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Table 1. HDAC inhibitory activity and p21 promoter assay dataIC 50 (µM)CompoundHDAC1 HDAC4 HDAC6p21 promoterassay EC 1000(µM)Chlamydocin 0.00015 - 1.100 -a CHAP15 0.00044 - 0.038 -1 >100 >100 >100 >2502 65 52 >100 863 2.1 0.15 21 3.64 15 19 >100 >255 13 18 >100 >256 0.65 0.77 14 6.67 0.31 0.20 >100 0.47a CHAP, cyclic hydroxamic-acid-containing peptide; IC 50 half maximal inhibitoryconcentration; EC 1000 , Effective concentration (10 fold)designing, we focused on the proposed deacetylation mechanism. We selected chlamydocinscaffold as the carrier of functional group and synthesized seven cyclic tetrapeptides inwhich the epoxyketone moiety of chlamydocin was replaced by seven different functionalgroups or zinc ligands. The functional groups or zinc ligands are azide, triazole, borate,acrylamide, chloroacetamide, oxyacetic hydroxamate and dioxyacetone. The optimal ligandfrom these compounds can be utilized as the preferred ligand for other HDAC inhibitors.To compare the effectiveness of azide, triazole and borate versus epoxyketone, compoundsin which these groups and the epoxyketone are in the same position were synthesized(Figure 1, compounds 1-3). We next synthesized compounds 4-7 in which the carbonylgroups of the functional groups were in the same position as in chlamydocin. All thecompounds were characterized by high resolution FAB-MS. The synthesized compoundswere subjected to HDAC inhibitory activity using HDAC1, HDAC4, HDAC6 and p21promoter assay, the results of which are shown in Table 1. All the compounds were lesspotent than chlamydocin which reveals that the extent of zinc binding affinities for theseligands in mechanism of HDAC inhibition is less than that of chlamydocin.In conclusion, our aim was to find potent zinc ligands/functional groups, which mayhave enhanced binding affinities for zinc in HDAC inhibition mechanism. We haveintroduced new and known functional groups to the chlamydocin scaffold and evaluatedthese functional groups in the same molecular condition as HDAC inhibitory activity andcompared with the reported compounds, CHAP15 and chlamydocin [3].References1. Finnin, M.S., Donigian, J.R., Cohen, A., Richon, V.M., Rifkind, R.A., Marks, P.A., Breslow, R.,Pavletich, N.P. Nature 401, 188-193 (1999).2. De Schepper, S., Bruwiere, H., Verhulst, T., Steller, U., Andries, L., Wouters, W., Janicot, M., Arts,J., Van Heusden, J. J. Pharmacol. Exp. Ther. 304, 881-888 (2003).3. Furumai, R., Komatsu, Y., Nishino, N., Khochbin, S., Yoshida, M., Horinouchi, S. Proc. Natl.Acad.Sci. U.S.A. 98, 87-92 (2001).351