[en] A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 microM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.
Kuo, M.H., Allis, C.D., Roles of histone acetyltransferases and deacetylases in gene regulation (1998) BioEssays, 20, pp. 615-626
Minucci, S., Pelicci, P.G., Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer (2006) Nat. Rev. Cancer, 6, pp. 38-51
Freiman, R.N., Tjian, R., Regulating the regulators: Lysine modifications make their mark (2003) Cell, 112, pp. 11-17
Polevoda, B., Sherman, F., The diversity of acetylated proteins (2002) GenomeBiology, 3. , Reviews0006.1-0006
Sambucetti, L.C., Fischer, D.D., Zabludoff, S., Kwon, P.O., Chamberlin, H., Trogan, N., Xu, H., Cohen, D., Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects (1999) J. Biol. Chem., 274, pp. 34940-34947
Dokmanovic, M., Clarke, C., Marks, P.A., Histone deacetylase inhibitors: Overview and perspectives (2007) Molecular Cancer Research, 5 (10), pp. 981-989. , http://mcr.aacrjournals.org/cgi/reprint/5/10/981, DOI 10.1158/1541-7786.MCR-07-0324
Ropero, S., Esteller, M., The role of histone deacetylases (HDACs) in human cancer (2007) Mol. Oncol., 1, pp. 19-15
De Ruijter, A.J., Van Gennip, A.H., Caron, H.N., Kemp, S., Van Kuilenburg, A.B., Histone deacetylases (HDACs): Characterization of the classical HDAC family (2003) Biochem. J., 370, pp. 737-749
Blander, G., Guarente, L., The Sir2 family of protein deacetylases (2004) Annu. Rev. Biochem., 73, pp. 417-435
Marks, P., Rifkind, R.A., Richon, V.M., Breslow, R., Miller, T., Kelly, W.K., Histone deacetylases and cancer: Causes and therapies (2001) Nat. Rev. Cancer, 1, pp. 194-202
Richon, V.M., Webb, Y., Merger, R., Sheppard, T., Jursic, B., Ngo, L., Civoli, F., Marks, P.A., Second generation hybrid polar compounds are potent inducers of transformed cell differentiation (1996) Proc. Natl. Acad. Sci. U.S.A., 93, pp. 5705-5708
Al-Janadi, A., Chandana, S.R., Cloney, B.A., Histone deacetylase: An attractive target for cancer therapy (2008) Drugs R&D., 9, pp. 369-383
Lane, A.A., Chabner, B.A., Histone deacetylase inhibitors in cancer therapy (2009) J. Clin Oncol., 27, pp. 5459-5468
Liu, T., Kuljaca, S., Tee, A., Marshall, G.M., Histone deacetylase inhibitors: Multifunctional anticancer agents (2006) Cancer. Treat. Rev., 32, pp. 157-165
Grant, S., Easley, C., Kirkpatrick, P., Vorinostat (2007) Nat. Rev. Drug Discovery, 6, pp. 21-22
Finnin, M.S., Donigian, J.R., Cohen, A., Richon, V.M., Rifkind, R.A., Marks, P.A., Breslow, R., Pavletich, N.P., Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors (1999) Nature, 401, pp. 188-193
Nielsen, T.K., Hildmann, C., Dickmanns, A., Schwienhorst, A., Ficner, R., Crystal structure of a bacterial class 2 histone deacetylase homologue (2005) J. Mol. Biol., 354, pp. 107-120
Somoza, J.R., Skene, R.J., Katz, B.A., Mol, C., Ho, J.D., Jennings, A.J., Luong, C., Tari, L.W., Structural snapshots of human HDAC8 provide insights into the class i histone deacetylases (2004) Structure, 12, pp. 1325-1334
Bouchain, G., Delorme, D., Novel hydroxamate and anilide derivatives as potent histone deacetylase inhibitors: Synthesis and antiproliferative evaluation (2003) Current Medicinal Chemistry, 10 (22), pp. 2359-2372. , DOI 10.2174/0929867033456585
Nagaoka, Y., Maeda, T., Kawai, Y., Nakashima, D., Oikawa, T., Shimoke, K., Ikeuchi, T., Uesato, S., Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors: Hydrophilic hydroxamates and 2-aminobenzamide-containing derivatives (2006) Eur. J. Med. Chem., 41, pp. 697-708
