結構與CA-4相似的抗微管蛋白化合物不只在有絲分裂中抑制微管的聚合作用導致癌細胞凋亡，還顯示具有選擇地癌細胞毒殺性的血管裂解劑之新穎性質。經由偽環方法的概念，一系列新型的2-羥基-3,4,5-三甲氧基二苯甲酮化合物已經被討論。A-63、A-65與A-68展現卓越的抗癌細胞增生能力在癌細胞株中。在深入的探討中，這些化合物也表現明顯的微管蛋白親和力在秋水仙素鍵結處與具潛力的血管裂解劑特性。
組蛋白去乙醯酶在抗癌治療的發展中已經被認為是一個有效標靶。組蛋白去乙醯酶抑制劑SAHA在臨床試驗成功激勵更多的探索在發展新穎的組蛋白去乙醯酶抑制劑。根據本實驗室之前的成果，將連接體修飾與特徵結構取代的概念運用在設計新穎的組蛋白去乙醯酶抑制劑。因此一系列苯基磺醯喹?與芳醯喹?已經被合成。在這些化合物中，在癌細胞株中展現具潛力表現的化合物B-37與B-38透露出具關鍵性的官能基醯基羥胺在喹?第七號或第八號位置是較佳的。以外，化合物B-39、B-41與B-43在癌細胞株中顯示傑出的抑制能力，化合物B-39有突出的活性表現在癌細胞株中伴隨半抑制濃度數值從0.08到0.29 μM。並且化合物B-39展現強效的抑制能力對於第一型、第二型與第六型組蛋白去乙醯酶伴隨半抑制濃度數值從10到15 nM。此外，化合物B-43有顯著的選擇性對於第八型組蛋白去乙醯酶在第六型組蛋白去乙醯酶。
近年，第六型組蛋白去乙醯酶在藥物探索中已經是受到關注的標靶。文獻顯示第六型組蛋白去乙醯酶調控許多重要的非組蛋白受質包含在癌細胞成形與神經退化發展中不正常的α型微管蛋白，熱休克蛋白90與tau蛋白。根據在被發表的第六型組蛋白去乙醯酶抑制劑中的特徵結構，一系列新穎的第六型組蛋白去乙醯酶抑制劑已經被設計與合成。化合物C-18與C-21表現強效的抑制活性對於第六型組蛋白去乙醯酶伴隨半抑制濃度數值分別為2.73與4.41 nM。並且上述化合物也顯示出色的選擇性對於第六型組蛋白去乙醯酶在第一型組蛋白去乙醯酶。以化合物C-21做為先導化合物進行更進一步的結構與活性關係探索，置於疏水區域的雙六圓環與在連接部分的氨亞甲基基團是較適合的對於選擇性第六型組蛋白去乙醯酶抑制劑。

Antitubulin agents structurally related to CA-4 have not only inhibited microtubule polymerization at mitosis with consequent apoptosis in cancer cells but also revealed the novel characteristic of selectively cytotoxic VDAs. A new series of 2-hydroxy-3,4,5-trimethoxybenzophenones based on the concept of pseudo ring approach have been explored. A-63, A-65 and A-68 have demonstrated advanced antiproliferative activities against cancer cell lines. In further investigation, they revealed the distinct tubulin affinity to the colchicine binding site and potential VDA properties.
Histone deacetylases have been considered as the effective target in the development of anticancer therapies. SAHA, the successful HDAC inhibitor in clinical trials, has encouraged further investigation in the development of novel HDAC inhibitors. According to lab’s previous achievement, the concept of linker modification and key motif replacement were applied to the design of novel HDAC inhibitors. Therefore, a series of arylsulfonylquinolines and aroylquinolines have been synthesized. Among them, B-37 and B-38, exhibited potential activities against cancer cell lines, disclosed the critical group of (E)-N-hydroxyacrylamide at the C-7 or C-8 position of quinoline is preferred. Besides, B-39, B-41 and B-43 displayed excellent inhibition against a panel of tumor cells. B-39 had superior activities against cancer cell lines with IC50 values ranging from 0.08 to 0.29 μM. Moreover, B-39 showed potent inhibition of HDAC1, 2, and 6 with IC50 values ranging from 10 to 15 nM. Furthermore, B-43 had the significant selectivity for HDAC8 over HDAC6.
