Synthesis of potential cancer therapeutic and diagnostic agents

Md Tohid, Siti Farah ORCID: https://orcid.org/0000-0002-4772-1062 2011. Synthesis of potential cancer therapeutic and diagnostic agents. PhD Thesis, Cardiff University.

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Abstract

The need to find novel anticancer agents with better potency, efficacy and safety are highly demanded. Therefore, the first part of the study was aimed to synthesise new compounds based on stilbenes, indole-based isoxazoles and tricyclic anilides as potential antitumour agents, which later will be evaluated for their anticancer properties. The syntheses of substituted stilbenes were achieved via catalyzed or uncatalyzed methods, yielding stilbene analogues in moderate to good yields. Preliminary antiproliferative studies on four cancer cell lines (prostate, non-small lung, colon and breast) demonstrated their antiproliferative potential in the micromolar range. Unfortunately, the stilbenes were unable to inhibit the Wnt-signaling pathway in colon cancer cells. Next, the synthesis of indole-based isoxazole analogues was achieved via two different methods affording the compounds in low to moderate yields. The compounds will later be tested for their anticancer properties. The synthesis of 3289-8625 (tricyclic anilides) analogues, compounds which showed potent inhibitory activites on the PDZ domain of Dishevelled (PDZ- Dvl) as an important component in the Wnt signaling pathway was also carried out. The synthesis was achieved via various methods which gave rise to the formation of two analogues, which showed better binding affinities towards the PDZ-Dvl compared to the parent compounds. Finally, the therapeutic potential of the stilbenes was expanded to the synthesis of stilbene-based analogues as novel positron emission tomography (PET) imaging probes especially for the detection of p-amyloid plaques in brain, which is a hallmark of Alzheimer's disease. The syntheses of stilbenes were sought using fluorine-19, using methods that can later be adapted for 18F-PET radiochemistry. The syntheses of stilbenes attached to 19F-linker were afforded in good yields. Stilbenes directly attached to potassium trifluoroborate were synthesised in moderate yield. Nevertheless, the attempt to synthesise stilbene derivatives attached to a potassium trifluoroborate linker using novel procedures failed.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303196270
Date of First Compliant Deposit:	30 March 2016
Last Modified:	25 Oct 2022 08:44
URI:	https://orca.cardiff.ac.uk/id/eprint/54438

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