Methods for Hydroxamic Acid Synthesis

Author(s): Mohammad A. Alam*.

Journal Name: Current Organic Chemistry

Volume 23 , Issue 9 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Substituted hydroxamic acid is one of the most extensively studied pharmacophores because of their ability to chelate biologically important metal ions to modulate various enzymes, such as HDACs, urease, metallopeptidase, and carbonic anhydrase. Syntheses and biological studies of various classes of hydroxamic acid derivatives have been reported in numerous research articles in recent years but this is the first review article dedicated to their synthetic methods and their application for the synthesis of these novel molecules. In this review article, commercially available reagents and preparation of hydroxylamine donating reagents have also been described.

Keywords: Hydroxamic acids, hydroxylamine, coupling reactions, catalytic reaction, mutagens, direct synthesis.

Neff, C.; Bellot, F.; Waern, J.B.; Lambert, F.; Brandel, J.; Serratrice, G.; Gaboriau, F.; Policar, C. Glycosiderophores: synthesis of tris-hydroxamate siderophores based on a galactose or glycero central scaffold, Fe(III) complexation studies. J. Inorg. Biochem., 2012, 112, 59-67.
Codd, R. Traversing the coordination chemistry and chemical biology of hydroxamic acids. Coord. Chem. Rev., 2008, 252, 1387-1408.
Griffith, D.M.; Szocs, B.; Keogh, T.; Suponitsky, K.Y.; Farkas, E.; Buglyo, P.; Marmion, C.J. Suberoylanilide hydroxamic acid, a potent histone deacetylase inhibitor; its X-ray crystal structure and solid state and solution studies of its Zn(II), Ni(II), Cu(II) and Fe(III) complexes. J. Inorg. Biochem., 2011, 105, 763-769.
Locock, K.E.S.; Yamamoto, I.; Tran, P.; Hanrahan, J.R.; Chebib, M.; Johnston, G.A.R.; Allan, R.D. γ-Aminobutyric Acid(C) (GABAC) Selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: amides and Hydroxamates. J. Med. Chem., 2013, 56, 5626-5630.
Flipo, M.; Charton, J.; Hocine, A.; Dassonneville, S.; Deprez, B.; Deprez-Poulain, R. Hydroxamates: relationships between structure and plasma stability. J. Med. Chem., 2009, 52, 6790-6802.
Alam, M.A.; Reddy, Y.S.; Ali, M.A. New and under explored epigenetic modulators in search of new paradigms. Med. Chem., 2015, 11, 271-285.
Susanto, J.M.; Colvin, E.K.; Pinese, M.; Chang, D.K.; Pajic, M.; Mawson, A.; Caldon, C.E.; Musgrove, E.A.; Henshall, S.M.; Sutherland, R.L.; Biankin, A.V.; Scarlett, C.J. The epigenetic agents suberoylanilide hydroxamic acid and 5AZA2′ deoxycytidine decrease cell proliferation, induce cell death and delay the growth of MiaPaCa2 pancreatic cancer cells in vivo. Int. J. Oncol., 2015, 46, 2223-2230.
Calugi, C.; Trabocchi, A.; Lalli, C.; Guarna, A. D-proline-based peptidomi-metic inhibitors of anthrax lethal factor. Eur. J. Med. Chem., 2012, 56, 96-107.
Silhar, P.; Silvaggi, N.R.; Pellett, S.; Capkova, K.; Johnson, E.A.; Allen, K.N.; Janda, K.D. Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies. Bioorg. Med. Chem., 2013, 21, 1344-1348.
Stowe, G.N.; Silhar, P.; Hixon, M.S.; Silvaggi, N.R.; Allen, K.N.; Moe, S.T.; Jacobson, A.R.; Barbieri, J.T.; Janda, K.D. Chirality holds the key for potent inhibition of the botulinum neurotoxin serotype a protease. Org. Lett., 2010, 12, 756-759.
Di Fiore, A.; Maresca, A.; Supuran, C.T.; De Simone, G. Hydroxamate represents a versatile zinc binding group for the development of new carbonic anhydrase inhibitors. Chem. Commun., 2012, 48, 8838-8840.
Rodrigues, G.C.; Feijo, D.F.; Bozza, M.T.; Pan, P.; Vullo, D.; Parkkila, S.; Supuran, C.T.; Capasso, C.; Aguiar, A.P.; Vermelho, A.B. Design, Synthesis and evaluation of hydroxamic acid derivatives as promising agents for the management of chagas’ disease. J. Med. Chem., 2014, 57, 298-308.
Fei, Z.; Kong, W.; Wang, H.; Peng, J.; Sun, F.; Yin, Y.; Bajwa, J.; Jiang, X. A scalable synthesis of a hydroxamic acid LpxC Inhibitor. Org. Process Res. Dev., 2012, 16, 1436-1441.
