Probing into 9’-substituted Suzuki-coupled noscapine ionic liquids as potent microtubule targeting anticancer agents with hemoglobin affinity

Abstract

On a global scale, lung cancer accounts for 18% of all cancer deaths making it the most lethal cancer. To restrain this, there has been continual research in the domain of microtubule-targeting anticancer agents but issues like toxicity, immunosuppression, effective delivery to tumor site, etc. persist to impede their clinical success. Unlike the other existing drugs in this regime; noscapine (a non-opioid alkaloid) is testified to be an intrinsically safer drug with minimal side effects. In this work, we have synthesized and evaluated novel 9’-substituted suzuki-coupled noscapine ionic liquid(s) as effectual anticancer drug(s) against non-small cell (H1299) lung cancer. We have devised a synthetic route (employed suzuki coupling for subsuming the biaryl pharmacophore and combined it with the idea of active pharmaceutical ingredient-based ionic liquids (API-ILs)) to yield the desired API-ILs followed by their characterization using associated analytical techniques like NMR, HRMS, etc. Following this, we have performed SAR analysis of the API-ILs using molecular docking with the target tubulin protein and preliminary in vitro screening against H1299 (non-small cancer) cells to opt for the most promising analogue i.e., [p-NO₂-Nos]I. Upon finding the most potent ionic liquid, we carried out MD simulations and MM-PBSA/GBSA calculations to get an insight into its interaction with tubulin and human hemoglobin using computational and spectroscopic studies respectively. From computational studies, we inferred that [p-NO₂-Nos]I forms a stable complex with tubulin mainly driven by non-polar interactions. From spectroscopic studies, we disclosed that [p-NO₂-Nos]I binds to human hemoglobin (Hb) in a 1:1 stoichiometric ratio with a binding constant (K_b) of ~ 1.38 × 10⁵ M⁻¹ at 298 K. Finally, we have examined the cytotoxicity of [p-NO₂-Nos]I against H1299 cancer cell line and compared it to [9-Br-Nos]IBr₂, noscapine and Paclitaxel. The IC₅₀ values for [p-NO₂-Nos]I came out to be 67.84 ± 4.84 µM at 48 h and 19.67 ± 3.1µM at 72 h, both of which were significantly lower than [9-Br-Nos]IBr₂ and Noscapine. The potent [p-NO₂-Nos]I was further screened using A549 cell line and similar results were observed relative to H1299 cell line. Overall, these findings envelop the potential of such enhanced spindle poisons against lung cancer.