Uesato, S., Kitagawa, M., Nagaoka, Y., Maeda, T., Kuwajima, H., Yamori, T., Novel histone deacetylase inhibitors: N -hydroxycarboxamides possessing a terminal bicyclic aryl group (2002) Bioorg. Med. Chem. Lett., 12, pp. 1347-1349
Jung, M., Brosch, G., Kolle, D., Scherf, H., Gerhauser, C., Loidl, P., Amide analogues of trichostatin A as inhibitors of histone deacetylase and inducers of terminal cell differentiation (1999) J. Med. Chem., 42, pp. 4669-4679
Breslow, R., Marks, P.A., Rifkind, R.A., Jursic, B., (1993) Novel Potent Inducers of Terminal Differentiation and Methods Thereof, , PTC Int. Appl. WO 93/07148, April 15
Stowell, J.C., Hout, R.I., Van Voast, L., The synthesis of N -hydroxy- N 1-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells (1995) J. Med. Chem., 38, pp. 1411-1413
Mai, A., Esposito, M., Sbardella, G., Massa, S., A new facile and expeditious synthesis of N -hydroxy- N 1-phenyloctanediamide, a potent inducer of terminal cytodifferentiation (2001) OPPI Briefs, 33, pp. 391-394
Gediya, L.K., Chopra, P., Purushottamachar, P., Maheshwari, N., Njar, V.C.O., A new simple and high-yield synthesis of suberoyl anilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells (2005) J. Med. Chem., 48, pp. 5047-5051
Marks, P.A., Breslow, R., Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug (2007) Nat. Biotechnol., 25, pp. 84-90
Meinke, P.T., Liberator, P., Histone deacetylase: A target for antiproliferative and antiprotozoal agents (2001) Curr. Med. Chem., 8, pp. 211-235
Kozikowski, A.P., Tapadar, S., Luchini, D.N., Hwan, K.K., Billadeau, D.D., Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: A new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6 (2008) J. Med. Chem., 51, pp. 4370-4373
Chen, Y., Lopez-Sanchez, M., Savoy, D.N., Billadeau, D.D., Dow, G.S., Kozikowski, A.P., A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum (2008) J. Med. Chem., 51, pp. 3437-3448
Kozikowski, A.P., Chen, Y., Gaysin, A.M., Savoy, D.N., Billadeau, D.D., Kim, K.H., Chemistry, biology, and QSAR studies of substituted biaryl hydroxamates and mercaptoacetamides as HDAC inhibitors - Nanomolar potency inhibitors of pancreatic cancer cell growth (2008) ChemMedChem., 3, pp. 487-501
Brunel, J.M., Salmi, C., Letourneux, Y., Efficient peptide coupling method of conjugated carboxylic acids with methyl ester amino acids hydrochloride. Application to the synthesis of Fa-Met, an important enzymatic substrate (2005) Tetrahedron Lett., 46, pp. 217-220
Vannini, A., Volpari, C., Filocamo, G., Casavola, E.C., Brunetti, M., Renzoni, D., Chakravarty, P., Di Marco, S., Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor (2004) Proc. Natl. Acad. Sci. U.S.A., 101, pp. 15064-15069
Clark, R.D., Strizhev, A., Leonard, J.M., Blake, J.F., Matthew, J.B., Consensus scoring for ligand/protein interactions (2002) J. Mol. Graphics Modell., 20, pp. 281-282
Kramer, B., Rarey, M., Lengauer, T., Evaluation of the FLEXX incremental construction algorithm for protein-ligand docking (1999) Proteins, 37, pp. 228-241
Betzi, S., Suhre, K., Chetrit, B., Guerlesquin, F., Morelli, X., GFscore: A general nonlinear consensus scoring function for high-throughput docking (2006) J. Chem. Inf. Model., 46, p. 1704
Rarey, M., Kramer, B., Lengauer, T., Klebe, G., A fast flexible docking method using an incremental construction algorithm (1996) J. Mol. Biol., 261, pp. 470-489
Rarey, M., Kramer, B., Lengauer, T., The particle concept: Placing discrete water molecules during protein-ligand docking predictions (1999) Proteins, 34, pp. 17-28
Fischle, W., Dequiedt, F., Hendzel, M.J., Guenther, M.G., Lazar, M.A., Voelter, W., Verdin, E., Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR (2002) Mol. Cell, 9, pp. 45-57
