9-Arylimino noscapinoids as potent tubulin binding anticancer agent: chemical synthesis and cellular evaluation against breast tumour cells

ABSTRACT

A library of 9-arylimino derivatives of noscapine was developed by coupling of Schiff base containing imine groups. Virtual screening using molecular docking with tubulin revealed three molecules, 12–14 that bind with high affinity. An improved predicted free energy of binding (FEB) of −5.390, −6.506 and −6.679 kcal/mol for the molecules 12–14 was found compared to noscapine (−5.135 kcal/mol). Furthermore, molecular dynamics simulation in combination with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) revealed robust binding free energy of −166.03, −169.75 and −170.63 kcal/mol for the molecules 12, 13 and 14, respectively. These derivatives were strategically synthesized and experimentally validated for their anticancer activity. Tubulin binding assay revealed substantial binding of molecules 12–14 with purified tubulin. Further, their anticancer activity was demonstrated using two cancer cell lines (MCF-7 and MDAMB-231) and a panel of primary breast tumour cells. All these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 30.1 and 5.8 µM, which is 1.7 to 7.52 fold lower than that of noscapine. Further, these novel derivatives arrest cell cycle in the G2/M-phase followed by induction of apoptosis. Thus, 9-arylimino noscapinoids 12–14 have a great potential to be a novel therapeutic agent for breast cancers.

KEYWORDS:

• Noscapine
• 9-arylimino noscapinoids
• tubulin binding
• anticancer agents
• breast cancer

Acknowledgements

We would like to acknowledge OHEPEE, Govt. of Odisha for providing financial support through World Bank under Centre of Excellence in Natural Products and Therapeutics, Sambalpur University. We are grateful to Dr Manu Lopus and UM-DAE Centre for Excellence in Basic Sciences, Mumbai for providing extended facilities. We are also grateful to Satyandra Kumar Singh, Center for Advance Research, Stem Cell and Tissue Culture Laboratory, King George’s Medical University for providing extended facilities to test the molecules with primary breast tumour cells.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplementary data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1891567.

Additional information

Funding

This work was supported by the OHEPEE Govt. of Odisha [OHEPEE-SU].