Recently, HDAC6 have been the attractive target for drug discovery. Literatures demonstrated HDAC6 regulate many important non-histone substrates including α-Tubulin, HSP90 and tau, which are abnormal in the development of oncogenesis and neurodegeneration. On the basis of characteristic structures among published HDAC6 inhibitors, a novel class of HDAC6 inhibitors have been designed and synthesized. C-18 and C-21 showed the potent inhibition against HDAC6 with respective IC50 values of 2.73 and 4.41 nM. Moreover, they displayed the outstanding selectivity for HDAC6 over HDAC1 in compared with published HDAC6 inhibitors. In further structure-activity relationship taking C-21 as lead compound, 6-6 fused ring in the hydrophobic area and the aminomethylene group in the connected part is favorable to selective HDAC6 inhibitors.

圖目錄 I
表目錄 III
流程目錄 IV
縮寫表 V
第一部份中文摘要 VI
第二部份中文摘要 VII
第一部份英文摘要 VIII
第二部份英文摘要 IX
壹、 第一部分緒論 1
1.1 前言 1
1.2 微管蛋白抑制劑 2
1.3 血管標靶藥劑（vascular-targeted agents；VTAs） 5
1.4 Combretastatin A-4的介紹與發展 8
貳、 第一部分實驗設計 14
2.1 新型微管蛋白抑制劑的設計 14
參、 第一部分結果與討論 17
3.1 2-hydroxy-3, 4, 5-trimethoxybenzophenone衍生物之合成 17
3.2 生物活性測試 21
肆、 第一部分結論 29
伍、 第二部分緒論-1 31
5.1 組蛋白去乙醯酶的介紹 31
2.2 組蛋白去乙醯酶抑制劑的發展 36
陸、 第二部分實驗設計-1 44
6.1 組蛋白去乙醯酶抑制劑的設計 44
柒、 第二部分結果與討論-1 46
7.1 2-arylsulfonylquinoline與2-aroylquinoline衍生物之合成 46
7.2 生物活性測試 51
捌、 第二部分結論-1 55
玖、 第二部分緒論-2 57
9.1 第六型組蛋白去乙醯酶的相關研究 57
9.2 第六型組蛋白去乙醯酶抑制劑的發展 58
壹拾、 第二部分實驗設計-2 62
10.1 第六型組蛋白去乙醯酶抑制劑的設計 62
壹拾壹、 第二部分結果與討論-2 65
11.1 第六型組蛋白去乙醯酶抑制劑之合成 65
11.2 生物活性測試 73
壹拾貳、 第二部分結論-2 76
壹拾參、 實驗部分 77
13.1 實驗儀器和檢驗方法 77
13.2 實驗藥品和溶劑 77
13.3 第一部分合成步驟 78
13.4 第二部分合成步驟-1 96
13.5 第二部分合成步驟-2 121
13.6 目標化合物之純度測試 162
13.7 生物活性評估方法 166
壹拾肆、 參考文獻 169

1.World Health Organization http://www.who.int/en/
2.行政院衛生福利部 http://www.mohw.gov.tw/CHT/Ministry/Index.aspx
3.Dumontet, C; Jordan, M. A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 2010, 9, 790-803.
4.Conde, C; Caceres, A. Microtubule assembly, organization and dynamics in axons and dendrites. Nat. Rev. Neurosci. 2009, 10, 319-332.
5.Walczak, C. E; Cai, S.; Khodjakov, A. Mechanisms of chromosome behavior during mitosis. Nat. Rev. Mol. Cell Biol. 2010, 11, 91-102.
6.Jordan, M. A; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 2004, 4, 253-265.
7.Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nat. Rev. Cancer 2010, 10, 194-204.
8.Folkman, J. Tumor Angiogenesis: Therapeutic Implications. N. Engl. J. Med. 1971, 285, 1182-1186.
9.Tozer, G. M; Kanthou, C; Baguley, B. C. Disrupting tumour blood vessels. Nat. Rev. Cancer 2005, 5, 423-435.
10.Siemann, D. W. Vascular-Targeted Therapies in Oncology. John Wiley & Sons, Ltd.
11.Siemann, D. W. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat. Rev. 2011, 37, 63-74.
