Synthesis and Evaluation of a Novel Series of β-Diketones and Related Compounds as Anticancer Agents

Mohammed, Al-Ameen Abubakar

Abstract

Abstract
β-Diketones are 1,3-dicarbonyl compounds containing two carbonyl compounds separated by a methylene carbon. This functional diketo group is found in natural sources and can be synthesised in the laboratory. They serve as a synthetic intermediate to medicinally important compounds such as flavonoids. The aim of this thesis is focused on the synthesis and cytotoxic evaluation of novel series of β-diketones bearing different substituents. 30 novel β-diketones and 19 benzoyl thiourea analogues have been synthesised, characterised, and tested for activity on 6 different cancer cell lines. All the β-diketones synthesised appeared as the enolic tautomer, with chemical shifts ranging between 16.25 ppm – 17.15 ppm. The synthesised compounds were tested on lung adenocarcinoma (A549), human bone osteosarcoma cells (U2OS) and three different human myeloid leukaemia cells: K-562, MOLT-4 and CCRF-CEM. An MTT-assay was carried out on the compounds to enable determine their activity. Among the cell lines tested with both series of β-diketones (BDKT) and benzoylthiourea (BTU), the A204 cells have shown greater sensitivity at a lower IC50s at micromolar range than the remaining cell lines. Unlike the other cell lines, the IC50 values of the BDKT series ranged from 3.61 µM to 23.82 µM. 31, 32 and 34 and 30 have the best activity with IC50s 3.61 µM, 3.63 µM and 3.78 µM and 3.87 respectively. Whereas A204 compounds treated BTU series showed lower IC50 values ranging from 3.39 µM to 9.36 µM, suggesting greater activity than the BDKT series. The most active compounds (with lower IC50 values < 4 µM) among the BTU series include 55 (3.39 µM), 56 (3.65 µM), 61 (3.75 µM) 60 (3.76 µM), and 53 (3.97). Molecular docking result analysis of the active compounds: 31, 32 and 34 from the BDKT series have revealed that the presence of halogen groups in the molecules is contributing to its activity. Also, of significant activity in 31,32 and 33 is the bonding interaction with cys241 amino acid residue located in the tubulin binding site. This interaction site is common for most microtubule inhibitors such as colchicine, combretastatin-A4 and curcumins.

Citation

Mohammed, A.-A. A. Synthesis and Evaluation of a Novel Series of β-Diketones and Related Compounds as Anticancer Agents. (Thesis). University of Salford

• Thesis Type: Thesis
• Deposit Date: Apr 12, 2022
• Publicly Available Date: Apr 12, 2022