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Title: Quinoline-8-carboxamide N-oxides as (bio)reductively-activated prodrugs of radiosensitisers and chemosensitisers
Author: Lord, Anna-Marie
ISNI:       0000 0001 3612 7327
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2007
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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme which is involved in control of DNA excision repair. PA,.RP-1 is implicated in the resistance of tumour cells to radiother~py or DNA-damaging chemotherapeutic agents. Inhibitors of PARP-1 may therefore be of use in the treatment of cancer as potentiators of radiotherapy and chemotherapy. Most potent inhibitors of PARP-1 are analogues of the nicotinamide of the substrate NAD+' and contain a carboxamide group in which the amide is constrained in an anti-conformation to the aromatic ring. ' Viable cells in hypoxic tissue present in many tumours are relatively resistant to radiotherapy and chemotherapeutic strategies. Previous studies have examined bioreductively-activated cytotoxins and prodrug systems which release drugs selectively in hypoxic tissue. The aim of the project was to develop novel hypoxiaactivate d N:-oxide prodrugs of PARP-1 inhibitors. Synthetic approaches to 3- and 2- - substituted quinoline-8-carboxamides and their corresponding N-oxides were studied. , A wide range of 3-substituted quinoline-8-carboxamides have been synthesised using 3-iodoquinoline-8-carboxamide as a precursor to palladium-catalysed coupling reactions, such as, Suzuki-Miyaura coupling, Stille coupling, and Sonogashira coupling. The intramolecular hydrogen-bond required for PARP-1 activity between the carboxamide N-H and the nitrogen of the quinoline was demonstrated by 1H NMR spectroscopy' and X-ray crystallography.' Suzuki-Miyaura coupling and Stille coupling of 2,8-dibromoquinoline proceeded in high regioselectivity for the 2-position. Lithium-bromine exchange, followed by quenching with trimethylsilylisocyanate led to the target 2-substituted qUinoline-8-carboxamides. A PARP-1 prodrug was designed based on N-oxide bioreduction. N-Oxidation of 3phenylquinoline- 8-carbonitrile with urea hydrogen peroxide complex and trifluoroacetic anhydride gave 8-cyano-3-phenylquinoline-1-oxide. Subsequent hydration with alkaline, hydrogen peroxide gave the target 8-carbamoyl-3-phenylquinoline-1-oxide. Attempts to form 8-carbamoylquinoline-1-oxide and 8-carbamoyl-2-phenylquinoline-1-oxide are also discussed. Quinoline-8-carboxamide and representative examples in the 3-subtituted and 2substituted quinoline-8-carboxamide series were evaluated for their inhibitory activity against recombinant human PARP-1. Seven compounds displayed inhibitory activityequal' or better ~han our lead compound S-aminoisoquinolin-1-(2H)-one (SAIQ), the most potent inhibitor being 2-methylquinoline-8-carboxamide (ICso = 0.5 IJM). 8Carbamoyl-3-phenylquinotine-1-oxide displayed inhibitory activity approximately equal to that of its non-oxide analogue 3-phenylquinoline-8-carboxamide.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available