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Title:	Synthesis of non-symmetrical curcumin derivatives as anti-cancer agents and adjuvant to paclitaxel chemoresistance on triple-negative breast cancer cells
Authors:	Khor Poh Yen (P97782)
Supervisor:	Lam Kok Wai, Assoc. Prof. Dr.
Keywords:	Breast Neoplasms Chemotherapy Drug Therapy Universiti Kebangsaan Malaysia -- Dissertations Dissertations, Academic -- Malaysia
Issue Date:	21-Jul-2022
Description:	Triple-negative breast cancer (TNBC) is the most aggressive subtype due to its insensitivity to targeted therapy and chemotherapy resistance. Hence, exploring new anti-TNBC agents is in urgent need. Curcumin has attracted much attention in the past decade due to its reputable anti-cancer properties. Various structural modifications have been performed to improve curcumin properties, including removing one copy of α,β- ketone [shortened chain into 1.5-dienone], altering the functional groups in the phenyl ring, or inserting a cyclic central linker as a core unit to replace the dienone chain. This study aimed to synthesise and test new non-symmetrical curcumin derivatives as anti- TNBC agents and their ability to sensitise paclitaxel (PTX) in TNBC cell lines. All compounds were tested on TNBC (MDA-MB-231 and HCC-1806) and non-TNBC (MCF-7) cell lines. Their selectivity was compared with non-cancerous cells (BEAS- 2B, BV-2, HEK-293 and pHME). Structure-activity relationship (SAR) analysis revealed that the presence of heterocyclic central linker and p-methyl group was necessary for the activity and selectivity against TNBC cell growth. Compound 5d was the most potent against the MDA-MB-231 cell line with an IC50 value of 0.38 ± 0.05 μM. It exerted approximately 2 to 9-fold higher selectivity towards MDA-MB-231 cells than non-cancerous cells. In comparison, compound 5e exhibited excellent growth inhibitory effect on the HCC-1806 cells with IC50 of 0.59 ± 0.16 μM and displayed nearly 1 to 6-fold more selectivity towards HCC-1806 over non-cancerous cells. Both compounds arrested the G2/M phase cell-cycle progression (P < 0.05), promoted apoptosis (P < 0.05) and inhibited the chymotrypsin-like activity of the 20S proteasome in both dose- and time-dependent manners (P < 0.05). Molecular docking analysis revealed that both compounds formed hydrogen bonding interactions with Thr1, a critical residue in the proteasome β5 subunit binding site (PDB ID: 5lf3) with favourable binding energies of -7.1 and -7.0 kcal/mol, respectively. On the other hand, the dicarbonyl curcumin derivatives attenuated the PTX-induced activation of TLR4/MyD88 signalling in the TNBC MDA-MB-231 cell line. At a concentration of 10 μM, compound 7f enhanced PTX activity approximately 4-fold (P < 0.05) in MDAMD- 231TLR4+. On the contrary, compound 7h synergistically improved PTX (0.01 – 1 μM) activity in both TNBC cells (combination index < 1). Fluorescence titration analysis indicated both compounds bound with TLR4 co-receptor MD-2 with excellent binding affinity with Kd values of 3.6 ± 0.7 μM (7f) and 3.2 ± 0.6 μM (7h), respectively. Docking analysis showed that both compounds occupied the MD-2 binding site (PDB ID: 2e59) and formed favourable interactions with the adjacent residues with good binding energies of -9.6 and -11.0 kcal/mol, respectively. Overall, this study imparted insights into the structural requirements for potentially developing new and novel anti- TNBC agents and their ability to sensitise TNBC cells to PTX by targeting the TLR4/MyD88-dependent pathway,Ijazah Doktor Falsafah
Pages:	178
Publisher:	UKM, Kuala Lumpur
Appears in Collections:	Faculty of Pharmacy / Fakulti Farmasi

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