12.Hollebecque, A.; Massard, C.; Soria, J. C. Vascular disrupting agents: a delicate balance between efficacy and side effects. Curr. Opin. Oncol. 2012, 24, 305-315.
13.Pettit, G. R.; Cragg, G. M.; Herald, D.; Schmidt, J. M.; Lohavanijaya, P. Isolation and structure of combretastatin. Can. J. Chem. 1982, 60, 1374-1376.
14.Dark, G. G.; Hill, S. A.; Prise, V. E.; Tozer, G. M.; Pettit, G. R.; Chaplin, D. J. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res. 1997, 57, 1829-1834.
15.http://clinicaltrials.gov/ct2/home
16.Delmonte A1, Sessa C. AVE8062: a new combretastatin derivative vascular disrupting agent. Expert Opin. Investig. Drugs 2009, 18, 1541-1548.
17.Siemann, D. W.; Chaplin, D. J.; Walicke, P. A. A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P). Expert Opin. Investig. Drugs 2009, 18, 189-197.
18.Fox, E.; Mosse'', Y. P.; Meany, H. M.; Gurney, J. G.; Khanna, G.; Jackson, H. A.; Gordon, G.; Shusterman, S.; Park, J. R.; Cohn, S. L.; Adamson, P. C.; London, W. B.; Maris, J. M.; Balis, F. M. Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children''s Oncology Group (ANBL0621). Pediatr. Blood Cancer. 2014, 61, 990-996.
19.Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-Grundy, C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R.; Tseng, B.; Kasibhatla, S.; Cai, S. X. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure-activity relationships of fused rings at the 7,8-positions. J. Med. Chem. 2007, 50, 2858-2864.
20.Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. A. Medicinal chemistry of combretastatin A4: present and future directions. J. Med. Chem. 2006, 49, 3033-3044.
21.Chen, S. M.; Meng, L. H.; Ding, J. New microtubule-inhibiting anticancer agents. Expert Opin. Invest. Drugs 2010, 3, 329−343.
22.Liu, Y. M.; Chen, H. L.; Lee, H. Y.; Liou, J. P. Tubulin inhibitors: a patent review. Expert Opin. Ther. Pat. 2014, 24, 69-88.
23.Kaur, R.; Kaur, G.; Gill, R. K.; Soni, R.; Bariwal, J. Recent developments in tubulin polymerization inhibitors: An overview. Eur. J. Med. Chem. 2014, 87, 89-124.
24.Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.; Boyd, M. R.; Hamel, E.; Pettit, R. K. Antineoplastic agents. 379. Synthesis of phenstatin phosphate. J. Med. Chem. 1998, 41, 1688-1695.
25.Pettit, G. R.; Grealish, M. P.; Herald, D. L.; Boyd, M. R.; Hamel, E.; Pettit, R. K. Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug. J. Med. Chem. 2000, 43, 2731-2737.
26.Liou, J. P.; Chang, J. Y.; Chang, C. W.; Chang. C. Y.; Mahindroo, N.; Kuo, F. M.; Hsieh, H. P. Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents. J. Med. Chem. 2004, 47, 2897-2905.
27.Alvarez, R.; Alvarez, C.; Mollinedo, F.; Sierra, B. G.; Medarde, M.; Pelaez, R. Isocombretastatins A: 1,1-diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds. Bioorg. Med. Chem. 2009, 17, 6422-6431.
28.Soussi, MA.; Provot, O1.; Bernadat, G.; Bignon, J.; Wdzieczak-Bakala, J.; Desravines, D.; Dubois, J.; Brion, JD1.; Messaoudi, S.; Alami, M. Discovery of azaisoerianin derivatives as potential antitumors agents. Eur. J. Med. Chem. 2014, 78, 178-189.
29.La Regina, G1.; Bai, R.; Rensen, W. M.; Di Cesare, E.; Coluccia, A.; Piscitelli, F.; Famiglini, V.; Reggio, A.; Nalli, M.; Pelliccia, S.; Da Pozzo, E.; Costa, B.; Granata, I.; Porta, A.; Maresca, B.; Soriani, A.; Iannitto, M. L.; Santoni, A.; Li, J.; Miranda Cona, M.; Chen, F.; Ni, Y.; Brancale, A.; Dondio, G.; Vultaggio, S.; Varasi, M.; Mercurio, C.; Martini, C.; Hamel, E.; Lavia, P.; Novellino, E.; Silvestri, R. Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors. J. Med. Chem. 2013, 56, 123−149.