Huguet, F.; Melet, A.; Alves de Sousa, R.; Lieutaud, A.; Chevalier, J.; Maigre, L.; Deschamps, P.; Tomas, A.; Leulliot, N.; Pages, J.M.; Artaud, I. Hydroxamic acids as potent inhibitors of FeII and MnIIE. coli methionine aminopeptidase: Biological activities and X-ray structures of oxazole hydroxamate-EcMetAP-Mn complexes. ChemMedChem, 2012, 7, 1020-1030.
Gao, J.; Cheng, Y.; Cui, W.; Chen, Q.; Zhang, F.; Du, Y.; Ji, M. 3D-QSAR and molecular docking studies of hydroxamic acids as peptide deformylase inhibitors. Med. Chem. Res., 2011, 21, 1597-1610.
Sengupta, P.; Puri, C.S.; Chokshi, H.A.; Sheth, C.K.; Midha, A.S.; Chitturi, T.R.; Thennati, R.; Murumkar, P.R.; Yadav, M.R. Synthesis, preliminary biological evaluation and molecular modeling of some new heterocyclic inhibitors of TACE. Eur. J. Med. Chem., 2011, 46, 5549-5555.
Tommasi, R.A.; Weiler, S.; McQuire, L.W.; Rogel, O.; Chambers, M.; Clark, K.; Doughty, J.; Fang, J.; Ganu, V.; Grob, J.; Goldberg, R.; Goldstein, R.; Lavoie, S.; Kulathila, R.; Macchia, W.; Melton, R.; Springer, C.; Walker, M.; Zhang, J.; Zhu, L.; Shultz, M. Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13. Bioorg. Med. Chem. Lett., 2011, 21, 6440-6445.
Kwak, S.Y.; Lee, S.; Choi, H.R.; Park, K.C.; Lee, Y.S. Dual effects of caffeoyl-amino acidyl-hydroxamic acid as an antioxidant and depigmenting agent. Bioorg. Med. Chem. Lett., 2011, 21, 5155-5158.
Nuti, E.; Santamaria, S.; Casalini, F.; Yamamoto, K.; Marinelli, L.; La Pietra, V.; Novellino, E.; Orlandini, E.; Nencetti, S.; Marini, A.M.; Salerno, S.; Taliani, S.; Da Settimo, F.; Nagase, H.; Rossello, A. Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation. Eur. J. Med. Chem., 2013, 62, 379-394.
Kelly, J.M.; Taylor, M.C.; Horn, D.; Loza, E.; Kalvinsh, I.; Bjorkling, F. Inhibitors of human histone deacetylase with potent activity against the african trypanosome trypanosoma brucei. Bioorg. Med. Chem. Lett., 2012, 22, 1886-1890.
Huang, C.Y.; Chi, L.L.; Huang, W.J.; Chen, Y.W.; Chen, W.J.; Kuo, Y.C.; Yuan, C.M.; Chen, C.N. Growth stimulating effect on queen bee larvae of histone deacetylase inhibitors. J. Agric. Food Chem., 2012, 60, 6139-6149.
Chen, X.; Wang, L.; Du, Y.; Wu, Y.; Jia, X.; Yang, Y.; Hong, B. Design, synthesis and biological evaluation of hydroxamic acid derivatives as potential high density lipoprotein (HDL) receptor CLA-1 up-regulating agents. Molecules, 2011, 16, 9178-9193.
Liu, Y-H.; Liang, W-L.; Lee, C-C.; Tsai, Y-F.; Hou, W-C. Antioxidant and semicarbazide-sensitive amine oxidase inhibitory activities of glucuronic acid hydroxamate. Food Chem., 2011, 129, 423-428.
Koncic, M.Z.; Barbaric, M.; Perkovic, I.; Zorc, B. Antiradical, chelating and antioxidant activities of hydroxamic acids and hydroxyureas. Molecules, 2011, 16, 6232-6242.
Fass, D.M.; Shah, R.; Ghosh, B.; Hennig, K.; Norton, S.; Zhao, W.N.; Reis, S.A.; Klein, P.S.; Mazitschek, R.; Maglathlin, R.L.; Lewis, T.A.; Haggarty, S.J. Effect of inhibiting histone deacetylase with short-chain carboxylic acids and their hydroxamic acid analogs on vertebrate development and neuronal chromatin. ACS Med. Chem. Lett., 2010, 2, 39-42.
Locock, K.E.; Yamamoto, I.; Tran, P.; Hanrahan, J.R.; Chebib, M.; Johnston, G.A.; Allan, R.D. Gamma-Aminobutyric Acid(C) (GABA) selective antagonists derived from the bioisosteric modification of 4-Aminocyclopent-1-enecarboxylic Acid: Amides and hydroxamates. J. Med. Chem., 2013, 56, 5626-5630.
Yu, C.W.; Chang, P.T.; Hsin, L.W.; Chern, J.W. Quinazolin-4-one Derivatives as selective histone deacetylase-6 inhibitors for the treatment of alzheimer’s disease. J. Med. Chem., 2013, 56, 6775-6791.
