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Article

In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells

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Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor Darul Ehsan, Malaysia
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UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang 43400, Selangor Darul Ehsan, Malaysia
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Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia
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Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang 43400, Selangor Darul Ehsan, Malaysia
5
Malaysia Genome Institute (MGI), National Institute of Biotechnology Malaysia (NIBM), Jalan Bangi, Kajang 43000, Malaysia
*
Authors to whom correspondence should be addressed.
Academic Editors: Mai Antonello and Loredana Salerno
Molecules 2020, 25(17), 3877; https://doi.org/10.3390/molecules25173877
Received: 26 June 2020 / Revised: 28 July 2020 / Accepted: 2 August 2020 / Published: 26 August 2020
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. View Full-Text
Keywords: diarylpentanoids; colorectal cancer; cytotoxicity; anti-proliferative; cell cycle; apoptosis; Bcl-2 inhibitor; molecular docking diarylpentanoids; colorectal cancer; cytotoxicity; anti-proliferative; cell cycle; apoptosis; Bcl-2 inhibitor; molecular docking
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MDPI and ACS Style

Leong, S.W.; Chia, S.L.; Abas, F.; Yusoff, K. In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells. Molecules 2020, 25, 3877. https://doi.org/10.3390/molecules25173877

AMA Style

Leong SW, Chia SL, Abas F, Yusoff K. In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells. Molecules. 2020; 25(17):3877. https://doi.org/10.3390/molecules25173877

Chicago/Turabian Style

Leong, Sze W., Suet L. Chia, Faridah Abas, and Khatijah Yusoff. 2020. "In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells" Molecules 25, no. 17: 3877. https://doi.org/10.3390/molecules25173877

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