Development of 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents for the management of breast cancer

Abstract

We developed 1,3-diynyl derivatives of noscapine (an opium alkaloid) through in silico combinatorial approach and screened out a panel of promising derivatives that bind tubulin and display anticancer activity. The selected derivatives such as 9-4-^tBu-Ph-Diyne (20p), 9-3,4-Di-Cl-Diyne (20k) and 9-3,4-Di-F-Diyne (22s) noscapinoids revealed improved predicted binding energy of −6.676 kcal/mol for 20p, −7.294 kcal/mol for 20k and −7.750 kcal/mol for 20s respectively in comparison to noscapine (−5.246 kcal/mol). These 1,3-diynyl derivatives (20p, 29k and 20s) were strategically synthesized in high yields by regioselective modification of noscapine scaffold and HPLC purified (purity is >96%). The decrease in intrinsic fluorescence of purified tubulin to 8.39%, 17.39% and 25.47% by 20p, 20k and 20s respectively, compared to control suggests their binding capability to tubulin. Their cytotoxicity activity was validated based on cellular studies using two human breast adenocarcinoma (MCF-7 and MDA-MB-231), a panel of primary breast tumor cells and one normal human embryonic kidney cell (293 T). The 1,3-diynyl noscapinoids, 20p, 20k and 20s inhibited cellular proliferation in all the cancer cells that ranged between 6.2 and 38.9 µM, without affecting the normal healthy cells (cytotoxicity is <5% at 100 µM). Further, these novel derivatives arrest cell cycle in the G2/M-phase, followed by induction of apoptosis to cancer cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.

Communicated by Ramaswamy H. Sarma

Keywords:

• Noscapine
• 1
• 3-diynyl-noscapinoids
• tubulin binding
• anticancer agents
• breast cancer

Acknowledgements

We would like to acknowledge the financial support provided by the Indian Council of Medical Research (Grant No. 5/13/13/2019/NCD-III) and Department of Science & Technology for infrastructure development under FIST grant (SR/FST/LS-I/2017/9). Rajesh Kumar Meher wishes to acknowledge the award of student research fellowship (DST/INSPIRE/Code No.: IF160351). 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 the tissue samples. CSIR-IICT communication No. IICT/Pubs/2021/263.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

Indian Council of Medical Research (Grant No. 5/13/13/2019/NCD-III) and Department of Science & Technology (FIST grant SR/FST/LS-I/2017/9).