Further insights into the multitarget anticancer activity of tetrahydrocarbazole-1-amine/5-arylidene-4-thiazolinone based hybrids

Ali, Basma S., Mohammed, Anber F., Menon, Varsha, Ramadan, Wafaa S., Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100, Kariuki, Benson M. ORCID: https://orcid.org/0000-0002-8658-3897, El-Awady, Raafat and Abdu-Allah, Hajjaj H.M. 2025. Further insights into the multitarget anticancer activity of tetrahydrocarbazole-1-amine/5-arylidene-4-thiazolinone based hybrids. Bioorganic Chemistry 164 , 108853. 10.1016/j.bioorg.2025.108853

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Abstract

Based on a previous study from our group, fifteen new tetrahydrocarbazoles (THC) incorporating 5-arylidene-4-thiazolinone scaffolds at one position were synthesized and characterized by spectroscopic, elemental and X-ray crystallographic techniques. The new hybrids were evaluated for their anti-proliferative activity against a panel of eight human cancer cell lines utilizing Sulforhodamine B (SRB) assay with doxorubicin as a reference. Among all synthesized THC based hybrids, compounds 11c and 12c revealed the highest potency and selectivity against Jurkat (IC50 1.44 ± 0.09 μM), U937 (IC50 1.77 ± 0.08 μM) and HCT-116 (IC50 6.75 ± 0.08 μM) cell lines, while against normal cell line HME1 (IC50 > 50 μM). To validate the multitarget approach, topoisomerases, tubulin and EGFR inhibition assays were performed. Results indicate that compound 11c inhibited Topo Iα (IC50 52.12 μM), Topo IIα (IC50 57.22 μM), EGFR (IC50 0.13 μM) and tubulin polymerization (IC50 8.46 μM) in higher than or comparable potency to the appropriate reference drugs. It also arrested the cell cycle at the G0/G1 phase and induced apoptosis. Molecular dynamic analysis strongly support intercalation into DNA as a dominant binding mode of compounds 11c and 12c within the binding site of Topo Iα and Topo IIα. Moreover, molecular docking study highlights potential binding interactions of compound 11c within tubulin and EGFR active sites. These findings provide a foundation for developing multitarget anticancer agents against leukemia, lymphoma and colon cancers.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Chemistry Schools > Pharmacy
Publisher:	Elsevier
ISSN:	0045-2068
Date of Acceptance:	4 August 2025
Last Modified:	18 Aug 2025 12:00
URI:	https://orca.cardiff.ac.uk/id/eprint/180492

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