Behrendt, C.T.; Kunfermann, A.; Illarionova, V.; Matheeussen, A.; Pein, M.K.; Grawert, T.; Kaiser, J.; Bacher, A.; Eisenreich, W.; Illarionov, B.; Fischer, M.; Maes, L.; Groll, M.; Kurz, T. Reverse fosmidomycin derivatives against the antimalarial drug target IspC (Dxr). J. Med. Chem., 2011, 54, 6796-6802.
Paris, M.; Porcelloni, M.; Binaschi, M.; Fattori, D. Histone deacetylase inhibitors: from bench to clinic. J. Med. Chem., 2008, 51, 1505-1529.
Supuran, C.T.; Carta, F.; Scozzafava, A. Metalloenzyme inhibitors for the treatment of Gram-negative bacterial infections: a patent review (2009-2012). Expert Opin. Ther. Pat., 2013, 23, 777-788.
Mai, A. Small-molecule chromatin-modifying agents: therapeutic applications. Epigenomics, 2010, 2, 307-324.
Mai, A. Hydroxamic Acids: Biological Properties and Potential Uses as Therapeutic Agents; Wiley Online Library, 2010.
Ganeshpurkar, A.; Kumar, D.; Singh, S.K. Strategies for the synthesis of Hydroxamic Acids. Curr. Org. Synth., 2018, 15, 154-165.
Trapencieris, P.; Strazdina, J.; Bertrand, P. Synthesis of small and medium size monocyclic hydroxamic acids.(Review). Chem. Heterocycl. Compd., 2012, 48, 833-855.
Codd, R.; Richardson-Sanchez, T.; Telfer, T.J.; Gotsbacher, M.P. Advances in the chemical biology of desferrioxamine B. ACS Chem. Biol., 2018, 13, 11-25.
Dhusia, K.; Bajpai, A.; Ramteke, P.W. Overcoming antibiotic resistance: Is siderophore Trojan horse conjugation an answer to evolving resistance in microbial pathogens? J. Control. Release, 2018, 269, 63-87.
Sritharan, M. Iron homeostasis in Mycobacterium tuberculosis: mechanistic insights into siderophore-mediated iron uptake. J. Bacteriol., 2016, 198, 2399-2409.
Shi, Y.T.; Jiang, W.; Auckloo, B.N.; Wu, B. Several classes of natural products with metal ion chelating ability. Curr. Org. Chem., 2015, 19, 1935-1953.
Schobert, R.; Biersack, B. Multimodal HDAC inhibitors with improved anticancer activity. Curr. Cancer Drug Targets, 2018, 18, 39-56.
NCI NCI Drug Dictionary (Belinostat). (2/27/2018),
NCI Panobinostat. Panobinostat is approved to be used with bortezomib and dexamethasone (2/27/2018),
Tak, W.Y.; Ryoo, B.Y.; Lim, H.Y.; Kim, D.Y.; Okusaka, T.; Ikeda, M.; Hidaka, H.; Yeon, J.E.; Mizukoshi, E.; Morimoto, M.; Lee, M.A.; Yasui, K.; Kawaguchi, Y.; Heo, J.; Morita, S.; Kim, T.Y.; Furuse, J.; Katayama, K.; Aramaki, T.; Hara, R.; Kimura, T.; Nakamura, O.; Kudo, M. Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients. Invest. New Drugs, 2018, 36, 1072-1084.
Mottamal, M.; Zheng, S.; Huang, T.L.; Wang, G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules, 2015, 20, 3898-3941.
Trials, C. Clinical study to evaluate the efficacy and safety of givinostat in ambulant patients with duchenne muscular dystrophy., (2/28/2018),
Clinical Trials, Phase I/II Dose-Escalation Study of the Pan-Histone Deacetylase (HDAC) Inhibitor PCI-24781 in Lymphoma. 2014.
Clinical Trials. A Phase I Study to Evaluate the Safety and Tolerability of the Histone Deacetylase Inhibitor, CHR-3996, in Patients With Advanced Solid Tumours. (3/3/2018),
Galloway, T.J.; Wirth, L.J.; Colevas, A.D.; Gilbert, J.; Bauman, J.E.; Saba, N.F.; Raben, D.; Mehra, R.; Ma, A.W.; Atoyan, R.; Wang, J.; Burtness, B.; Jimeno, A. A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous Cell Carcinoma. Clin. Cancer Res., 2015, 21, 1566-1573.
Sun, S.; Zhang, Y.; Zheng, J.; Duan, B.; Cui, J.; Chen, Y.; Deng, W.; Ye, B.; Liu, L.; Chen, Y.; Du, J.; Gu, L. HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation. Cell Death Dis., 2018, 9, 1-13.
Grassadonia, A.; Cioffi, P.; Simiele, F.; Iezzi, L.; Zilli, M.; Natoli, C. Role of hydroxamate-based histone deacetylase inhibitors (hb-hdacis) in the treatment of solid malignancies. Cancers, 2013, 5, 919-942.
