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Title:	Synthesis and biological activity of chromone derivatives as potential anti-triple negative breast cancer agents
Authors:	Rajibul Islam (P100397)
Supervisor:	Lam Kok Wai, Assoc. Prof. Dr.
Keywords:	Breast Neoplasms Protein Kinases Carcinogenesis Universiti Kebangsaan Malaysia -- Dissertations Dissertations, Academic -- Malaysia
Issue Date:	21-Feb-2022
Description:	Triple-negative breast cancer (TNBC) is the most aggressive and metastatic subtype of breast cancer with a poor prognosis. Unfortunately, there is no targeted therapy available to this date. Hence, it is urgent to develop new and effective anti-TNBC drugs to treat this fatal disease. Over the past decade, it has been reported that multiple protein kinases are involved in TNBCs oncogenesis by their aberrant activation due to genomic amplification, mutation, and other mechanisms. Targeting the tyrosine kinases and kinases involved in the cell-cycle regulation could provide an opportunity to develop novel drugs for TNBC treatment. Recently, a group of specific flavonoids known as chromones have demonstrated interesting activity on TNBC cell proliferation by inhibiting the activity of certain crucial cancer cells survival protein kinases such as cyclin-dependent kinases. In our present study, we have designed and synthesized several new chromones based derivatives and tested their biological effects on the TNBC MDA-MB-231 cell line. First, we utilized several chemical reactions to obtain the target compounds, including Claisen condensation, Baker-Venkataraman rearrangement, Suzuki cross-coupling, nitro reduction, aldehyde reduction and nucleophilic substitution reactions. The result showed that out of all newly synthesized compounds screened at 20 ?M, compound C5 exerted around 80% inhibition on MDAMB- 231 cells proliferation. Further testing revealed that it exhibited an IC50 value of 11.71 ± 0.79 ?M while exhibited modest selectivity against the normal embryonic kidney cell, HEK-293, with an IC50 value of 13.23 ± 0.88 μM. Moreover, it induced 16.6%, 18.5% (P < 0.05), and 54.6% (P < 0.05) of cell apoptosis at 5 μM, 10 μM and 20 μM, respectively against MDA-MB-231 cells. In a separate study, when the compound was tested at different concentrations (5, 10, and 20 μM) in combination with a potent chemotherapy drug doxorubicin, there was a low to moderate synergistic response on MDA-MB-231 cells with improved IC50 values of 0.078 ± 0.003 μM, 0.055 ± 0.008 μM and 0.042 ± 0.005 μM, respectively than doxorubicin when used as a single agent with IC50 value of 0.132 ± 0.02 μM. Furthermore, kinase profiling assay revealed that compound C5 inhibited multiple kinases, particularly PIM1 and PIM2, with 59.8% and 66.7% inhibition, respectively, at a single concentration of 10 ?M. Finally, a molecular docking study revealed that compound C5 exhibited interesting binding interactions with PIM1 (PDB ID: 1yi3) and PIM2 (PDB ID: 4x7q) with favourable binding energies -9.1 and -9.7 kcal/mol, respectively. Overall, the present study has provided insights into the structural requirements of this series of small-molecule chromone compounds in treating and sensitizing TNBC MDA-MB-231 cells to doxorubicin by targeting the activity of protein kinases, especially PIM1 and PIM2,Ijazah Sarjana Sains
Pages:	160
Publisher:	UKM, Kuala Lumpur
Appears in Collections:	Faculty of Pharmacy / Fakulti Farmasi

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