The discovery and synthesis of novel adenosine substituted 2,3-dihydro-1H-isoindol-1-ones: Potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 1, 2004, Pages 81-85

  Jagtap, Prakash G ^a   Southan, Garry J ^a   Baloglu, Erkan ^a   Ram, Siya ^a   Mabley, Jon G ^a   Marton, Anita ^a   Salzman, Andrew ^a   Szabó, Csaba ^a  

^a INOTEK CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; BENZOIC ACID DERIVATIVE; ISOINDOLE DERIVATIVE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; PIPERAZINE DERIVATIVE; SUCCINIC ACID DERIVATIVE;

ARTICLE; DRUG POTENCY; DRUG SYNTHESIS; HYDROLYSIS; IC 50; INHIBITION KINETICS; STRUCTURE ACTIVITY RELATION;

EID: 0348147641     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.10.007     Document Type: Article

References (23)

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2. For recent reviews on the PARP-1 inhibitors see: (a) Zhang J. PARP as a Therapeutic Target. 2002;CRC, Boca Raton, FL, (b) Szabó C. Cell Death: The Role of PARP. 2000;CRC, Boca Raton, FL, (c) Szabó C., Virág L. Pharmacol. Rev. 54:2002;375.
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18. + in buffer is 20 nM/L) for 20 min. The cells were then scraped from the wells and placed in Eppendorf tubes containing 200 μL of 50% (w/v) ice-cold trichloroacetic acid (TCA). The tubes were then placed at 4 °C. After 4 h, the tubes were centrifuged at 1800g for 10 min and the supernatant removed. The pellets were washed twice with 500 μL ice-cold 5% TCA. The pellets were solubilized in 250 μL NaOH (0.1 M) containing 2% SDS overnight at 37 °C and the PARP activity was then determined by measuring the radioactivity incorporated using a Wallac scintillation counter. The solubilized protein (250 μL) was mixed with 5 mL of scintillant (ScintiSafe Plus, Fisher Scientific) before being counted for 10 min. The compounds described as inhibitors of PARP-1 are capable of permeating whole cells, a property necessary for therapeutic efficacy.
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23. Compound 8a (EB-47) was used for in vivo experimentation. This piperazine linked adenosine derivative exerts cytoprotective effects in oxidatively damaged cells, and shows protection in in vivo models of reperfusion injury and inflammation. The in vivo experimental results will be published elsewhere.