Nguyen-Trung, A.T.; Tritsch, D.; Grosdemange-Billiard, C.; Rohmer, M. Synthesis of tetrazole analogues of phosphonohydroxamic acids: An attempt to improve the inhibitory activity against the DXR. Bioorg. Med. Chem. Lett., 2013, 23, 1643-1647.
Loppenberg, M.; Muller, H.; Pulina, C.; Oddo, A.; Teese, M.; Jose, J.; Holl, R. Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors. Org. Biomol. Chem., 2013, 11, 6056-6070.
Parker, H.L.; Sherwood, J.; Hunt, A.J.; Clark, J.H. Cyclic carbonates as green alternative solvents for the heck reaction. ACS Sustain. Chem.& Eng., 2014, 2, 1739-1742.
Ramsay, S.L.; Freeman, C.; Grace, P.B.; Redmond, J.W.; MacLeod, J.K. Mild tagging procedures for the structural analysis of glycans. Carbohydr. Res., 2001, 333, 59-71.
Shen, J.; Woodward, R.; Kedenburg, J.P.; Liu, X.; Chen, M.; Fang, L.; Sun, D.; Wang, P.G. Histone deacetylase inhibitors through click chemistry. J. Med. Chem., 2008, 51, 7417-7427.
Nikitjuka, A.; Jirgensons, A. Synthesis of hydroxamic acids by using the acid labile O-2-Methylprenyl Protecting Group. Synlett, 2012, 2972-2974.
Martin, N.I.; Woodward, J.J.; Marletta, M.A. NG-hydroxyguanidines from primary amines. Org. Lett., 2006, 8, 4035-4038.
Miller, M.J.; Zhao, G.; Vakulenko, S.; Franzblau, S. M?llmann, U. New C-3′ hydroxamate-substituted and more lipophilic cyclic hydroxamate cephalosporin derivatives as a potential new generation of selective antimicrobial agents. Org. Biomol. Chem., 2006, 4, 4178-4185.
Kwak, S.Y.; Yang, J.K.; Choi, H.R.; Park, K.C.; Kim, Y.B.; Lee, Y.S. Synthesis and dual biological effects of hydroxycinnamoyl phenylalanyl/prolyl hydroxamic acid derivatives as tyrosinase inhibitor and antioxidant. Bioorg. Med. Chem. Lett., 2013, 23, 1136-1142.
Porcheddu, A.; Giacomelli, G. Angeli−Rimini’s reaction on solid support: A new approach to hydroxamic acids. J. Org. Chem., 2006, 71, 7057-7059.
Cal, M.; Jaremko, M.; Jaremko, L.; Stefanowicz, P. Solid phase synthesis of peptide hydroxamic acids on poly(ethylene glycol)-based support. J. Pept. Sci., 2013, 19, 9-15.
Butler, K.V.; Kalin, J.; Brochier, C.; Vistoli, G.; Langley, B.; Kozikowski, A.P. Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J. Am. Chem. Soc., 2010, 132, 10842-10846.
Kozlov, M.V.; Kleymenova, A.A.; Konduktorov, K.A.; Kochetkov, S.N. A new synthesis of 6-N-hydroxy-4-(2-methyl-l,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylmethyl)benzamide, tubastatin a, a highly selective inhibitor of histone deacetylase. uss. J. Bioorg. Chem., 2013, 39, 102-105.
Marson, C.M.; Savy, P.; Rioja, A.S.; Mahadevan, T.; Mikol, C.; Veerupillai, A.; Nsubuga, E.; Chahwan, A.; Joel, S.P. Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides. J. Med. Chem., 2006, 49, 800-805.
Hendricks, J.A.; Keliher, E.J.; Marinelli, B.; Reiner, T.; Weissleder, R.; Mazitschek, R. In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA). J. Med. Chem., 2011, 54, 5576-5582.
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. J. Med. Chem., 2008, 51, 3437-3448.
Kim, D.K.; Lee, J.Y.; Kim, J.S.; Ryu, J.H.; Choi, J.Y.; Lee, J.W.; Im, G.J.; Kim, T.K.; Seo, J.W.; Park, H.J.; Yoo, J.; Park, J.H.; Kim, T.Y.; Bang, Y.J. Synthesis and biological evaluation of 3-(4-substituted-phenyl)-N-hydroxy-2-propenamides, a new class of histone deacetylase inhibitors. J. Med. Chem., 2003, 46, 5745-5751.
Cai, X.; Zhai, H.X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C.J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquina-zolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem., 2010, 53, 2000-2009.
Salmi-Smail, C.; Fabre, A.; Dequiedt, F.; Restouin, A.; Castellano, R.; Garbit, S.; Roche, P.; Morelli, X.; Brunel, J.M.; Collette, Y. Modified cap group suberoylanilide hydroxamic acid histone deacetylase inhibitor derivatives reveal improved selective antileukemic activity. J. Med. Chem., 2010, 53, 3038-3047.
