48. Ingham OJ, Paranal RM, Smith WB et al (2016) Development of a potent and selective
HDAC8 inhibitor. ACS Med Chem Lett 7:929–932
49. Luckhurst CA, Breccia P, Stott AJ et al (2015) Potent, selective, and CNS-penetrant
tetrasubstituted cyclopropane class IIa histone deacetylase (HDAC) inhibitors. ACS Med
Chem Lett 7:34–39
50. Ossenkoppele GJ, Lowenberg B, Zachee P et al (2013) A phase I first-in-human study with
tefinostat – a monocyte/macrophage targeted histone deacetylase inhibitor – in patients with
advanced haematological malignancies. Br J Haematol 162:191–201
51. Zheng S, Guo S, Zhong Q et al (2018) Biocompatible boron-containing prodrugs of belinostat
for the potential treatment of solid tumors. ACS Med Chem Lett 9:149–154
52. Ganesan A (2016) Multitarget drugs: an epigenetic epiphany. ChemMedChem 11:1227–1241
53. de Lera AR, Ganesan A (2016) Epigenetic polypharmacology: from combination therapy to
multitargeted drugs. Clin Epigenetics 8:105
54. Cai X, Zhai HX, Wang J et al (2010) Discovery of 7-(4-(3-ethynylphenylamino)-7methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting
HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 53:2000–2009
55. Qian C, Lai CJ, Bao R et al (2012) Cancer network disruption by a single molecule inhibitor
targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin
Cancer Res 18:4104–4113
56. Shigematsu N, Ueda H, Takase S et al (1994) FR901228, a novel antitumor bicyclic
depsipeptide produced by Chromobacterium violaceum No. 968. II. Structure determination.
J Antibiot 47:311–314
57. Nakajima H, Kim YB, Terano H et al (1998) FR901228, a potent antitumor antibiotic, is a
novel histone deacetylase inhibitor. Exp Cell Res 241:126–133
58. Furumai R, Matsuyama A, Kobashi N et al (2002) FK228 (depsipeptide) as a natural prodrug
that inhibits class I histone deacetylases. Cancer Res 62:4916–4921
59. Taori K, Paul VJ, Luesch H (2008) Structure and activity of largazole, a potent
antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J Am Chem
Soc 130:1806–1807
60. Wang C, Henkes LM, Doughty LB et al (2011) Thailandepsins: bacterial products with potent
histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. J Nat
Prod 74:2031–2038
61. Ganesan A (2015) Macrocyclic inhibitors of zinc-dependent histone deacetylases (HDACs).
In: Levin J (ed) Macrocycles in drug discovery. RSC, Cambridge, pp 109–140
62. Maolanon AR, Kristensen HM, Leman LJ et al (2017) Natural and synthetic macrocyclic
inhibitors of the histone deacetylase enzymes. Chembiochem 18:5–49
63. Ganesan A (2016) Romidepsin and the zinc-binding thiol family of natural product HDAC
inhibitors. In: Fischer J, Childers WE (eds) Successful drug discovery, vol 2. Wiley-VCH,
Weinheim, pp 13–30
64. Stolze SC, Kaiser M (2013) Case studies of the synthesis of bioactive cyclodepsipeptide
natural products. Molecules 18:1337–1367
65. Chen QY, Chaturvedi PR, Luesch H (2018) Process development and scale-up total synthesis
of largazole, a potent class I histone deacetylase inhibitor. Org Process Res Dev 22:190–199
66. Poli G, di Fabio R, Ferrante L et al (2017) Largazole analogues as histone deacetylase
inhibitors and anticancer agents: an overview of structure–activity relationships.
