Synthesis and Anti-Cancer Activity of Novel Imidazo[5,4-f]benzimidazolequinones

Abstract

Chapter 1; A literature review of chemotherapeutic agents, bioreductive prodrugs and polycyclic diazoles, along with the aims and objects of the thesis is presented. Chapter 2; A review of 'oxidative' homolytic aromatic substitutions carried out in the presence of the 'reductant' Bu3SnH is presented. This is followed by the first report of one-pot double intramolecular homolytic aromatic substitutions of alkyl radicals onto heteroarenes. Bu3SnH / ACCN (1,1-azobis(cyclohexanecarbonitrile)) mediated double six-membered radical cyclizations using phenylselenides proceeded in excellent yield to give dipyrido ring-fused imidazo[5,4-f]benzimidazole and imidazo[4,5-f]benzimidazole. Optimized yields of 5 and 7-membered radical cyclizations were obtained through ring activation with camphorsulfonic acid or acetic anhydride. Annulated imidazobenzimidazoles were converted into iminoquinone and quinone derivatives for anti-cancer studies. Chapter 3; A review of oxidative cyclizations of ortho-substituted tertiary-anilines is presented. A mechanism for oxidative cyclizations of o-tert-amino acetanilides to give alicyclic ring-fused diazoles is proposed using the hydrogen-bonded amine-Noxide intermediate (X-ray crystal structure provided). Oxone¿ in formic acid is shown to give high yields of annulated benzimidazoles, as well as [1,4]oxazino ringfused, and unsymmetrical pentacyclic imidazo[5,4-f]benzimidazoles. Imidazo[5,4- f]benzimidazoles were converted into quinones, and an X-ray crystal structure of [1,4]oxazino[4,3-a][1,4]oxazino[4',3':1,2]imidazo[5,4-f]benzimidazoliumquinone di(trifluoroacetate) obtained. Chapter 4; Cytotoxicity towards two human cancer cell lines known to over-express NAD(P)H:quinone oxidoreductase 1 (NQO1), as well as a human normal fibroblast cell line is presented. Increasing the alicyclic ring size or the degree of ring fusion, resulted in decreased cytotoxicity, while the [1,4]-oxazino ring increased toxicity. Mitomycin C (MMC) showed higher cytotoxicity than the synthesized compounds, and computational docking of MMC into the active site of NQO1 revealed it to be a better substrate for NQO1 than the synthesized compounds. Cytotoxicity testing performed at the US National Cancer Institute using 60 human cancer cell lines showed an iminoquinone to be particularly potent, with a good correlation to NQO1. Chapter 5; All experimental detail is described for Chapter 2, 3 and 4.