30.Chen, H.; Li, Y.; Sheng, C.; Lv, Z.; Dong, G.; Wang, T.; Liu, J.; Zhang, M.; Li, L.; Zhang, T.; Geng, D.; Niu, C.; Li, K. Design and synthesis of cyclopropylamide analogues of combretastatin-A4 as novel microtubule-stabilizing agents. J. Med. Chem. 2013, 56, 685−699.
31.O''Boyle, N. M.; Carr, M.; Greene, L.M.; Bergin, O.; Nathwani, S. M.; McCabe, T.; Lloyd, D. G.; Zisterer, D. M.; Meegan, M. J. Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents. J. Med. Chem. 2010, 53, 8569–8584.
32.Liu, Z. Y.; Wang, Y. M.; Han, Y. X.; Liu, L.; Jin, J.; Yi, H.; Li, Z. R.; Jiang, J. D.; Boykin, D. W. Synthesis and antitumor activity of novel 3,4-diaryl squaric acid analogs. Eur. J. Med. Chem. 2013, 65, 187-194.
33.Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Preti, D.; Aghazadeh, Tabrizi, M.; Brancale, A.; Fu, X. H.; Li, J.; Zhang, S. Z.; Hamel, E.; Bortolozzi, R.; Basso, G.; Viola, G. Synthesis and evaluation of 1,5-disubstituted tetrazoles as rigid analogues of combretastatin A-4 with potent antiproliferative and antitumor activity. J. Med. Chem. 2012, 55, 475−488.
34.Chen, T.; Luo, Y.; Hu, Y.; Yang, B.; Lu, W. Synthesis and biological evaluation of novel 1,6-diaryl pyridin-2(1H)-one analogs. Eur. J. Med. Chem. 2013, 64, 613-620.
35.Zheng, S.; Zhong, Q.; Mottamal, M.; Zhang, Q.; Zhang, C.; Lemelle, E.; McFerrin, H.; Wang, G. Design, synthesis, and biological evaluation of novel pyridine-bridged analogues of combretastatin-A4 as anticancer agents. J. Med. Chem. 2014, 57, 3369−3381.
36.Combes, S.; Barbier, P.; Douillard, S.; McLeer-Florin, A.; Bourgarel-Rey, V.; Pierson, J. T.; Fedorov, A.Y.; Finet J. P.; Boutonnat. J.; Peyrot, V. Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins. Part 2. J. Med. Chem. 2011, 54, 3153–3162.
37.Lai, M. J.; Chang, J. Y.; Lee, H. Y.; Kuo, C. C.; Lin, M. H.; Hsieh, H. P.; Chang, C. Y.; Wu, J. S.; Wu, S. Y.; Shey, K. S.; Liou, J. P. Synthesis and biological evaluation of 1-(4''-Indolyl and 6''-Quinolinyl) indoles as a new class of potent anticancer agents. Eur. J. Med. Chem. 2011, 46, 3623-3629.
38.Lu, Y.; Chen, J.; Wang, J.; Li, C. M.; Ahn, S.; Barrett, C. M.; Dalton, J. T.; Li, W.; Miller, D.D. Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents. J. Med. Chem. 2014, 57, 7355−7366.
39.Zhao, D. G.; Chen, J.; Du, Y. R.; Ma, Y. Y.; Chen, Y. X.; Gao, K.; Hu, B. R. Synthesis and structure-activity relationships of N-methyl-5,6,7-trimethoxylindoles as novel antimitotic and vascular disrupting agents. J. Med. Chem. 2013, 56, 1467−1477.
40.Hsieh, C. C.; Lee, H. Y.; Nien, C. Y.; Kuo, C.C.; Chang, C. Y.; Chang, J. Y.; Liou, J. P. Synthesis and biological evaluation of 4-aroyl-6,7,8-trimethoxyquinolines as a novel class of anticancer agents. Molecules 2011, 16, 2274-2284.
