Synthesis and in Vitro Cytotoxicity Evaluation of Phenanthrene Linked 2,4- Thiazolidinediones as Potential Anticancer Agents

Abstract

Objective: To synthesize a series of phenanthrene-thiazolidinedione hybrids and explore their cytotoxic potential against human cancer cell lines of A-549 (lung cancer), HCT-116 and HT-29 (colon cancer), MDA MB-231 (triple negative breast cancer), BT-474 (breast cancer) and (mouse melanoma) B16F10 cells. Methods: A new series of phenanthrene-thiazolidinedione hybrids was synthesized via Knoevenagel condensation of phenanthrene-9-carbaldehyde and N-alkylated thiazolidinediones. The cytotoxicity (IC50) of the synthesized compounds was determined by MTT assay. Apoptotic assays like (AO/EB) and DAPI staining, cell cycle analysis, JC-1 staining and Annexin V binding assay studies were performed for the most active compound (Z)-3-(4-bromobenzyl)-5-((2,3,6,7- tetramethoxyphenanthren-9-yl)methylene)thiazolidine-2,4-dione (17b). Molecular docking, dynamics and evaluation of pharmacokinetic (ADME/T) properties were also carried out by using Schrödinger. Results and Discussion: From the series of tested compounds, 17b unveiled promising cytotoxic action with IC50 value of 0.985 ± 0.02 μM on HCT-116 human colon cancer cells. The treatment of HCT-116 cells with 17b demonstrated distinctive apoptotic morphology like shrinkage of cells, horseshoe shaped nuclei formation and chromatin condensation. Flow-cytometry analysis revealed the G0/G1 phase cell cycle arrest in a dose dependent fashion. The AO/EB, DAPI, DCFDA, Annexin-V and JC-1 staining studies were performed in order to determine the effect of compound on cell viability. Computational studies were performed by using Schrödinger to determine the stability of the ligand with the DNA. Conclusion: The current study provides an insight on developing a series of phenanthrene thiazolidinedione derivatives as potential DNA interactive agents which might aid in colon cancer therapy.

Triazolo‐linked benzimidazoles as tubulin polymerization inhibitors and DNA intercalators: Design, synthesis, cytotoxicity, and docking studies

“…AO permeates the intact cell membrane and stains the nuclei green, while EB stains only the nuclei of cells which have lost membrane integrity to red‐colored fluorescence. [ 20,52 ] It can be inferred from Figure 8 that the control cells exhibited normal morphology and appeared green in color. Whereas the cells treated with compound 12j clearly unveiled the morphological changes such as cell shrinkage, membrane blebbing, chromatin condensation, and apoptotic body formation, dose‐dependently implying that the compound prompted apoptosis in SK‐Mel‐28 cells.…”

“…AO permeates the intact cell membrane and stains the nuclei green, while EB stains only the nuclei of cells which have lost membrane integrity to red-colored fluorescence. [20,52] It can be inferred from Figure 8 reported method. [38,53,54] As shown in Figure 9 Effect of 12j on reactive oxygen species (ROS) generation.…”

Expedition of sulfur‐containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update

“…Molecular docking studies revealed that compound 89 is a potential molecule to be advanced as a DNA interactive cytotoxic representative for colon cancer therapy. 123 The structures of various thiazolidinedione molecules supplemented by their SAR are illustrated in Figures 11 and 12. Figure 13 on the other hand displays a brief SAR regarding the heterocyclic rings which can be hybridized with these scaffolds to obtain potential cytotoxic candidates.…”

“…Additionally, 89 lead to apoptosis induction and caused cell cycle arrest at the G0/G1 phase. Molecular docking studies revealed that compound 89 is a potential molecule to be advanced as a DNA interactive cytotoxic representative for colon cancer therapy 123 …”

Synthesis, anticancer evaluation and in silico studies of novel N‐substituted arylidenethiazolidine‐2,4‐dione derivatives as adenosine monophosphate‐activated protein kinase activators

“…In the quest of newer and potent anticancer agents, molecular-hybridization approach turned out as an important strategy in the design and development of small molecule-based kinase inhibitors/activators for cancer therapy [9,10]. For that purpose, thiazolidine 2,4-dione skeleton has been extensively utilized to obtain novel anticancer agents [11][12][13]. For instance, combination of 2,4-thiazolidinone with privileged scaffolds (Figure 1) such as pyrazole (I) [14], thiazole (II) [15], pyridine (III) [16], quinoline (IV) [17], coumarin (V) [18], and indole (VI) [19] led to potent anticancer activities against numerous cell growths.…”