A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation

Abstract

Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug.

A Novel Class of N‐Sulfonyl and N‐Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells

“…Tubulin‐binding studies have previously discovered that noscapine reduces the rate of polymerisation, represented as maximal initial velocity (V max ), in a concentration‐dependant manner . This microtubule‐destabilising effect of noscapine has also been retained by several noscapinoids . To determine if the antimitotic effect of 14 q is due to interaction with tubulin subunits, tubulin polymerisation studies were done in the absence or presence of known tubulin ligands (10 μM) – paclitaxel ( 3 ) and noscapine ( 4 ) (Figure ).…”

1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure

“…As a MT‐destabilising agent, noscapine ( 1 ) was previously found to reduce the maximum initial velocity (V max ) of tubulin polymerisation in a concentration‐dependant manner [6] . This inhibitory action has also been consistently observed across the years by various noscapine research groups [11,12,24,37] . The key compounds of this series, 14 e and 20 , were evaluated for their capacity to inhibit tubulin polymerisation.…”

“…[6] This inhibitory action has also been consistently observed across the years by various noscapine research groups. [11,12,24,37] The key compounds of this series, 14 e and 20, were evaluated for their capacity to inhibit tubulin polymerisation. Tubulin polymerisation was induced with GTP, followed by addition of ligands at 10 μM.…”

Noscapine as Anticancer Agent & Its Role in Ovarian Cancer

“…Over the past years, many analogs of Noscapine have been synthesized and tested for anti-cancer activity, which is found superior to the parent Noscapine. These derivatives were chemically synthesized by modifying the parent Noscapine, whereas keeping the parent scaffold intact [24]. There are three generations of noscapinoids; first-generation noscapinoids were chemically synthesized by modifying isoquinoline and benzofuranone rings of Noscapine [25].…”