N2,N9-Bis(Substituted benzyl)-β-Carbolineum Bromides as Potential Anticancer Therapeutics: Design, Synthesis, Cytotoxicity, Drug-DNA Intercalation and In-Silico Binding Properties

Abstract

The present study reports a series of novel N2,N9-bis(substituted benzyl)-β-carbolineum bromides (4a-f) synthesized from L-tryptophan in three steps with excellent yields (>80%). The structures of synthesized compounds 4a-f were confirmed by 1H- and 13C-NMR, FT-IR, LC-MS (ESI-MS) spectrum and elemental analysis. Meanwhile, the crystal structure for compound 4f was determined by X-ray single-crystal diffraction. The crystal belongs in monoclinic space group in P121/c1 space group with a = 13.253(6) Å, b = 20.809(10) Å, c = 9.116(6) Å, β = 107.215(13)°, V = 2401.4(19) Å3 and Z = 4, F(000) = 1048, Dc = 1.403 Mg/m3 and µ = 1.743 mm−1. Compounds 4a-f were evaluated for their in-vitro anticancer activity against selected human cancer cell lines, such as HT-29 (colorectal adenocarcinoma), HeLa (cervical carcinoma), HepG2 (hepatocellular carcinoma) and K562 (chronic myelogenous leukaemia, CML). Results showed that compounds 4a-f exerted excellent cytotoxicity effect with IC50 values ranging from 0.36-1.08 µM against K562 human CML cell line. It was found that synthesized β-carbolines are much less toxic towards non-cancer cell lines BALB/c3T3 and Hs-27, in comparison to cisplatin and doxorubicin, which were employed as positive controls. To investigate the binding mode of these compounds against DNA, spectroscopic studies were conducted. Subsequent UV-Visible and in-silico (molecular docking) studies revealed that compound 4f interacts with DNA through intercalation. Based on the present findings, it was suggested that compound 4f has a great potential to be developed as a novel anticancer agent.