41.Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Preti, D.; Aghazadeh, Tabrizi, M.; Brancale, A.; Fu, X. H.; Li, J.; Zhang, S. Z.; Hamel, E.; Bortolozzi, R.; Porcu, E.; Basso, G.; Viola, G. Discovery and optimization of a series of 2-aryl-4-amino-5-(3'',4'',5''-trimethoxybenzoyl)thiazoles as novel anticancer agents. J. Med. Chem. 2012, 55, 5433–5445.
42.Lee, J.; Kim, S. J.; Choi, H.; Kim, Y. H.; Lim, I. T.; Yang, H. M.; Lee, C. S.; Kang, H. R.; Ahn, S. K.; Moon, S. K.; Kim, D. H.; Lee, S.; Choi, N. S.; Lee, K. J. Identification of CKD-516: a potent tubulin polymerization inhibitor with marked antitumor activity against murine and human solid tumors. J. Med. Chem. 2010, 53, 6337–6354.
43.Liou, J. P.; Chang, Y. L.; Kuo, F. M.; Chang, C. W.; Tseng, H. Y.; Wang, C. C.; Yang, Y. N.; Chang, J. Y.; Lee, S. J.; Hsieh, H. P. Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. J. Med. Chem. 2004, 47, 4247-4257.
44.Hadimani, M. B.; Macdonough, M. T.; Ghatak, A.; Strecker, T. E.; Lopez, R.; Sriram, M.; Nguyen, B. L.; Hall, J. J.; Kessler, R. J.; Shirali, A. R.; Liu, L.; Garner, C. M.; Pettit, G. R.; Hamel, E.; Chaplin, D. J.; Mason, R. P.; Trawick, M. L.; Pinney, K. G. Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent. J. Nat. Prod. 2013, 76, 1668−1678.
45.Flynn, B. L.; Gill, G. S.; Grobelny, D. W.; Chaplin, J. H.; Paul, D.; Leske, A. F.; Lavranos, T. C.; Chalmers, D. K.; Charman, S. A.; Kostewicz, E.; Shackleford, D. M.; Morizzi, J.; Hamel, E.; Jung, M. K.; Kremmidiotis, G. Discovery of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a tubulin polymerization inhibitor with potent antiproliferative and tumor vascular disrupting properties. J. Med. Chem. 2011, 54, 6014–6027.
46.Lee, H. Y.; Chang, J. Y.; Nien, C. Y.; Kuo, C. C.; Shih, K. H.; Wu, C. H.; Chang, C. Y.; Lai, W. Y.; Liou, J. P. 5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2. J. Med. Chem. 2011, 54, 8517−8525.
47.Lee, H. Y.; Chang, J. Y.; Chang, L. Y.; Lai, W. Y.; Lai, M. J.; Shih, K. H.; Kuo, C. C.; Chang, C. Y.; Liou, J. P. Concise syntheses of N-aryl-5,6,7-trimethoxyindoles as antimitotic and vascular disrupting agents: application of the copper-mediated Ullmann-type arylation. Org. Biomol. Chem. 2011, 9, 3154-3157.
48.Chuang, H. Y.; Chang, J. Y.; Lai, M. J.; Kuo, C. C.; Lee, H. Y.; Hsieh, H. P.; Chen, Y. J.; Chen, L. T.; Pan, W. Y.; Liou, J. P. 2-amino-3,4,5-trimethoxybenzophenones as potent tubulin polymerization inhibitors. ChemMedChem 2011, 6, 450-456.
49.Matsumoto, M.; Kobayashi, K.; Hotta,Y. Acid-catalyzed oxidation of benzaldehydes to phenols by hydrogen peroxide. J. Org. Chem. 1984, 49, 4740-4741.
50.Fukuda,Y.; Furuta, H.; Kusama, Y.; Ebisu, H.; Oomori, Y.; Terashima, S. Novel cyclopropapyrroloindole derivative (AT-3510) bearing methoxycarbonyl and trifluoromethyl groups. J. Med. Chem. 1999, 42, 1448-1458.
51.Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Nakamura, H.; Fujikawa, M. Halogenation using quaternary ammonium polyhalides. IV. selective bromination of phenols by use of tetraalkylammonium tribromides. Bull. Chem. Soc. Jpn. 1987, 60, 4187-4189.