Cho, Y.S.; Whitehead, L.; Li, J.; Chen, C.H.; Jiang, L.; Vogtle, M.; Francotte, E.; Richert, P.; Wagner, T.; Traebert, M.; Lu, Q.; Cao, X.; Dumotier, B.; Fejzo, J.; Rajan, S.; Wang, P.; Yan-Neale, Y.; Shao, W.; Atadja, P.; Shultz, M. Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824). J. Med. Chem., 2010, 53, 2952-2963.
Cho, M.; Choi, E.; Yang, J.S.; Lee, C.; Seo, J.J.; Kim, B.S.; Oh, S.J.; Kim, H.M.; Lee, K.; Park, S.K.; Kwon, H.J.; Han, G. Discovery of pyridone-based histone deacetylase inhibitors: Approaches for metabolic stability. ChemMedChem, 2013, 8, 272-279.
Wang, F.; Lu, W.; Zhang, T.; Dong, J.; Gao, H.; Li, P.; Wang, S.; Zhang, J. Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors. Bioorg. Med. Chem., 2013, 21, 6973-6980.
Kozlov, M.V.; Kleymenova, A.A.; Romanova, L.I.; Konduktorov, K.A.; Smirnova, O.A.; Prasolov, V.S.; Kochetkov, S.N. Benzohydroxamic acids as potent and selective anti-HCV agents. Bioorg. Med. Chem. Lett., 2013, 23, 5936-5940.
Wagner, F.F.; Olson, D.E.; Gale, J.P.; Kaya, T.; Weiwer, M.; Aidoud, N.; Thomas, M.; Davoine, E.L.; Lemercier, B.C.; Zhang, Y.L.; Holson, E.B. Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif. J. Med. Chem., 2013, 56, 1772-1776.
Kozlov, M.V.; Kleymenova, A.A.; Romanova, L.I.; Konduktorov, K.A.; Smirnova, O.A.; Prasolov, V.S.; Kochetkov, S.N. Benzohydroxamic acids as potent and selective anti-HCV agents. Bioorg. Med. Chem. Lett., 2013, 23, 5936-5940.
Yang, K.; Nong, K.; Gu, Q.; Dong, J.; Wang, J. Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model. Eur. J. Med. Chem., 2018, 151, 389-400.
Katritzky, A.R.; Kirichenko, N.; Rogovoy, B.V. Efficient conversions of carboxylic acids into O-alkyl, N-alkyl and O,N-dialkylhydroxamic acids. Synthesis, 2003, 2777-2780.
Kozlov, M.V.; Kleymenova, A.A.; Konduktorov, K.A.; Malikova, A.Z.; Kamarova, K.A.; Novikov, R.A.; Kochetkov, S.N. Synthesis of (Z)-N-hydroxy-3-methoxy-3-phenylacrylamide as new selective inhibitor of hepatitis C virus replication. Russ. J. Bioorganic Chem., 2016, 42, 191-197.
Ho, C.Y.; Strobel, E.; Ralbovsky, J.; Galemmo, R.A., Jr Improved solution- and solid-phase preparation of hydroxamic acids from esters. J. Org. Chem., 2005, 70, 4873-4875.
Liang, X.; Lee, C.J.; Zhao, J.; Toone, E.J.; Zhou, P. Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. J. Med. Chem., 2013, 56, 6954-6966.
Lee, J.H.; Mahendran, A.; Yao, Y.; Ngo, L.; Venta-Perez, G.; Choy, M.L.; Kim, N.; Ham, W.S.; Breslow, R.; Marks, P.A. Development of a histone deacetylase 6 inhibitor and its biological effects. PNAS, 2013, 110, 15704-15709.
Giacomelli, G.; Porcheddu, A.; Salaris, M. Simple one-flask method for the preparation of hydroxamic acids. Org. Lett., 2003, 5, 2715-2717.
Massa, S.; Mai, A.; Sbardella, G.; Esposito, M.; Ragno, R.; Loidl, P.; Brosch, G. 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides, a new class of synthetic histone deacetylase inhibitors. J. Med. Chem., 2001, 44, 2069-2072.
Mai, A.; Massa, S.; Ragno, R.; Esposito, M.; Sbardella, G.; Nocca, G.; Scatena, R.; Jesacher, F.; Loidl, P.; Brosch, G. Binding mode analysis of 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide: A new synthetic histone deacetylase inhibitor inducing histone hyperacetylation, growth inhibition, and terminal cell differentiation. J. Med. Chem., 2002, 45, 1778-1784.
Chen, J.B.; Chern, T.R.; Wei, T.T.; Chen, C.C.; Lin, J.H.; Fang, J.M. Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme A reductase for cancer treatment. J. Med. Chem., 2013, 56, 3645-3655.
Bouchain, G.; Leit, S.; Frechette, S.; Khalil, E.A.; Lavoie, R.; Moradei, O.; Woo, S.H.; Fournel, M.; Yan, P.T.; Kalita, A.; Trachy-Bourget, M.C.; Beaulieu, C.; Li, Z.; Robert, M.F.; MacLeod, A.R.; Besterman, J.M.; Delorme, D. Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. J. Med. Chem., 2003, 46, 820-830.
