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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010SPOS Route to Novel 9-Anilinoacridine Derivatives:Biological EvaluationGary Gellerman 1* , Tamara Brider 1 , Arie Budovsky 2 , andStella Aronov 21 Department of Biological Chemistry, Ariel University Center of Samaria, Ariel, 40700,Israel; 2 Department of Molecular Biology, Ariel University Center of Samaria,Ariel, 40700, IsraelIntroductionA highly efficient derivatization of medicinally-important 9-aminoacridine (9-AA) at theamine position using S N Ar reaction on solid phase is described. The resulting 9-anilino-acridines (9-AnA), bis-9-anilinoacridines and their peptidyl derivatives are easilyobtained in good yields from accessible starting materials, rapidly generating novelpotential DNA intercalators with variable spacer lengths and charged, polar or hydrophobicresidues at desired positions, which can increase binding affinity, conformation stability,intracellular transport and/or biological activity. The synthetic routes reported in this workare generally applicable and significantly expanding the scope of potential 9-AA anticancerhits. In vitro anticancer activity of representative compounds has been evaluated.Results and DiscussionThe 9-aminoacridine (9-AA) core fragment is a structure of interest to medicinal chemistsand appears in many biologically active compounds, mostly with anticancer and antimalariaapplications. In the field of antitumor DNA-intercalating agents, 9-anilinoacridinederivatives play an important role due to their antiproliferative properties [1]. Severalcancer chemotherapeutics based on the 9-aminoacridine scaffold, such as Amsacrine andLedakrin, have been developed. So far, 9-AA analogs have been prepared through severalstep synthesis involving harsh conditions and laborious purification of intermediates andONH 2Rink AmideMBHAFmocGly-OH orFmoc(L)Ser(tBu)-OH orFmoc(L)Lys(Boc)-OH orFmoc(L)Arg(Pbf )-OHb,cNH-AA(PG)-HHO 2Cb,d,eNO 2FH 2 NConjugationsiteAANHNO 2NHN1a AA = Lys (95%, 92% purity)b AA = Gly (84%, 91% purity)c AA = Ser (90%, 93% purity)d AA = Arg (86%, 89% purity)ClCl-TrtResinorNH 2Rink AmideMBHAFmoc-(L)Lys(Fmoc)-OH orFmoc-(L)Orn(Fmoc)-OH orFmoc-(L)DAB(Fmoc)-OHa,c for Cl-Trt resinb,c for Rink Amide resinX-(L)AA(H)-HX = O, NHO2NHO 2 CCO2HF4aorNO 2F4bb,d,f for Cl-Trt resinb,d,e for Rink AmideMBHAresinXOC CHO(CH 2 )nNHONO 2NHo NO 2mpNHNa. NMM, DCM, 40min, rt; b. PyBoP, NMM, DMF, 40min, rt;c. 20% Piperidine/DMF 2 x 20 min; d. 9-AA, Cs 2 CO 3 , DMF, 24h, rt;e. TFA/H 2 O/EDT (95:2.5:2.5); f. 3%TFA in DCM.N2a X = OH, m-N 2 O, p -9-AA, n = 4 (88%, 91% purity)b X = NH 2 , m-N 2 O, p -9-AA, n = 4 (82%, 83% purity)c X = NH 2 , p-N 2 O, o-9-AA, n = 3 (79%, 89% purity)d X = NH 2 , m-N 2 O, p -9-AA, n = 2 (86%, 90% purity)Scheme 1. SPOS of mono and bispeptidyl-9-anilinoacridine derivatives 1 and 2 by S N Ar.Scheme 1. SPOS of mono and bispeptidyl-9-anilinoacridine derivatives 1 and 2 by S N Ar.230