Structure and activity relationship of 2-(substituted benzoyl)- hydroxyindoles as novel CaMKII inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 5, 2011, Pages 1456-1458

  Komiya, Masafumi ^a   Asano, Shigehiro ^a   Koike, Nobuyuki ^a   Koga, Erina ^a   Igarashi, Junetsu ^a   Nakatani, Shogo ^a   Isobe, Yoshiaki ^a  

^a DAINIPPON SUMITOMO PHARMA CO LTD   (Japan)

Author keywords

Calmodulin; CaMKII; Indole; Inhibitor; Kinase

Indexed keywords

CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE II; INDOLE DERIVATIVE; N [2 [[N [3 (4 CHLOROPHENYL) 2 PROPENYL] N METHYLAMINO]METHYL]PHENYL] N (2 HYDROXYETHYL) 4 METHOXYBENZENESULFONAMIDE; PHENYL GROUP; PROTEIN SERINE THREONINE KINASE INHIBITOR;

ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; STRUCTURE ACTIVITY RELATION;

CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE TYPE 2; ENZYME ACTIVATION; INDOLES; INHIBITORY CONCENTRATION 50; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79951721639     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.012     Document Type: Article

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18. Expression and purification of CaMKII: CaMKII was purified according to the method of Brickey et al. (Biochem. Biophys. Res. Commun. 1990, 173, 578) with some modifications. cDNA encoding CaMKII was sub-cloned into the transfer vector pFastBac1. Bacmids were generated in DH10Bac cells, and CaMKII recombinant baculovirus stocks were prepared according to the protocol of Bac-to-Bac Baculovirus Expression System (invitrogen, USA). Sf9 cells were maintained in Sf900 II medium and infected with CaMKII recombinant baculovirus stocks. The cells were harvested 3 days post-infection and CaMKII was affinity purified using Calmodulin Sepharose 4B (GE healthcare).
19. 33P ATP) was added to the diluted test substances and the whole was incubated for 20 min at 30 °C. After incubation, the reaction was terminated by transfer of a 16 μL aliquot onto the appropriate area of a P30 Filtermat (PerkinElmer, USA), and the labeled substrate was captured by a negatively charged filtermat. Phosphorylation was linear with respect to time under these conditions. The filtermat was washed three times, each for 5 min with 75 mM phosphoric acid, dried, and then spotted by MicroScintO (PerkinElmer, USA). The radioactivity was counted in TopCount NXT (PerkinElmer, USA). CPM counts were calculated for transfer of a phosphate group per minute per 1 mg CaMKII.
20. 2O: C, 75.75; H, 4.66; N, 4.21. Found: C, 75.96; H, 4.55; N, 4.27.