Synthesis and evaluation of novel functionalised indoles as anticancer agents

This thesis outlines the design and application of new routes towards a range of novel bisindolylmaleimide and indolo[2,3-a]carbazole derivatives, and evaluation of their biological effects and their chemotherapeutic potential. A key part of this work focussed on utilising a hydroxymaleimide as a replacement for the prevalent lactam/maleimide functionality and forming a series of novel derivatives through substitution on the indole nitrogens. To achieve this, a robust synthetic strategy was developed which allowed access to key maleic anhydride intermediates using Perkin-type methodology. These hydroxymaleimides were further modified via a Lossen rearrangement to furnish a series of analogues containing a 6-membered F-ring. The theme of F-ring modulation was further expanded through the utilisation of a second route involving the design and synthesis of β-keto ester intermediates, which afforded novel derivatives containing pyrazolone and isocytosine headgroups, and various N-substituents. Work on a further route involving a dione intermediate resulted in the isolation of a bisindolyl derivative with a novel imidazole F-ring. Following the synthesis of 42 novel compounds, extensive screening was undertaken using the NCI-60 cell line screen, with twelve candidates progressing to evaluation via the five dose assay. This led to the identification of several lead compounds with high cytotoxicity and excellent selectivity profiles, which included derivatives with low nanomolar GI50 values against specific cancer cell lines, and also derivatives with selective cytotoxicity. Preliminary results from a kinase screen indicated noteworthy selectivity towards GSK3α/β and PIM1 kinases, with low micromolar IC50 values being observed for these enzymes.

The application of aryne chemistry and use of α-diazo carbonyl derivatives in indazole synthesis with biological evaluation

This thesis outlines the synthetic chemistry involved in the preparation of a range of novel indazole compounds and details the subsequent investigation into their potential as biologically active agents. The synthetic route utilised in this research to form the indazole structure was the [3+2] dipolar cycloaddition of diazo carbonyl compounds with reactive aryne intermediates generated in situ. The preparation of further novel indazole derivatives containing different functional groups and substituents was performed by synthesising alternative 1,3- dipole and dipolarophile analogues and provided additionally diverse compounds. Further derivatisation of the indazole product was made possible by deacylation and alkylation methods. Transformation reactions were performed on alkenecontaining ester side chains to provide novel epoxide, aldehyde and tertiary amine derivatives. The first chapter is a review of the literature beginning with a short overview on the structure, reactivity and common synthetic routes to diazo carbonyl derivatives. More attention is given to the use of diazo compounds as 1,3-dipoles in cycloaddition reactions or where the diazo group is incorporated into the final product. A review of the interesting background, structure and reactivity of aryne intermediates is also presented. In addition, some common syntheses of indazole compounds are presented as well as a brief discussion on the importance of indazole compounds as therapeutic agents. The second chapter discusses the synthetic routes employed towards the synthesis of the range of indazoles. Initially, the syntheses of the diazo carbonyl and aryne precursors are described. Next, the synthetic methods to prepare the indazole compounds are provided followed by discussion on derivatisation of the indazole compounds including N-deacylation, N-benzylation and ester side-chain transformation of some alkene-containing indazoles. A series of novel indazole derivatives were submitted for anti-cancer screening at the U.S National Cancer Institute (NCI). A number of these derivatives were identified as hit compounds, with excellent growth inhibition. The results obtained from biological evaluation from the NCI are provided with further results pending from the Community for Open Antimicrobial Drug Discovery. The third chapter details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research.