52.Qiu, J. Epigenetics: unfinished symphony. Nature 2006, 11, 143-145.
53.Egger, G.; Liang, G.; Aparicio, A.; Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004, 429, 457-463.
54.Copeland, R. A.; Solomon, M. E.; Richon, V. M. Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 2009, 8, 724-732.
55.Kazantsev, A. G.; Thompson, L. M. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat. Rev. Drug Discov. 2008, 7, 854-868.
56.Yao, Y. L.; Yang, W. M. Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their nonhistone substrates. J. Biomed Biotechnol. 2011, 2011, 146493.
57.Minucci, S.; Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 2006, 6, 38-51.
58.Biel, M.; Wascholowski, V.; Giannis, A. Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes. Angew. Chem. Int. Ed. 2005, 44, 3186-3216.
59.Willyard, C. The saving switch. Nat. Med. 2010, 16, 18-21.
60.Marks, P. A.; Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat. Biotechnol. 2007, 25, 84-90.
61.Grant, S.; Easley, C.; Kirkpatrick, P. Vorinostat. Nat. Rev. Drug Discov. 2007, 6, 21-22.
62.Johnstone, R. W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug. Discov. 2002, 1, 287-299.
63.Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 2006, 5, 769-784.
64.Spiegel, S.; Milstien, S.; Grant, S. Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene 2012, 31, 537-551.
65.Falkenberg, K. J.; Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 2014, 13, 673-691.
66.Shultz, M.D.; Cao, X.; Chen, C. H.; Cho, Y. S.; Davis, N. R.; Eckman, J.; Fan, J.; Fekete, A.; Firestone, B.; Flynn, J.; Green, J.; Growney, J. D.; Holmqvist, M.; Hsu, M.; Jansson, D.; Jiang, L.; Kwon, P.; Liu, G.; Lombardo, F.; Lu, Q.; Majumdar, D.; Meta, C.; Perez, L.; Pu, M.; Ramsey, T.; Remiszewski, S.; Skolnik, S.; Traebert, M.; Urban, L.; Uttamsingh, V.; Wang, P.; Whitebread, S.; Whitehead, L.; Yan-Neale, Y.; Yao, Y. M.; Zhou, L.; Atadja, P. Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. J. Med. Chem. 2011, 54, 4752-4772.
67.Gattin, Z.; van Gunsteren, W. F. Influence of backbone fluorine substitution upon the folding equilibrium of a beta-heptapeptide. Helv. Chim. Acta. 2005, 88, 1630-1657.
68.Bots, M.; Johnstone, R. W. Rational combinations using HDAC inhibitors. Clin. Cancer Res. 2009, 15, 3970-3977.
69.Saito, A.; Yamashita, T.; Mariko, Y.; Nosaka, Y.; Tsuchiya, K.; Ando, T.; Suzuki, T.; Tsuruo, T.; Nakanishi, O. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc. Natl. Acad. Sci. 1999, 96, 4592−4597.
70.Arts, J1.; King, P.; Marien, A.; Floren, W.; Belien, A.; Janssen, L.; Pilatte, I.; Roux, B.; Decrane, L.; Gilissen, R.; Hickson, I.; Vreys, V.; Cox, E.; Bol, K.; Talloen, W.; Goris, I.; Andries, L.; Du Jardin, M.; Janicot, M.; Page, M.; van Emelen, K.; Angibaud, P. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin. Cancer Res. 2009, 15, 6841-6851.
71.Furlan, A.; Monzani, V.; Reznikov, L. L.; Leoni, F.; Fossati, G.; Modena, D.; Mascagni, P.; Dinarello, C. A. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol. Med. 2011, 17, 353-362.
72.Wang, H.; Yu, N.; Chen, D.; Lee, K. C.; Lye, P. L.; Chang, J. W.; Deng, W.; Ng, M. C.; Lu, T.; Khoo, M L.; Poulsen, A.; Sangthongpitag, K.; Wu, X.; Hu, C.; Goh, K. C.; Wang, X.; Fang, L.; Goh, K. L.; Khng, H. H.; Goh, S. K.; Yeo, P.; Liu, X.; Bonday, Z.; Wood, J. M.; Dymock, B. W.; Kantharaj, E.; Sun, E. T. Discovery of (2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile. J. Med. Chem. 2011, 54, 4694-4720.