Woo, S.H.; Frechette, S.; Abou Khalil, E.; Bouchain, G.; Vaisburg, A.; Bernstein, N.; Moradei, O.; Leit, S.; Allan, M.; Fournel, M.; Trachy-Bourget, M.C.; Li, Z.; Besterman, J.M.; Delorme, D. Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors. J. Med. Chem., 2002, 45, 2877-2885.
Hugenberg, V.; Riemann, B.; Hermann, S.; Schober, O.; Schafers, M.; Szardenings, K.; Lebedev, A.; Gangadharmath, U.; Kolb, H.; Walsh, J.; Zhang, W.; Kopka, K.; Wagner, S. Inverse 1,2,3-triazole-1-yl-ethyl substituted hydroxamates as highly potent matrix metalloproteinase inhibitors: (radio)synthesis, in vitro and first in vivo evaluation. J. Med. Chem., 2013, 56, 6858-6870.
Varasi, M.; Thaler, F.; Abate, A.; Bigogno, C.; Boggio, R.; Carenzi, G.; Cataudella, T.; Dal Zuffo, R.; Fulco, M.C.; Rozio, M.G.; Mai, A.; Dondio, G.; Minucci, S.; Mercurio, C. Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors. J. Med. Chem., 2011, 54, 3051-3064.
Thaler, F.; Varasi, M.; Abate, A.; Carenzi, G.; Colombo, A.; Bigogno, C.; Boggio, R.; Zuffo, R.D.; Rapetti, D.; Resconi, A.; Regalia, N.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.; Mercurio, C. Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors. Eur. J. Med. Chem., 2013, 64, 273-284.
Thaler, F.; Colombo, A.; Mai, A.; Amici, R.; Bigogno, C.; Boggio, R.; Cappa, A.; Carrara, S.; Cataudella, T.; Fusar, F.; Gianti, E.; di Ventimiglia, S.J.; Moroni, M.; Munari, D.; Pain, G.; Regalia, N.; Sartori, L.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.; Mercurio, C.; Varasi, M. Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors. J. Med. Chem., 2010, 53, 822-839.
Freskos, J.N.; Asmelash, B.; Gaston, K.R.; Karwa, A.; Marzan, T.A.; Nickols, M.A.; Rogers, T.E.; Schoenstein, T.; Sympson, C.J.; Vu, B. Design and synthesis of MMP inhibitors with appended fluorescent tags for imaging and visualization of matrix metalloproteinase enzymes. Bioorg. Med. Chem. Lett., 2013, 23, 5566-5570.
Mahboobi, S.; Sellmer, A.; Winkler, M.; Eichhorn, E.; Pongratz, H.; Ciossek, T.; Baer, T.; Maier, T.; Beckers, T. Novel chimeric histone deacetylase inhibitors: A series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity. J. Med. Chem., 2010, 53, 8546-8555.
Lai, M.J.; Huang, H.L.; Pan, S.L.; Liu, Y.M.; Peng, C.Y.; Lee, H.Y.; Yeh, T.K.; Huang, P.H.; Teng, C.M.; Chen, C.S.; Chuang, H.Y.; Liou, J.P. Synthesis and biological evaluation of 1-arylsulfonyl-5-(N-hydroxyacryl-amide)indoles as potent histone deacetylase inhibitors with antitumor activity in vivo. J. Med. Chem., 2012, 55, 3777-3791.
Suzuki, T.; Ota, Y.; Ri, M.; Bando, M.; Gotoh, A.; Itoh, Y.; Tsumoto, H.; Tatum, P.R.; Mizukami, T.; Nakagawa, H.; Iida, S.; Ueda, R.; Shirahige, K.; Miyata, N. Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries. J. Med. Chem., 2012, 55, 9562-9575.
Pabba, C.; Gregg, B.T.; Kitchen, D.B.; Chen, Z.J.; Judkins, A. Design and synthesis of aryl ether and sulfone hydroxamic acids as potent histone deacetylase (HDAC) inhibitors. Bioorg. Med. Chem. Lett., 2011, 21, 324-328.
McAllister, L.A.; Montgomery, J.I.; Abramite, J.A.; Reilly, U.; Brown, M.F.; Chen, J.M.; Barham, R.A.; Che, Y.; Chung, S.W.; Menard, C.A.; Mitton-Fry, M.; Mullins, L.M.; Noe, M.C.; O’Donnell, J.P.; Oliver, R.M., III; Penzien, J.B.; Plummer, M.; Price, L.M.; Shanmugasundaram, V.; Tomaras, A.P.; Uccello, D.P. Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents. Bioorg. Med. Chem. Lett., 2012, 22, 6832-6838.
