In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells
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 insertio...
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| Format: | Article |
| Language: | English |
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Multidisciplinary Digital Publishing Institute
2020
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| Online Access: | http://psasir.upm.edu.my/id/eprint/89458/1/LOVO.pdf |
| _version_ | 1825936683618533376 |
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| author | Leong, Sze Wei Chia, Suet Lin Abas, Faridah Yusoff, Khatijah |
| author_facet | Leong, Sze Wei Chia, Suet Lin Abas, Faridah Yusoff, Khatijah |
| author_sort | Leong, Sze Wei |
| collection | UPM |
| description | 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-4H-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 IC50 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-4H-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. |
| first_indexed | 2024-03-06T10:48:01Z |
| format | Article |
| id | upm.eprints-89458 |
| institution | Universiti Putra Malaysia |
| language | English |
| last_indexed | 2024-03-06T10:48:01Z |
| publishDate | 2020 |
| publisher | Multidisciplinary Digital Publishing Institute |
| record_format | dspace |
| spelling | upm.eprints-894582021-09-02T00:08:41Z http://psasir.upm.edu.my/id/eprint/89458/ In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells Leong, Sze Wei Chia, Suet Lin Abas, Faridah Yusoff, Khatijah 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-4H-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 IC50 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-4H-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. Multidisciplinary Digital Publishing Institute 2020 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/89458/1/LOVO.pdf Leong, Sze Wei and Chia, Suet Lin and Abas, Faridah and Yusoff, Khatijah (2020) In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells. Molecules, 25 (17). pp. 1-16. ISSN 1420-3049 https://www.mdpi.com/1420-3049/25/17/3877 10.3390/molecules25173877 |
| spellingShingle | Leong, Sze Wei Chia, Suet Lin Abas, Faridah Yusoff, Khatijah In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells |
| title | In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells |
| title_full | In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells |
| title_fullStr | In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells |
| title_full_unstemmed | In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells |
| title_short | In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells |
| title_sort | in vitro and in silico evaluations of heterocyclic containing diarylpentanoids as bcl 2 inhibitors against lovo colorectal cancer cells |
| url | http://psasir.upm.edu.my/id/eprint/89458/1/LOVO.pdf |
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