title: 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.
authors: Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
authors: Peter E
authors: PE
authors: Ghaly
authors: Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.|Genetic Engineering and Biotechnology Institute, City of Scientific Research and Technological Application, New Borg El-Arab City, Alexandria, 21934, Egypt.
authors: Rabab M
authors: RM
authors: Abou El-Magd
authors: Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
authors: Cassandra D M
authors: CD
authors: Churchill
authors: Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.|Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors: Jack A
authors: JA
authors: Tuszynski
authors: Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
authors: F G
authors: FG
authors: West
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008870:Microtubules / Q000187:drug effects; D008958:Models, Molecular; D009665:Noscapine / Q000031:analogs & derivatives* / Q000737:chemistry; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D014404:Tubulin; D009665:Noscapine; D017239:Paclitaxel
keywords: docking; fluorescence quenching; microtubules; noscapine; tubulin