A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

Peter E Ghaly,F G West,Rabab M Abou El-Magd,Jack A Tuszynski,Cassandra D M Churchill

doi:10.18632/oncotarget.9642

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.

Highlights

Noscapine, a phthalide isoquinoline alkaloid, is a natural product that was first isolated and characterized in 1817 by Pierre-Jean Robiquet [1] from the opium poppy, Papaver somniferum
In this paper we report on the synthesis and testing of a novel noscapine analogue
We report the effect of this novel compound 8, on SKBR-3 breast cancer cells, its affinity towards tubulin, as well as its effects on microtubule polymerization

Summary

Introduction

A phthalide isoquinoline alkaloid, is a natural product that was first isolated and characterized in 1817 by Pierre-Jean Robiquet [1] from the opium poppy, Papaver somniferum. It is widely used in many countries as an antitussive (cough suppressant) agent and has a low toxicity profile [2]. Many noscapine analogues have been synthesized and tested, showing anti-cancer activity superior to the parent noscapine. The first generation noscapinoids were generated by chemically modifying the isoquinoline and benzofuranone rings of noscapine. This includes the 9'-halogenated (chloro-, bromo- and iodo-noscapine) [11], 9'-amino [12], 9'-nitro [13] and the 9'-azido analogues [14]. Third-generation noscapinoids were synthesized by modifying the substituents coupled to the nitrogen of the isoquinoline ring (Figure 1) [17]

Methods

Results

Conclusion