5-Aminoisoquinolin-1(2H)-one hydrochloride (5-AIQ.HCI) is a potent, water-soluble PARP-1 inhibitor that exhibits outstanding activity in a wide range of disease models in vivo. The aim of this project is the design and synthesis of derivatives with substituents at the 4-positoin of 5-AIQ. The modes of cyclisation of methyl 2-(substituted)alkynyl-3-nitrobenzoates with different electrophiles (ICI, PhSeCI, HgSO4) were studied. The exclusive formation of isocoumarins demonstrates the influence of the nitro group in directing electrophile-driven cyclisations towards the 6-endo-dig mode. The crystal structure of 5-nitro-3-phenyl-4-phenylselenylisocoumarin showed intermolecular and intramolecular ?-stacking. Attempted synthesis of 4-benzyl-5-nitroisoquinolin-1-one by selective reduction of the nitrile of methyl 2-(1-cyano-2-phenylethyl)-3-nitrobenzamide failed. Bromination of 5-nitro-isoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but Pd(0)-catalysed cross-couplings (Stille, Sonogashira, Suzuki-Miyaura) of this and of 4-bromo-5-AIQ failed. An alternative approach was Pd-catalysed cyclisation of N-(2-alkenyl)-2-iodo-3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh₃)₄ gave 2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydro-isoquinolin-1-one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide gave 2-benz-hydryl-4-benzyl-5-nitroisoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. These products are not interconvertible. The secondary amides N-allyl-2-iodo-3-nitrobenzamide and N N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively, under optimised conditions (Pd(PPh₃)₄, Et₃N, Bu₄NCI, 150°C, rapid heating). Hydrogen gave 4-methyl- and 4-benzyl-5-amino-isoquinolin-1-ones. The 4-substituted 5-AIQs were evaluated for inhibition of recombinant human PARP-1 activity. Three were more potent than 5-AIQ; 5-amino-4-methylisoquinolin-1-one (IC₅₀ = 0.25 μM), 5-amino-4-benzylisoquinolin-1-one (IC₅₀ = 0.5 μM) and 5-amino-4-bromoisoquinolin-1-one (IC₅₀ = 1.0 μM).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:512320 |
| Date | January 2008 |
| Creators | Dhami, Archana |
| Contributors | Threadgill, Michael ; Lloyd, Matthew |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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