73.Mandl-Weber, S.; Meinel, F. G.; Jankowsky, R.; Oduncu, F.; Schmidmaier, R.; Baumann, P. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br. J. Haematol. 2010, 149, 518-528.
74.Zhou, N.; Moradei, O.; Raeppel, S.; Leit, S.; Frechette, S.; Gaudette, F.; Paquin, I.; Bernstein, N.; Bouchain, G.; Vaisburg, A.; Jin, Z.; Gillespie, J.; Wang, J.; Fournel, M.; Yan, P. T.; Trachy-Bourget, M. C.; Kalita, A.; Lu, A.; Rahil, J.; MacLeod, A. R.; Li, Z.; Besterman, J. M.; Delorme, D. Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor. J. Med. Chem. 2008, 51, 4072-4075.
75.Buggy, J. J.; Cao, Z. A.; Bass, K. E.; Verner, E.; Balasubramanian, S.; Liu, L.; Schultz, B. E.; Young, P. R.; Dalrymple, S. A. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol. Cancer Ther. 2006, 5, 1309-1317.
76.Santo, L.; Hideshima, T.; Kung, A. L.; Tseng, J. C.; Tamang, D.; Yang, M.; Jarpe, M.; van Duzer, J. H.; Mazitschek, R.; Ogier, W. C.; Cirstea, D.; Rodig, S.; Eda, H.; Scullen, T.; Canavese, M.; Bradner, J.; Anderson, K. C.; Jones, S. S.; Raje, N. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012, 119, 2579-2589.
77.Qian, C.; Lai, C. J.; Bao, R.; Wang, D. G.; Wang, J.; Xu, G. X.; Atoyan, R.; Qu, H.; Yin, L.; Samson, M.; Zifcak, B.; Ma, A. W.; DellaRocca, S.; Borek, M.; Zhai, H. X.; Cai, X.; Voi, M. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin. Cancer Res. 2012, 18, 4104-4113.
78.Graham, M. A.; Raw, S. A.; Andrews, D. M.; Good, C. J.; Matusiak, Z. S.; Maybury, M.; Stokes, E. S. E.; Turner, A. T. Flexible and scalable route to HDAC inhibitors containing an unusual trisubstituted pyridine Core. Org. Process Res. Dev. 2012, 16, 1283−1292.
79.Paris, M.; Porcelloni, M.; Binaschi, M.; Fattori, D. Histone deacetylase inhibitors:from bench to clinic. J. Med. Chem. 2008, 51, 1505-1529.
80.Marson, C. M.; Matthews, C. J.; Yiannaki, E.; Atkinson, S. J.; Soden, P. E.; Shukla, L.; Lamadema, N.; Thomas, N. S. Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit. J. Med. Chem. 2013, 56, 6156-6174.
81.Abdel-Magid, A. F. Histone Deacetylase 4 (HDAC4) Inhibitors: A Promising Treatment for Huntington''s Disease. ACS Med. Chem. Lett. 2013, 4, 692-693.
82.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.
83.Balasubramanian, S.; Ramos, J.; Luo, W.; Sirisawad, M.; Verner, E.; Buggy, J. J. A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia 2008, 22, 1026-1034.
84.Tang, G.; Wong, J. C.; Zhang, W.; Wang, Z.; Zhang, N.; Peng, Z.; Zhang, Z.; Rong, Y.; Li, S.; Zhang, M.; Yu, L.; Feng, T.; Zhang, X.; Wu, X.; Wu, J. Z.; Chen, L. Identification of a novel aminotetralin class of HDAC6 and HDAC8 selective inhibitors. J. Med. Chem. 2014, 57, 8026−8034.
85.Cai, X1.; 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-methoxyquinazolin- 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.
86.Ko, K. S.; Steffey, M. E.; Brandvold, K. R.; Soellner, M. B. Development of a chimeric c-Src kinase and HDAC inhibitor. ACS Med. Chem. Lett. 2013, 4, 779−783.
87.Mahboobi, S.; Dove, 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.
88.Mahboobi, S.; Dove, S.; Sellmer, A.; Winkler, M.; Eichhorn, E.; Pongratz, H.; Ciossek, T.; Baer, T.; Maier, T.; Beckers, T. Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rβ, and histone deacetylases. J. Med. Chem. 2009, 52, 2265-2279.
