Journal article
Cyclohepta[b]thiophenes as Potential Antiproliferative Agents: Design, Synthesis, In Vitro, and In Vivo Anticancer Evaluation
ACS pharmacology & translational science, Vol.3(5), pp.965-977
10/09/2020
DOI: 10.1021/acsptsci.0c00096
PMCID: PMC7551711
PMID: 33073194
Abstract
Several thiophene featuring compounds are known for their promising antiproliferative activity. Prompted by the urgent need to identify new potent anticancer agents, 16 compounds of benzamides, benzylamines, and urea analogues incorporating a cyclohepta[b]thiophene scaffold were synthesized and biologically evaluated with a cell proliferation assay using the A549 nonsmall cell lung cancer cell line. Compound 17 demonstrated both potent and broad-spectrum anticancer activity with submicromolar 50% growth inhibition (GI50) values. It also showed superior antiproliferative activity (vs nocodazole) in OVACAR-4, OVACAR-5, CAKI-1, and T47D cell lines with GI50 values of 2.01 (vs 22.28), 2.27 (vs 20.75), 0.69 (vs 1.11), and 0.362 (vs 81.283) μM, respectively. Additionally, compound 17 displayed minimal cytotoxicity based on 50% lethal concentration (LC50) values toward all tested cell lines. Further cell-based mechanistic studies of compound 17 revealed its ability to induce cell cycle arrest of A549 cells as evidenced by dose dependent G2/M accumulation. Furthermore, induction of early apoptosis along with activation of caspase 3, 8, and 9 were confirmed in A549 cells treated with compound 17. Targeting tubulin polymerization may explain the mechanism of the antiproliferative activity of compound 17 based on cell cycle analysis, detected apoptosis, and in vitro inhibition of tubulin polymerization. In vitro data were further supported by in vivo antitumor efficacy studies of compound 17 in a CT26 murine model for which the results showed a reduction in the tumor growth compared to untreated mice. Overall, compound 17 has the potential to function as a promising candidate for further development of potent anticancer chemotherapeutics.
Details
- Title: Subtitle
- Cyclohepta[b]thiophenes as Potential Antiproliferative Agents: Design, Synthesis, In Vitro, and In Vivo Anticancer Evaluation
- Creators
- Somaya A Abdel-Rahman - Department of Medicinal ChemistryAshraf K El-Damasy - Department of Medicinal ChemistryGhada S Hassan - Department of Medicinal ChemistryEmad I Wafa - Department of Pharmaceutical Sciences and Experimental TherapeuticsSean M Geary - Department of Pharmaceutical Sciences and Experimental TherapeuticsAzza R Maarouf - Department of Medicinal ChemistryAliasger K Salem - Department of Pharmaceutical Sciences and Experimental Therapeutics
- Resource Type
- Journal article
- Publication Details
- ACS pharmacology & translational science, Vol.3(5), pp.965-977
- DOI
- 10.1021/acsptsci.0c00096
- PMID
- 33073194
- PMCID
- PMC7551711
- NLM abbreviation
- ACS Pharmacol Transl Sci
- ISSN
- 2575-9108
- eISSN
- 2575-9108
- Publisher
- American Chemical Society
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: P30 CA086862
- Language
- English
- Date published
- 10/09/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
- Record Identifier
- 9984216723302771