Interaction of β-Carboline Alkaloids with RNA

Abstract

β-Carboline alkaloids are present in medicinal plants such as Peganum harmala L., which have been used as folk medicine in anticancer therapy. Recently, they have drawn attention because of their antitumor activities. Despite considerable interest and investigations on alkaloid-DNA complexes, reports on alkaloid-RNA interaction are very limited. This study is the first attempt to investigate the binding of β-carboline alkaloids (harmine, harmane, harmaline, harmalol, and tryptoline) with yeast RNA. The effect of alkaloid complexation on RNA aggregation and condensation was investigated in aqueous solution at physiological conditions, using constant RNA concentration (6.25 mM) and various alkaloid:polynucleotide (phosphate) ratios of 1:240, 1:160, 1:80, 1:40, 1:20, 1:10, 1:5, 1:2, and 1:1. Fourier transform infrared and UV-visible spectroscopic methods were used to determine the ligand-binding modes, the binding constants, and the stability of alkaloid-RNA complexes in aqueous solution. Spectroscopic evidence showed major binding of alkaloids to RNA with overall binding constants of K(harmine)-RNA = 2.95 × 10⁷ M⁻¹, K(harmane)-RNA = 5.62 × 10⁵ M⁻¹, K(harmaline)-RNA = 7.47 × 10⁵ M⁻¹, K(harmalol)-RNA = 4.32 × 10⁵ M⁻¹, and K(tryptoline)-RNA = 3.21 × 10⁵ M⁻¹. The affinity of alkaloids-RNA binding is in the order of harmine > harmaline > harmane > harmalol > tryptoline. No biopolymer secondary structural changes were observed upon alkaloid interaction and RNA remains in the A-family structure in these complexes.

Binding affinity and in vitro cytotoxicity of harmaline targeting different motifs of nucleic acids: An ultimate drug designing approach

“…Binding constant and stoichiometry values inferred strong preference of harmaline towards ss poly(A), followed by ds CT DNA, ds poly(G)·poly(C), and least binding affinity with clover leaf tRNA Phe . The binding constant of harmaline with both DNA and RNA has been found to be very close to the values reported by Nafisi et al…”

“…Binding constant and stoichiometry values inferred strong preference of harmaline towards ss poly(A), followed by ds CT DNA, ds poly(G)·poly(C), and least binding affinity with clover leaf tRNA Phe . The binding constant of harmaline with both DNA and RNA has been found to be very close to the values reported by Nafisi et al 42,43 The strong fluorescence spectrum of harmaline further provides a suitable tool to observe the interaction phenomena. Harmaline gave a high emission spectral peak at 480.…”

Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids

“…Substitution of formate at R 3 and aryl at R 9 of the tricyclic skeleton respectively decreased neurotoxicity and increased the inhibitory effects of the alkaloids that made them ideal agents to be used as novel antitumor drugs with lesser side effects. [55] Several in vitro and in vivo studies have revealed that these cytotoxicity and antitumor effects of P. harmala are related to its interaction with RNA,[59] DNA and its synthesis,[5660] and inhibition of human Topoisomerase. [58] In a study conducted in Iran, it was shown using the DNA relaxation assay that the extract of P. harmala inhibits human DNA Topoisomerase I.…”

The novel synthetic compound 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b]indole induces mitotic arrest and apoptosis in human COLO 205 cells

“…Carbazole alkaloids are well-known natural compounds, some of which display anticancer activity (24)(25)(26). The β-carboline alkaloids occurring in medicinal plants have gained attention because of their antitumor effects (27). However, research on the anticancer activity of α-carboline (isostere of β-carboline) derivatives is relatively limited.…”