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. 2021 Apr 1:15:1459-1476.
doi: 10.2147/DDDT.S297013. eCollection 2021.

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

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 Li  4
Affiliations

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

Shagufta Naz et al. Drug Des Devel Ther. .

Abstract

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: anticancer activity; antioxidant activity; molecular docking; pyridine; thiazole.

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Conflict of interest statement

The authors report no conflicts of interest for this work.

Figures

Figure 1
Figure 1
Synthesis of 2-aminothiazole and 2-aminopyridine derivatives.
Figure 2
Figure 2
Proposed reaction mechanism to synthesize compound S5.
Figure 3
Figure 3
Proposed reaction mechanism to synthesize compound S6.
Figure 4
Figure 4
DPPH radical scavenging activity of synthesized derivatives.
Figure 5
Figure 5
IC50 values of compounds and cisplatin (standard) as observed in the parent (A2780*) and cisplatin-resistant (A2780CISR**) ovarian cancer cell lines. Data are presented as mean ± SEM. One way ANOVA was used for the analysis of these results (n=5).
Figure 6
Figure 6
Post docking analysis visualized by Discovery Studio Visualizer in both 2D and 3D poses in the protein structures of p110a isoform of PI3K. Interaction between S3c and p110a isoform of PI3K (A and B), S5b and p110a isoform of PI3K (C and D). 3D poses (A and C) and 2D (B and D).
Figure 7
Figure 7
Post docking analysis visualized by Discovery Studio Visualizer in both 2D and 3D styles with EGFR. Interaction between S3c and EGFR (A and B), S5b and EGFR (C and D). 3D poses (A and C) and 2D (B and D).
Figure 8
Figure 8
Post docking analysis visualized by Discovery Studio Visualizer in both 2D and 3D poses in the protein structures of VEGFR. Interaction between S3c and VEGFR (A and B), S5b and VEGFR (C and D). 3D poses (A and C) and 2D (B and D).
Figure 9
Figure 9
Post docking analysis visualized by Discovery Studio Visualizer in both 2D and 3D styles with PDGFR. Interaction between S3c and PDGFR (A and B), S5b and PDGFR (C and D). 3D poses (A and C) and 2D (B and D).
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