De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells

Akshay Ravish; Rashmi Shivakumar; Zhang Xi; Min Hee Yang; Ji-Rui Yang; Ananda Swamynayaka; Omantheswara Nagaraja; Mahendra Madegowda; Arunachalam Chinnathambi; Sulaiman Ali Alharbi; Vijay Pandey; Gautam Sethi; Kwang Seok Ahn; Peter E Lobie; Basappa Basappa

doi:10.3390/bioengineering10020159

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells

Bioengineering (Basel). 2023 Jan 24;10(2):159. doi: 10.3390/bioengineering10020159.

Authors

Akshay Ravish¹, Rashmi Shivakumar¹, Zhang Xi², Min Hee Yang³, Ji-Rui Yang⁴, Ananda Swamynayaka⁵, Omantheswara Nagaraja⁵, Mahendra Madegowda⁵, Arunachalam Chinnathambi⁶, Sulaiman Ali Alharbi⁶, Vijay Pandey^{4

7}, Gautam Sethi⁸, Kwang Seok Ahn³, Peter E Lobie^{2

4

7}, Basappa Basappa¹

Affiliations

¹ Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
² Shenzhen Bay Laboratory, Shenzhen 518055, China.
³ Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
⁴ Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
⁵ Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India.
⁶ Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
⁷ Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
⁸ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.

Abstract

In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC₅₀ value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC.

Keywords: DFT; STAT3; de novo design; human breast cancer; imidazopyridine; pyrazolines.

Grants and funding

This work was supported by DBT-NER, and Vision Group on Science and Technology (CESEM), Government of Karnataka. This work was also supported by Singapore MOE Tier 1 grant to GS. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2021R1I1A2060024). This work was also supported by the Shenzhen Key Laboratory of Innovative Oncotherapeutics (ZDSYS20200820165400003) (Shenzhen Science and Technology Innovation Commission), China; Shenzhen Development and Reform Commission Subject Construction Project ([2017]1434), China; Overseas Research Cooperation Project (HW2020008) (Tsinghua Shenzhen International Graduate School), China; Tsinghua University Stable Funding Key Project (WDZC20200821150704001); the Shenzhen Bay Laboratory (21310031), China and TBSI Faculty Start-up Funds, China. This project was supported by Researchers Supporting Project number (RSP2023R5), King Saud University, Riyadh, Saudi Arabia.