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.
A novel vanadium-catalyzed one-pot domino reaction of 1,2-diketones with amidines has been identified that enables their transformation into imides and amides. The reaction proceeds by dual acylation of amidines via oxidative C(CO)-C(CO) bond cleavage of 1,2-diketones to afford N,N'-diaroyl-N-arylbenzamidine intermediates. In the reaction, these intermediates are easily hydrolyzed into imides and amides through vanadium catalysis. This method provides a practical, simple, and mild synthetic approach to access a variety of imides as well as amides in high yields. Moreover, one-step construction of imide and amide bonds with a long-chain alkyl group is an attractive feature of this protocol.
A series of new 5‐morpholino‐thiophene‐indole/oxindole hybrids has been designed and synthesized using molecular hybridization approach. The synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines such as triple negative breast (MDA‐MB‐231), liver (SK‐Hep‐1), breast (MCF‐7), colon (HCT‐116) mouse melanoma (B16F10) and compared with normal human lung epithelial cell line (BEAS‐2B). Among the tested hybrids 11a–o and 13a–d, the compound 11f [(Z)‐N′‐((1‐Benzyl‐1H‐indol‐3‐yl)methylene)‐5‐morpholino‐4‐(p‐tolyl)thiophene‐2‐carbohydrazide] showed significant cytotoxic activity on HCT‐116 cancer cell line with IC50 value of 8.98 ± 0.6 μM. Cell cycle analysis revealed that compounds arrested the cell cycle in sub‐G1 phase. Moreover, JC‐1, acridine orange, DAPI nucleic acid, DCFDA staining studies suggest that one of the representative compound 11 f inhibited the cell proliferation through apoptosis. Further, molecular docking and relative viscosity studies of 11 f indicated the minor groove binding towards CT‐DNA.
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