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Amino Acid Conjugates of Aminothiazole and Aminopyridine as Potential Anticancer Agents: Synthesis, Molecular Docking and in vitro Evaluation

Authors Naz S, Shah FA, Nadeem H, sarwar S, Tan Z, Imran M, Ali T, Li JB, Li S

Received 11 December 2020

Accepted for publication 27 February 2021

Published 1 April 2021 Volume 2021:15 Pages 1459—1476


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Qiongyu Guo

Shagufta Naz,1,2 Fawad Ali Shah,1 Humaira Nadeem,1 Sadia Sarwar,1 Zhen Tan,3 Muhammad Imran,1 Tahir Ali,2 Jing Bo Li,2 Shupeng Li4

1Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan; 2Shenzhen University Clinical Research Center for Neurological Diseases, Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, People’s Republic of China; 3Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 4State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of China

Correspondence: Humaira Nadeem
Riphah Institute of Pharmaceutical Sciences, Riphah International University, G-7/4, 7th Avenue, Islamabad, 44000, Pakistan
Tel +92 51-2891835
Fax +92 51-8350180
Email [email protected]
Shupeng Li
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of China
Email [email protected]

Purpose: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate this therapeutic failure. The current study demonstrated the synthesis of 2-aminothiazole [S3(a-d) and S5(a-d)] and 2-aminopyridine [S4(a-d) and S6(a-d)] derivatives that can target multiple cellular networks implicated in cancer development.
Methods: Biological assays were performed to investigate the antioxidant and anticancer potential of synthesized compounds. Redox imbalance and oxidative stress are hallmarks of cancer, therefore, synthesized compounds were preliminarily screened for their antioxidant activity using DPPH assay, and further five derivatives S3b, S3c, S4c, S5b, and S6c, with significant antioxidant potential, were selected for investigation of in vitro anticancer potential. The cytotoxic activities were evaluated against the parent (A2780) and cisplatin-resistant (A2780CISR) ovarian cancer cell lines. Further, Molecular docking studies of active compounds were performed to determine binding affinities.
Results: Results revealed that S3c, S5b, and S6c displayed promising inhibition in cisplatin-resistant cell lines in comparison to parent cells in terms of both resistance factor (RF) and IC50 values. Moreover, S3c proved to be most active compound in both parent and resistant cell lines with IC50 values 15.57 μM and 11.52 μM respectively. Our docking studies demonstrated that compounds S3c, S5b, and S6c exhibited significant binding affinity with multiple protein targets of the signaling cascade.
Conclusion: Anticancer activities of compounds S3c, S5b, and S6c in cisplatin-resistant cell lines suggested that these ligands may contribute as lead compounds for the development of new anticancer drugs.

Keywords: thiazole, pyridine, antioxidant activity, anticancer activity, molecular docking

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