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In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2020 Aug 26; Vol. 25 (17). Date of Electronic Publication: 2020 Aug 26. - Publication Year :
- 2020
-
Abstract
- In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4 H -thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC <subscript>50</subscript> values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4 H -thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.
- Subjects :
- Cell Line, Tumor
Colorectal Neoplasms metabolism
Colorectal Neoplasms pathology
Humans
Proto-Oncogene Proteins c-bcl-2 metabolism
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Colorectal Neoplasms drug therapy
G2 Phase Cell Cycle Checkpoints drug effects
Heterocyclic Compounds chemistry
Heterocyclic Compounds pharmacology
M Phase Cell Cycle Checkpoints drug effects
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 25
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 32858795
- Full Text :
- https://doi.org/10.3390/molecules25173877