The Synthesis and Biological Evaluation of Novel Anticancer Agents

Pearson, Vikki Clark (1999) The Synthesis and Biological Evaluation of Novel Anticancer Agents. PhD thesis, University of Glasgow.

Full text available as:
[thumbnail of 13834100.pdf] PDF
Download (6MB)


Two separate cancer topics are included in our studies of the synthesis and biological evaluation of novel anticancer agents. These topics are synthesis of antimelanoma agents to combat malignant melanoma and synthesis of MAP kinase inhibitors designed to interfere with cell signalling pathways. In the chemotherapeutic approach towards malignant melanoma treatment a selective approach can be adopted in drug design. Melanin is synthesised within specialised cells called melanocytes and malignant melanoma results when the control of melanocytic cell division is disturbed leading to excessive melanin production. The target strategy behind malignant melanoma drug design exploits specifically Tyrosinase, an enzyme crucial to melanin synthesis and unique to the melanocyte. Tyrosinase catalyses the conversion of L-tyrosine (i) into dopaquinone (ii). Design strategies concentrate on phenolic prodrugs modelled on the natural substrate (i) of the oxidase enzyme. Tyrosinase catalyses the conversion of the phenolic prodrug into the corresponding o-quinone. These o-quinones are the mediators of cytotoxicity believed to impair the melanocytes' metabolism by combining with sulfhydryl-containing entities crucial to the cell cycle such as DNA polymerase. Alternatively the o-quinones may participate in a cyclic redox process resulting in the production of active oxygen species. The parent drug in the antimelanoma field, (iii), has been found to possess significant activity. An extensive programme of research was performed by Neil Lant at the University of Glasgow into the structure activity relationships of related compounds. Our programme of research involved the synthesis of three sets of target compounds modelled on the lead compound designed as substrates for Tyrosinase. These tertiary amides (iv), amidine salts (v) and tyrphostins (vi) were successfully prepared and biologically evaluated for in vitro antimelanoma activity and relative substrate activity for Tyrosinase. The lipophilic tertiary amides (iv) proved to be the most successful as potential antimelanoma agents with the A/-benzyl methyl analogue in particular exhibiting good levels of cytotoxicity and selectivity for Tyrosinase-containing melanoma cell lines with GI50 values in the range 5-30muM. Furthermore this compound was a Tyrosinase substrate. Although the amidine salts indicated some levels of cytotoxicity and selectivity their cytotoxicity is believed to be the result of a non-Tyrosinase mediated mechanism of action. In general this biological behaviour exhibited by the amidines (v) was mirrored by the tyrphostins (vi). In conclusion we believe that the combination of the lipophilic nature of the tertiary amides and the close structural resemblance to the parent compound (iii) provided the series (iv) with better antimelanoma activity than the other two series (v) and (vi). The second area of cancer chemotherapy research investigated is concerned with cell signalling pathways and inhibition of mitogen-activated protein (MAP) kinases which will prevent division of cancer cells. In our studies into MAP kinase inhibitors we employed 2-iminolactone derivative (vii) as our lead which had been identified from a preliminary screen within the Robins research group. This compound is modelled on serine, an amino acid residue phosphorylated by the MAP kinase enzyme. Our programme of research first investigated the optimum position of the methoxy substituent on the benzene ring of the lead compound with the series (viii) prepared. The corresponding open chain derivatives (ix) and the coumarins (x) were also prepared. [diagram] The in vitro inhibitory assay results for the 2-iminolactones (viii) and tyrphostins (ix) indicated worthwhile candidates for a more detailed study into MAP kinase inhibitory behaviour. However, the coumarins (x) did not exhibit inhibitory behaviour. In response to the biological study results the preparation of thiophene bioisosteric replacements (xi) and (xii) of the 2-iminolactone (viii) and tyrphostins (ix) was proposed. Only the thiophene tyrphostins (xii) were successfully prepared and the MAPK inhibitory activity shown by the thiophene tyrphostins appeared to support the strategy behind their design. [diagram].

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: David Robins
Keywords: Organic chemistry, Pharmacology
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-76355
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 15:22
Last Modified: 19 Nov 2019 15:22

Actions (login required)

View Item View Item


Downloads per month over past year