ChemMedChem 12:1917–1926
67. Benelkebir H, Marie S, Hayden A et al (2011) Total synthesis of largazole and analogues:
HDAC inhibition, antiproliferative activity and metabolic stability. Bioorg Med Chem
19:3650–3658
68. Yao Y, Tu Z, Liao C et al (2015) Discovery of novel class I histone deacetylase inhibitors with
promising in vitro and in vivo antitumor activities. J Med Chem 58:7672–7680
24
A. Ganesan
HDAC8 inhibitor. ACS Med Chem Lett 7:929–932
49. Luckhurst CA, Breccia P, Stott AJ et al (2015) Potent, selective, and CNS-penetrant
tetrasubstituted cyclopropane class IIa histone deacetylase (HDAC) inhibitors. ACS Med
Chem Lett 7:34–39
50. Ossenkoppele GJ, Lowenberg B, Zachee P et al (2013) A phase I first-in-human study with
tefinostat – a monocyte/macrophage targeted histone deacetylase inhibitor – in patients with
advanced haematological malignancies. Br J Haematol 162:191–201
51. Zheng S, Guo S, Zhong Q et al (2018) Biocompatible boron-containing prodrugs of belinostat
for the potential treatment of solid tumors. ACS Med Chem Lett 9:149–154
52. Ganesan A (2016) Multitarget drugs: an epigenetic epiphany. ChemMedChem 11:1227–1241
53. de Lera AR, Ganesan A (2016) Epigenetic polypharmacology: from combination therapy to
multitargeted drugs. Clin Epigenetics 8:105
54. Cai X, Zhai HX, Wang J et al (2010) Discovery of 7-(4-(3-ethynylphenylamino)-7methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting
HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 53:2000–2009
55. Qian C, Lai CJ, Bao R et al (2012) Cancer network disruption by a single molecule inhibitor
targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin
Cancer Res 18:4104–4113
56. Shigematsu N, Ueda H, Takase S et al (1994) FR901228, a novel antitumor bicyclic
depsipeptide produced by Chromobacterium violaceum No. 968. II. Structure determination.
J Antibiot 47:311–314
57. Nakajima H, Kim YB, Terano H et al (1998) FR901228, a potent antitumor antibiotic, is a
novel histone deacetylase inhibitor. Exp Cell Res 241:126–133
58. Furumai R, Matsuyama A, Kobashi N et al (2002) FK228 (depsipeptide) as a natural prodrug
that inhibits class I histone deacetylases. Cancer Res 62:4916–4921
59. Taori K, Paul VJ, Luesch H (2008) Structure and activity of largazole, a potent
antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J Am Chem
Soc 130:1806–1807
60. Wang C, Henkes LM, Doughty LB et al (2011) Thailandepsins: bacterial products with potent
histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. J Nat
Prod 74:2031–2038
61. Ganesan A (2015) Macrocyclic inhibitors of zinc-dependent histone deacetylases (HDACs).
In: Levin J (ed) Macrocycles in drug discovery. RSC, Cambridge, pp 109–140
62. Maolanon AR, Kristensen HM, Leman LJ et al (2017) Natural and synthetic macrocyclic
inhibitors of the histone deacetylase enzymes. Chembiochem 18:5–49
63. Ganesan A (2016) Romidepsin and the zinc-binding thiol family of natural product HDAC
inhibitors. In: Fischer J, Childers WE (eds) Successful drug discovery, vol 2. Wiley-VCH,
Weinheim, pp 13–30
64. Stolze SC, Kaiser M (2013) Case studies of the synthesis of bioactive cyclodepsipeptide
natural products. Molecules 18:1337–1367
65. Chen QY, Chaturvedi PR, Luesch H (2018) Process development and scale-up total synthesis
of largazole, a potent class I histone deacetylase inhibitor. Org Process Res Dev 22:190–199
66. Poli G, di Fabio R, Ferrante L et al (2017) Largazole analogues as histone deacetylase
inhibitors and anticancer agents: an overview of structure–activity relationships.
ChemMedChem 12:1917–1926
67. Benelkebir H, Marie S, Hayden A et al (2011) Total synthesis of largazole and analogues:
HDAC inhibition, antiproliferative activity and metabolic stability. Bioorg Med Chem
19:3650–3658
68. Yao Y, Tu Z, Liao C et al (2015) Discovery of novel class I histone deacetylase inhibitors with
promising in vitro and in vivo antitumor activities. J Med Chem 58:7672–7680
24
A. Ganesan