This review article proposes a comprehensive report of the design strategies engaged in the development of various sulfur-bearing cytotoxic agents. The outcomes of various studies depict that the sulfur heterocyclic framework is a fundamental structure in diverse synthetic analogs representing a myriad scope of therapeutic activities. A number of five-, six-and seven-membered sulfur-containing heterocyclic scaffolds, such as thiazoles, thiadiazoles, thiazolidinediones, thiophenes, thiopyrans, benzothiazoles, benzothiophenes, thienopyrimidines, simple and modified phenothiazines, and thiazepines have been discussed. The subsequent studies of the derivatives unveiled their cytotoxic effects through multiple mechanisms (viz. inhibition of tyrosine kinases, topoisomerase I and II, tubulin, COX, DNA synthesis, and PI3K/Akt and Raf/MEK/ERK signaling pathways), and several others. Thus, our concise illustration explains the design strategy and anticancer potential of these five-and six-membered sulfur-containing heterocyclic molecules along with a brief outline on seven-membered sulfur heterocycles. The thorough assessment of antiproliferative activities with the reference drug allows a proficient assessment of the structure-activity relationships (SARs) of the diversely synthesized molecules of the series.
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.
The unprecedented efficiency, reliability and adaptability in drug discovery, with the growing number of applications and impact, have made Click Chemistry fascinating to the scientific community. The specificity, biocompatibility along with other principles of click chemistry offers a reliable platform for the synthesis of drug-like molecules that can expedite the drug discovery process. This account summarizes such successes of versatile click reactions from our research group towards the development of functional molecules.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.