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Click ferrocenyl-erlotinib conjugates active against erlotinib-resistant non-small cell lung cancer cells in vitro.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2022 Feb; Vol. 119, pp. 105514. Date of Electronic Publication: 2021 Nov 24. - Publication Year :
- 2022
-
Abstract
- Thanks to development of erlotinib and other target therapy drugs the lung cancer treatment have improved a lot in recent years. However, erlotinib-resistant lung cancer remains an unsolved clinical problem which demands for new therapeutics to be developed. Herein we report the synthesis of a library of 1,4- and 1,5-triazole ferrocenyl derivatives of erlotinib together with their anticancer activity studies against erlotinib-sensitive A549 and H1395 as well as erlotinib-resistant H1650 and H1975 cells. Studies showed that extend of anticancer activity is mainly related to the length of the spacer between the triazole and the ferrocenyl entity. Among the series of investigated compounds two isomers commonly bearing C(O)CH <subscript>2</subscript> CH <subscript>2</subscript> spacer have shown superior to erlotinib activity against erlotinib-resistant H1650 and H1975 cells whereas compound with short methylene spacer devoid of any activity. In-depth biological studies for the most active compound showed differences in its mechanism of action in compare to erlotinib. The latter is known EGFR inhibitor whereas their ferrocenyl congener exerts anticancer activity mainly as ROS-inducer which activates mitochondrial pathway of apoptosis in cancer cells. However, docking studies suggested that the most active compound can also binds to the active site of EGFR TK in a similar way as erlotinib.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Carcinoma, Non-Small-Cell Lung metabolism
Carcinoma, Non-Small-Cell Lung pathology
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm drug effects
Drug Screening Assays, Antitumor
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Erlotinib Hydrochloride chemistry
Humans
Iron Compounds chemistry
Lung Neoplasms metabolism
Lung Neoplasms pathology
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Structure-Activity Relationship
Triazoles chemistry
Antineoplastic Agents pharmacology
Carcinoma, Non-Small-Cell Lung drug therapy
Erlotinib Hydrochloride pharmacology
Iron Compounds pharmacology
Lung Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Triazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 119
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34864281
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105514