 3-trifluoroacetyl substituted 7-acetamido-2-aryl-3-bromoindoles were found to exhibit significant cytotoxicity against the two cancer cell lines and also to inhibit tubulin polymerization. Molecular docking (in silico) of the 2-aryl-5-bromo-3-(trifluoroacetyl)indoles into the colchicine-binding domain of α,β-tubulin interface predicted the presence of a hydrogen bond between the the amide and 3-trifluoroacetyl moieties with some of the protein residues [6]. The propensity of the amide moiety to serve as a dual hydrogen-bond donor and acceptor plays a significant role in the interaction of bioactive compounds with the receptors [4,7].…”

“…Recourse to the literature revealed a paper describing the transformation of a series of α-trifluoromethylated ketoximes to afford optically active α-trifluoromethylated amines, which are important sources of fluorinated pharmaceuticals [9]. We considered the cytotoxicity of the 2-arylindole derivatives [5,6,10] in combination with the literature SAR analyses on indole oximes [1] to transform the strong hydrogen bond accepting trifluoroacetyl group into dual hydrogen-bond donating and accepting α-trifluoromethylated ketoxime function based on the 7-acetyl-2-aryl-3-bromoindole as substrates. The main aim was to study the molecular structure and hydrogen bonding potential of the resultant 3-trifluoroacetyloxime substituted 7-acetamido-2-aryl-3-bromoindole derivatives in the solid state by means of single crystal X-ray diffraction (XRD) technique.…”