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https://ptsldigital.ukm.my/jspui/handle/123456789/485662Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | Lam Kok Wai, Assoc. Prof. Dr. | - |
| dc.contributor.author | Khor Poh Yen (P97782) | - |
| dc.date.accessioned | 2023-10-10T08:28:46Z | - |
| dc.date.available | 2023-10-10T08:28:46Z | - |
| dc.date.issued | 2022-07-21 | - |
| dc.identifier.other | ukmvital:130133 | - |
| dc.identifier.uri | https://ptsldigital.ukm.my/jspui/handle/123456789/485662 | - |
| dc.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 | - |
| dc.language.iso | eng | - |
| dc.publisher | UKM, Kuala Lumpur | - |
| dc.relation | Faculty of Pharmacy / Fakulti Farmasi | - |
| dc.rights | UKM | - |
| dc.subject | Breast Neoplasms | - |
| dc.subject | Chemotherapy | - |
| dc.subject | Drug Therapy | - |
| dc.subject | Universiti Kebangsaan Malaysia -- Dissertations | - |
| dc.subject | Dissertations, Academic -- Malaysia | - |
| dc.title | Synthesis of non-symmetrical curcumin derivatives as anti-cancer agents and adjuvant to paclitaxel chemoresistance on triple-negative breast cancer cells | - |
| dc.type | Theses | - |
| dc.format.pages | 178 | - |
| Appears in Collections: | Faculty of Pharmacy / Fakulti Farmasi | |
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| File | Description | Size | Format | |
|---|---|---|---|---|
| ukmvital_130133+Source01+Source010.PDF Restricted Access | 6.39 MB | Adobe PDF |  View/Open |
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