Approaches to new DNA-repair inhibitors for applications in cancer therapy

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).EThOS - Electronic Theses Online ServiceGBUnited Kingdo

1,4-Cycloaddition of Anthracenes and Practical Method for the Synthesis of Chiral Diamino Alcohols

The dissertation presents the Diels-Alder reactions of electron-rich 9,10-unsubstituted anthracenes. DMAD is a unique dienophile being able to give 1,4-cycloadditions. The exclusive 1,4-cycloadduct was obtained from the reaction of DMAD and 1,5-bis(pyrrolidin-1-yl)anthracene in 78% yield, the highest yield for the 1,4-cycloaddition of 9,10-unsubstituted anthracenes. The work also describes a practical method for the synthesis of chiral diamino alcohols with up to two chiral centres through the hydrolysis of 2-imidazolines. By applying this approach, Phaol was synthesised in large scale and in high yield (71% total yield from (S)-phenylalaninol). The catalytic activity in the asymmetric Michael reaction of 2-nitropropane and α,β-unsaturated enones of (S)-2-(((S)-2-amino-3-phenylpropyl)amino)-3-phenylpropan-1-ol, a diamino alcohol prepared in gram scale, was screened. In addition, the catalytic activity in the MVK-based MBH reaction of the two 2-imidazolines (1R, 2S)-1-((S)-4-(tert-butyl)-2-(4-methoxyphenyl)-4,5-dihydro-1H-imidazol-1-yl)-2,3-dihydro-1H-inden-2-ol and (1R, 2S)-1-((S)-4-(tert-butyl)-2-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-imidazol-1-yl)-2,3-dihydro-1H-inden-2-ol was tested

Bioreductively targeted inhibitors of DNA repair - radiosensitisers and chemo-sensitisers

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN010676 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Design and synthesis of selective inhibitors of poly(ADP-ribose)polymerase-2

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Quinoline-8-carboxamide N-oxides as (bio)reductively-activated prodrugs of radiosensitisers and chemosensitisers

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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Síntesis, evaluación biofísica y biológica de derivados de N-fenilbenzamida dirigidos al ADN mitocondrial de parásitos cinetoplástidos

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 15-07-2022Kinetoplastid parasites are responsible for three most common and neglected vector-bornehuman diseases, which are the focus of this Thesis: leishmaniasis, which is caused byLeishmania spp., human African trypanosomiasis caused by Trypanosoma brucei spp., andChagas disease caused by Trypanosoma cruzi. All of them display high morbidity and mortalityrates mainly in developing countries.Kinetoplastid parasites are characterised by the presence of a disk-shaped mitochondrial DNA,named as “kinetoplast DNA” (kDNA), comprising > 70% AT base pairs. Kinetoplastid cellshapes change during the complex differentiation processes that occur in their life cycles. Thesedifferentiations are key to the successful transfer of the parasite between vector and host, andvice versa.Despite the social and economic burden of kinetoplastid diseases, the chemotherapeutic arsenalto treat them remains underdeveloped. Hence, there is an urgent need for new safeantitrypanosomal and leishmanicidal treatments...Los parásitos cinetoplástidos son responsables de las tres enfermedades humanas desatendidas que son transmitidas por vectores, y que son el centro de esta Tesis: la leishmaniasis, que es causada por Leishmania spp., la tripanosomiasis africana humana causada por Trypano somabrucei spp., y la enfermedad de Chagas causada por Trypanosoma cruzi. Todos ellos presentanaltas tasas de morbilidad y mortalidad principalmente en países en vías de desarrollo.Los parásitos cinetoplastídicos se caracterizan por la presencia de un ADN mitocondrial enforma de disco, denominado “ADN cinetoplasto” (ADNc), que comprende > 70 % de pares debases AT. Las formas de las células de los cinetoplastos cambian durante los complejosprocesos de diferenciación que ocurren en sus ciclos de vida. Estas diferenciaciones son clavepara la transferencia exitosa del parásito entre el vector y el huésped, y viceversa.A pesar de la carga social y económica de las enfermedades cinetoplástidas, el arsenalquimioterapéutico para tratarlas sigue estando poco desarrollado. Por lo tanto, existe unanecesidad urgente de nuevos tratamientos antitripanosómicos y leishmanicidas que ofrezcanseguridad y eficacia...Fac. de FarmaciaTRUEunpu

Development of novel benzimidazole- based COX Inhibitors new synthetic strategies and screening of heterocyclic structures

Dissertação para obtenção do Grau de Doutor em Química, especialidade Química OrgânicaFundação para a Ciência e Tecnologia - (SFRH/BD/63407/2009 and PTDC/QUI/65187/2006