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.

Malose Mphahlele,Nishal Parbhoo

doi:10.3390/ph11020059

Malose Mphahlele, Nishal Parbhoo

Open Access

https://doi.org/10.3390/ph11020059

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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.

Highlights

Microtubule targeting agents have an established history of utility in the treatment of cancer and have been instrumental as biological probes to identify the nature of tubulin and the role of tubulin dynamics in mitosis [1]
Compounds 2a–d and 4a–d were subjected to Trifluoroacetic anhydride (TFAA) (1.2 equiv.) in THF under reflux for 5 h to afford the corresponding 7-acetyl 5a–d and 7-acetamido substituted 5-bromo-3-trifluoroacetylindoles 5e–h in moderate to high yields
An acetamido group elicited some cytotoxicity in derivatives 4b–d against both cell lines, which increased significantly upon incorporation of a trifluoroacetyl group in 5e–h

Summary

Introduction

Microtubule targeting agents have an established history of utility in the treatment of cancer and have been instrumental as biological probes to identify the nature of tubulin and the role of tubulin dynamics in mitosis [1]. A nitrogen-containing group on the fused benzo ring of the indole derivatives, on the other hand, was found to lead to increased cytotoxicity against the HeLa and A549 cell lines as well as HIV-1 inhibition activity [6]. A hydrogen bond acceptor such as a formyl group at position 3 of the indole framework of compound (a), for example, facilitates interaction with biological receptors and enhance anticancer activity [9]. Literature precedents revealed that the presence of a trifluoromethyl group at the C-3 position of an indole framework results in increased affinity for lipids (lipophilicity) and metabolic stability of the molecule as well as its activity profile more so than the 3-unsubstituted or 3-acetyl analogues [2,11,12,13]

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