Comparative assessment of 9-bromo noscapine ionic liquid and noscapine: Synthesis, in-vitro studies plus computational & biophysical evaluation with human hemoglobin

Abstract

Noscapine is a proficient anticancer drug active against wide variety of tumors including lung cancer. Over time, several noscapine analogues have been assessed to maximize the efficiency of the drug, amongst which 9-bromo noscapine remains one of the most potent analogues till date. In the present work, we have synthesized 9-bromo noscapine ionic liquid [9-Br-Nos]IBr2, an active pharmaceutical ingredient based ionic liquid (API-IL) to address the existing issues of solubility and targeted drug delivery in the parent alkaloid as well as the synthesized analogues. We have devised a novel two-step synthesis route (first-ever ionic to ionic bromination) to obtain the desired [9-Br-Nos]IBr2 which is advantageous to its organic analogue in terms of increased solubility, lesser reaction time and better yield. Furthermore, we have compared 9-bromo noscapine ionic liquid with noscapine based on its binding interaction with human hemoglobin (Hb) studied via computational along with spectroscopic studies, and bioactivity against non-small cell lung cancer. We inferred formation of a complex between [9-Br-Nos]IBr2 and Hb in the stoichiometric ratio of 1:1, similar to noscapine. At 298 K, [9-Br-Nos]IBr2-Hb binding was found to exhibit Kb and ∆G of 36,307 M−1 and -11.5 KJmol−1, respectively, as compared to 159 M−1 and -12.5 KJmol−1 during Noscapine-Hb binding. This indicates a more stronger and viable interaction between [9-Br-Nos]IBr2 and Hb than the parent compound. From computational studies, the observed higher stability of [9-Br-Nos]I and better binding affinity with Hb with a binding energy of −91.75 kcalmol−1 supported the experimental observations. In the same light, novel [9-Br-Nos]IBr2 was found to exhibit an IC50 = 95.02 ± 6.32 μM compared to IC50 = 128.82 ± 2.87 μM for noscapine on A549 (non-small lung cancer) cell line at 48 h. Also, the desired ionic liquid proved to be more cytotoxic inducing a mortality rate of 87 % relative to 66 % evoked by noscapine at concentrations of 200 μM after 72 h.