89.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.
90.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.
91.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.
92.Baud, M. G.; Leiser, T.; Haus, P.; Samlal, S.; Wong, A. C.; Wood, R. J.; Petrucci, V.; Gunaratnam, M.; Hughes, S. M.; Buluwela, L.; Turlais, F.; Neidle, S.; Meyer-Almes, F. J.; White, A. J.; Fuchter, M. J. Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets. J. Med. Chem. 2012, 55, 1731−1750.
93.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-hydroxyacrylamide)indoles as potent histone deacetylase inhibitors with antitumor activity in vivo. J. Med. Chem. 2012, 55, 3777−3791.
94.Mahboobi, S.; Sellmer, A.; Hocher, H.; Garhammer, C.; Pongratz, H.; Maier, T.; Ciossek, T.; Beckers, T. 2-aroylindoles and 2-aroylbenzofurans with N-hydroxyacrylamide substructures as a novel series of rationally designed histone deacetylase inhibitors. J. Med. Chem. 2007, 50, 4405-4418.
95.Littke, A. F.; Fu, G. C. A versatile catalyst for Heck reactions of aryl chlorides and aryl bromides under mild conditions. J. Am. Chem. Soc. 2001, 123, 6989-7000.
96.Li, Y.; Shin, D.; Kwon, S. H. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J. 2013, 280, 775-793.
97.Dallavalle, S.; Pisano, C.; Zunino, F. Development and therapeutic impact of HDAC6-selective inhibitors. Bio. Pharm. 2012, 84, 756-765.
98.Valenzuela-Fernandez, A.; Cabrero, J. R.; Serrador, J. M.; Sanchez-Madrid, F. HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol. 2008, 18, 291-297.
99.Kalin, J. H.; Bergman, J. A. Development and therapeutic implications of selective histone deacetylase 6 inhibitors J. Med. Chem. 2013, 56, 6297−6313.
100.Valente, S.; Mai, A. Small-molecule inhibitors of histone deacetylase for the treatment of cancer and non-cancer diseases a patent review (2011-2013). Expert Opin. Ther. Pat. 2014, 24, 401-415.
101.Haggarty, S. J.; Koeller, K. M.; Wong, J. C.; Grozinger, C. M.; Schreiber, S. L. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl. Acad Sci. U. S. A. 2003, 100, 4389-4394.
102.Bergman, J. A.; Woan, K.; Perez-Villarroel, P.; Villagra, A.; Sotomayor, E. M.; Kozikowski, A. P. Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. J. Med. Chem. 2012, 55, 9891-9899.
103.HDAC inhibitors and therapeutic methods using the same. WO2012106343A2.
104.Selective inhibitors of histone deacetylase isoform 6 and methods thereof . WO2012178208A2.
105.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.
106.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.
107.Blackburn, C.; Barrett, C.; Chin, J.; Garcia, K.; Gigstad, K.; Gould, A.; Gutierrez, J.; Harrison, S.; Hoar, K.; Lynch, C.; Rowland, R. S.; Tsu, C.; Ringeling, J.; Xu, H. Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N-hydroxybenzamide with high selectivity for the HDAC6 isoform. J. Med. Chem. 2013, 56, 7201−7211.
108.Jochems, J.; Boulden, J.; Lee, B. G.; Blendy, J. A.; Jarpe, M.; Mazitschek, R.; Van Duzer, J. H.; Jones, S.; Berton, O. Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology 2014, 39, 389-400.
109.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. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 15704-15709.
110.Lee, H. Y.; Tsai, A. C.; Chen, M. C.; Shen, P. J.; Cheng, Y. C.; Kuo, C. C.; Pan, S. L.; Liu, Y. M.; Liu, J. F.; Yeh. T. K.; Wang, J. C.; Chang, C. Y.; Chang, J. Y.; Liou, J. P. Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells. J. Med. Chem. 2014, 57, 4009−4022.
111.Margolis, B. J.; Long, K. A.; Laird, D. L.; Ruble, J. C.; Pulley, S. R. Assembly of 4-aminoquinolines via palladium catalysis: a mild and convenient alternative to SNAr methodology. J. Org. Chem. 2007, 72, 2232-2235.