Tetrahydrobenzothiophene derivatives ameliorate Mia PaCa-2 cell progression and induces apoptosis via inhibiting EGFR2 tyrosine kinase signal.
| Title: | Tetrahydrobenzothiophene derivatives ameliorate Mia PaCa-2 cell progression and induces apoptosis via inhibiting EGFR2 tyrosine kinase signal. |
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| Authors: | Rahman A; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru, Karnataka 577548, India.; Sandeep Kumar Jain R; Laboratory of Experimental Medicine, Department of Biotechnology, Kuvempu University, Shankargatta, Shimoga, Karnataka 577451, India.; Meghana P; Laboratory of Experimental Medicine, Department of Biotechnology, Kuvempu University, Shankargatta, Shimoga, Karnataka 577451, India.; Nippu BN; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru, Karnataka 577548, India.; Manjunatha KS; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru, Karnataka 577548, India.; Rajaput PS; Laboratory of Experimental Medicine, Department of Biotechnology, Kuvempu University, Shankargatta, Shimoga, Karnataka 577451, India.; Kumaraswamy HM; Laboratory of Experimental Medicine, Department of Biotechnology, Kuvempu University, Shankargatta, Shimoga, Karnataka 577451, India.; Satyanarayan ND; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru, Karnataka 577548, India. Electronic address: satya1782005@gmail.com. |
| Source: | Bioorganic chemistry [Bioorg Chem] 2024 Feb; Vol. 143, pp. 106968. Date of Electronic Publication: 2023 Nov 24. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier; Original Publication: New York, London, Academic Press. |
| MeSH Terms: | Antineoplastic Agents*/chemistry ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/metabolism; Gefitinib/pharmacology ; Humans ; Protein-Tyrosine Kinases ; Apoptosis ; ErbB Receptors ; Cell Line, Tumor ; Cell Proliferation |
| Abstract: | A series of new thiophene analogues with acarbonitrile-basedmoiety were designed and synthesized via structural optimization. The conjugates were assessed for their in-vitro cytotoxic activity against a human pancreatic cancer cell line (Mia PaCa-2) and among them compound 5b showed IC50 value of 13.37 ± 2.37 μM. The compounds 5b (20 µM & 25 µM) and 7c (30 & 35 µM) also showed reduced clonogenicity, enhanced ROS and decreased mitochondrial membrane potential in Mia PaCa-2 cells. Treatment with these compounds also increased apoptotic population as evident with the double staining assay. Among the evaluated series, compounds 5b, 5g, 7c, and 9a attained a greater inhibitory potency than first generation's reversible EGFR inhibitor, Gefitinib. EGFR2 enzyme inhibitory studies revealed that 5b efficiently and arbitrarily suppressed the development of EGFR2 dependent cells and inhibited the enzymatic activity with an IC50 value of 0.68 µM; interestingly, the most effective molecule 5b with N-methyl piperazine substitution, has 1.29-fold greater potency than well-known EGFR inhibitor Gefitinib and increased Gefitinib's anti-growth impact with 2.04 folds greater against Mia PaCa-2. The in-vitro studies were validated with in-silico docking studies wherein compounds 5b and 7c exhibited binding energies of -8.2 and -7.4 Kcal/mol respectively. The present study reveals that tetrahydrobenzothiophene based analogues could be a promising lead for the evolution of potent chemo preventives over pancreatic cancer.; (Copyright © 2023 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: EGFR2; Mia PaCa-2; PDAC; Piperazine; Tyrosine kinase |
| Substance Nomenclature: | EC 2.7.10.1 (Protein-Tyrosine Kinases); S65743JHBS (Gefitinib); 0 (Antineoplastic Agents); EC 2.7.10.1 (ErbB Receptors) |
| Entry Date(s): | Date Created: 20231126 Date Completed: 20240124 Latest Revision: 20250221 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.bioorg.2023.106968 |
| PMID: | 38007893 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't