Gryder, B.E.; Rood, M.K.; Johnson, K.A.; Patil, V.; Raftery, E.D.; Yao, L.P.; Rice, M.; Azizi, B.; Doyle, D.F.; Oyelere, A.K. Histone deacetylase inhibitors equipped with estrogen receptor modulation activity. J. Med. Chem., 2013, 56, 5782-5796.
Guerrant, W.; Patil, V.; Canzoneri, J.C.; Oyelere, A.K. Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors. J. Med. Chem., 2012, 55, 1465-1477.
Chen, L.; Wilson, D.; Jayaram, H.N.; Pankiewicz, K.W. Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment. J. Med. Chem., 2007, 50, 6685-6691.
Remiszewski, S.W.; Sambucetti, L.C.; Bair, K.W.; Bontempo, J.; Cesarz, D.; Chandramouli, N.; Chen, R.; Cheung, M.; Cornell-Kennon, S.; Dean, K.; Diamantidis, G.; France, D.; Green, M.A.; Howell, K.L.; Kashi, R.; Kwon, P.; Lassota, P.; Martin, M.S.; Mou, Y.; Perez, L.B.; Sharma, S.; Smith, T.; Sorensen, E.; Taplin, F.; Trogani, N.; Versace, R.; Walker, H.; Weltchek-Engler, S.; Wood, A.; Wu, A.; Atadja, P. N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: Discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl ]-2-propenamide (NVP-LAQ824). J. Med. Chem., 2003, 46, 4609-4624.
Deprez-Poulain, R.; Flipo, M.; Piveteau, C.; Leroux, F.; Dassonneville, S.; Florent, I.; Maes, L.; Cos, P.; Deprez, B. Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors. J. Med. Chem., 2012, 55, 10909-10917.
Zhang, W.; Zhang, L.; Li, X.; Weigel, J.A.; Hall, S.E.; Mayer, J.P. Solid-phase synthesis of C-terminal peptide hydroxamic acids. J. Comb. Chem., 2001, 3, 151-153.
Nandurkar, N.S.; Petersen, R.; Qvortrup, K.; Komnatnyy, V.V.; Taveras, K.M.; Le Quement, S.T.; Frauenlob, R.; Givskov, M.; Nielsen, T.E. A convenient procedure for the solid-phase synthesis of hydroxamic acids on PEGA resins. Tetrahedron Lett., 2011, 52, 7121-7124.
Glenn, M.P.; Kahnberg, P.; Boyle, G.M.; Hansford, K.A.; Hans, D.; Martyn, A.C.; Parsons, P.G.; Fairlie, D.P. Antiproliferative and phenotype-transforming antitumor agents derived from cysteine. J. Med. Chem., 2004, 47, 2984-2994.
Marastoni, E.; Bartoli, S.; Berettoni, M.; Cipollone, A.; Ettorre, A.; Fincham, C.I.; Mauro, S.; Paris, M.; Porcelloni, M.; Bigioni, M.; Binaschi, M.; Nardelli, F.; Parlani, M.; Maggi, C.A.; Fattori, D. Benzofused hydroxamic acids: Useful fragments for the preparation of histone deacetylase inhibitors. Part 1: hit identification. Bioorg. Med. Chem. Lett., 2013, 23, 4091-4095.
Yin, Z.; Low, K.; Lye, P. N-linked hydroxylamine resin: Solid-phase synthesis of hydroxamic acids. Synth. Commun., 2005, 35, 2945-2950.
Hou, J.; Li, Z.; Fang, Q.; Feng, C.; Zhang, H.; Guo, W.; Wang, H.; Gu, G.; Tian, Y.; Liu, P.; Liu, R.; Lin, J.; Shi, Y.K.; Yin, Z.; Shen, J.; Wang, P.G. Discovery and extensive in vitro evaluations of NK-HDAC-1: A chiral histone deacetylase inhibitor as a promising lead. J. Med. Chem., 2012, 55, 3066-3075.
Marek, L.; Hamacher, A.; Hansen, F.K.; Kuna, K.; Gohlke, H.; Kassack, M.U.; Kurz, T. Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells. J. Med. Chem., 2013, 56, 427-436.
Lu, Q.; Yang, Y.T.; Chen, C.S.; Davis, M.; Byrd, J.C.; Etherton, M.R.; Umar, A.; Chen, C.S. Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors. J. Med. Chem., 2004, 47, 467-474.
Lu, Q.; Wang, D.S.; Chen, C.S.; Hu, Y.D.; Chen, C.S. Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. J. Med. Chem., 2005, 48, 5530-5535.
Burkhart, J.L.; Diehl, B.; Schmitt, M.J.; Kazmaier, U. A straightforward approach to MMP-2 and MMP-9 inhibitors based on chelate claisen rearrangements. Eur. J. Org. Chem., 2012, 2012, 567-575.
Nottingham, M.; Bethel, C.R.; Pagadala, S.R.; Harry, E.; Pinto, A.; Lemons, Z.A.; Drawz, S.M.; Akker, F.; Carey, P.R.; Bonomo, R.A.; Buynak, J.D. Modifications of the C6-substituent of penicillin sulfones with the goal of improving inhibitor recognition and efficacy. Bioorg. Med. Chem. Lett., 2011, 21, 387-393.
Cosner, C.C.; Bhaskara Reddy Iska, V.; Chatterjee, A.; Markiewicz, J.T.; Corden, S.J.; Löfstedt, J.; Ankner, T.; Richer, J.; Hulett, T.; Schauer, D.J.; Wiest, O.; Helquist, P. Evolution of concise and flexible synthetic strategies for trichostatic acid and the potent histone deacetylase inhibitor trichostatin A. Eur. J. Org. Chem., 2013, 2013, 162-172.
Cosner, C.C.; Helquist, P. Concise, convergent syntheses of (+/-)-trichostatin A utilizing a Pd-catalyzed ketone enolate alpha-alkenylation reaction. Org. Lett., 2011, 13, 3564-3567.
Nuti, E.; Casalini, F.; Santamaria, S.; Gabelloni, P.; Bendinelli, S.; Da Pozzo, E.; Costa, B.; Marinelli, L.; La Pietra, V.; Novellino, E.; Margarida Bernardo, M.; Fridman, R.; Da Settimo, F.; Martini, C.; Rossello, A. Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors. Eur. J. Med. Chem., 2011, 46, 2617-2629.
Fogli, S.; Banti, I.; Stefanelli, F.; Picchianti, L.; Digiacomo, M.; Macchia, M.; Breschi, M.C.; Lapucci, A. Therapeutic potential of sulindac hydroxamic acid against human pancreatic and colonic cancer cells. Eur. J. Med. Chem., 2011, 46, 2617-2629.
Oyelere, A.K.; Chen, P.C.; Guerrant, W.; Mwakwari, S.C.; Hood, R.; Zhang, Y.; Fan, Y. Non-peptide macrocyclic histone deacetylase inhibitors. J. Med. Chem., 2009, 52, 456-468.
Grolla, A.A.; Podesta, V.; Chini, M.G.; Di Micco, S.; Vallario, A.; Genazzani, A.A.; Canonico, P.L.; Bifulco, G.; Tron, G.C.; Sorba, G.; Pirali, T. Synthesis, biological evaluation, and molecular docking of Ugi products containing a zinc-chelating moiety as novel inhibitors of histone deacetylases. J. Med. Chem., 2009, 52, 2776-2785.
Tazzari, V.; Cappelletti, G.; Casagrande, M.; Perrino, E.; Renzi, L.; Del Soldato, P.; Sparatore, A. New aryldithiolethione derivatives as potent histone deacetylase inhibitors. J. Med. Chem., 2009, 52, 2776-2785.
Guandalini, L.; Cellai, C.; Laurenzana, A.; Scapecchi, S.; Paoletti, F.; Romanelli, M.N. Design, synthesis and preliminary biological evaluation of new hydroxamate histone deacetylase inhibitors as potential antileukemic agents. Bioorg. Med. Chem. Lett., 2008, 18, 5071-5074.
Sørensen, M.D.; Blæhr, L.K.A.; Christensen, M.K.; Høyer, T.; Latini, S.; Hjarnaa, P-J.V.; Björkling, F. Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumour activity. Bioorg. Med. Chem. Lett., 2003, 11, 5461-5484.
Mai, A.; Massa, S.; Pezzi, R.; Simeoni, S.; Rotili, D.; Nebbioso, A.; Scognamiglio, A.; Altucci, L.; Loidl, P.; Brosch, G.; Class, I.I. IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J. Med. Chem., 2005, 48, 3344-3353.
Kurz, T.; Widyan, K. O-Protected 3-hydroxy-oxazolidin-2,4-diones: Novel precursors in the synthesis of alpha-hydroxyhydroxamic acids. Org. Biomol. Chem., 2004, 2, 2023-2027.
Agarwal, S.; Gupta, M.; Choudhury, B. Bioprocess development for nicotinic acid hydroxamate synthesis by acyltransferase activity of Bacillus smithii strain IITR6b2. J. Ind. Microbiol. Biotechnol., 2013, 40, 937-946.
Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.; Vigo, D.; Martinelli, M. Efficient continuous flow synthesis of hydroxamic acids and suberoylanilide hydroxamic acid preparation. J. Org. Chem., 2009, 74, 3540-3543.
Papadopoulos, G.N.; Kokotos, C.G. Photoorganocatalytic One-Pot synthesis of hydroxamic acids from aldehydes. Chem. Eur. J., 2016, 22, 6964-6967.
Dettori, G.; Gaspa, S.; Porcheddu, A.; De Luca, L. One-Pot synthesis of hydroxamic acids from aldehydes and hydroxylamine. Adv. Synth. Catal., 2014, 356, 2709-2713.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [978 - 993]
Pages: 16
DOI: 10.2174/1385272823666190424142821
Price: $58

Article Metrics

PDF: 13