Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Article abstract of DOI:10.1002/cbdv.201800027

In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a?–?4i, 6a?–?6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g?–?4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC₅₀ values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.

Full text of DOI:10.1002/cbdv.201800027

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R
O
O
N
H
Ethyl 7-aminoheptanoate.HCl
PyBOP, DBU, acetonitrile
OH
N
OC2H5
H2N-CHO
rfx
NH
R
R
NH2
N
N
O
3a-i
2a-i
R
1a-i
H
H2N-OH.HCl
N
NHOH
CH3OH, NaOH/H2O
-5 o
C
N
N
O
4a-i
O
O
O
N
OCH3
R
H2N
OCH3
O
OH
H2N-CHO
NH
H
N
.HCl
R
R
rfx
PyBOP, DBU, acetonitrile
NH2
N
N
1a-i
2a-i
5a-i
O
R
NHOH
H
N
H2N-OH.HCl
CH3OH, NaOH/H2O
-5 o
N
N
C
6a-i
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: δ 10.37
(1H, s, NH), 8.70 (1H, s, OH), 8.45 (1H, s, H-2’), 8.25 (1H, s, 4’-NH), 8.24 (1H, d,
: δ 169.62 (C-1), 159.81 (C-4’), 155.64 (C-2’), 149.51 (C-2”)
:
δ 10.35 (1H, s, NH), 8.68 (1H, s, OH), 8.42 (1H, s, H-2’), 8.14 (1H, s, 4’-NH), 8.13 (1H, d,
: δ 169.58
(C-1),
: δ
10.34 (1H, s, NH), 8.68 (1H, s, OH), 8.40 (1H, s, H-2’), 8.13 (1H, s, 4’-NH), 8.12 (1H, s, H-5’), 7.57 (1H,
: δ 169.59 (C-1),
159.44 (C-4’), 154.88 (C-2’), 147.77 (C-2”), 135.39 (C-6’), 134.48 (C-7’), 127.73 (C-8’), 122.11 (C-5’), 115.25 (C-1”), 40.91 (C-7),
32.71 (C-2), 28.93 (C-6), 28.89 (C-4), 26.78 (C-5), 25.58 (C-3), 21.74 (6’-
: δ 10.34 (1H, s, NH), 8.68 (1H, s, OH), 8.38 (1H, s, H-2’), 8.15 (1H, d,
: δ 169.58 (C-1), 162.72 (C-7’), 159.52 (C-4’), 156.16 (C-2’), 151.86 (C-2”), 124.71 (C-5’),
116.93 (C-6’), 109.62 (C-1”), 107.33 (C-8’), 55.92 (7’-O
: δ10.38 (1H, s, NH), 8.67 (1H, s, OH), 8.47 (1H, s, H-2’), 8.12 (1H, s, H-5’), 8.08 (1H, t,
: δ
169.54 (C-1), 159.36 (C-7’), 156.12 (C-4’), 150.19 (C-2’), 149.37 (C-6’), 134.87 (C-2”), 107.09 (C-1”), 104.40 (C-8’), 100.25
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: δ
10.34 (1H, s, NH), 8.67 (1H, s, OH), 8.45 (1H, s, H-2’), 8.35-8.33 (2H, m, 4’-NH, H-5’), 7.44-7.39 (2H, m, H-8’, H-6’), 3.54-3.50
(2H, m, H-7a, H-7b), 1.95 (2H, t,
: δ 169.57 (C-1), 165.72 (C-7’), 163.73 (C-4’), 159.60 (C-2’),
156.78 (C-2”), 151.60 (C-5’,
: δ
10.33 (1H, s, NH), 8.69 (1H, s, OH), 8.45 (1H, s, H-2’), 8.19 (1H, s, 4’-NH), 8.11 (1H, dd,
: δ
169.59 (C-1), 160.04 (C-6’,
: δ
10.30 (1H, s, NH), 8.64 (1H,s , OH), 8.45 (1H, s, H-2’), 8.40 (1H, s, 4’-NH), 8.31 (1H, s, H-5’), 7.74 (1H,
: δ 169.58 (C-1), 159.09
(C-4’), 156.02 (C-2’), 147.25 (C-2”), 133.27 (C-6’), 130.14 (C-7’), 130.01 (C-8’), 122.54 (C-5’), 116.26 (C-1”), 41.09 (C-7), 32.71
(C-2), 28.86 (C-6), 28.73 (C-4), 26.75 (C-5), 25.56 (C-3)
: δ 10.36 (1H, s, NH), 8,69 (1H, s, OH), 8.53 (1H, s, H-2’), 8.35 (1H, s, 4’-NH), 8.06 (1H, s, H-8’), 7.93 (1H, d,
: δ 169.60 (C-1),
159.59 (C-4’), 155.56 (C-2’), 143.76 (C-7’), 141.83 (C-2”), 128.39 (C-8’), 120.96 (C-5’), 116.78 (C-6’), 108.06 (C-1”), 41.24 (C-7),
32.70 (C-2), 28.84 (C-6), 28.69
: δ 11.16
(1H, s, NH), 9.00 (1H, s, OH), 8.91 (1H, t,
: δ 164.63 (C-1),
159.84 (C-4’), 155.49 (C-2’), 149.63 (C-2”), 143.23 (C-5), 133
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: δ 11.15 (1H, s, NH), 9.02 (1H, s, OH), 8.81 (1H, t,
: δ 159.70 (C-4’), 155.59 (C-2’), 147.88 (C-2”),
143.34 (C-7’), 143.28 (C-5), 131.78 (C-2),
: δ 11.11 (1H, s, NH), 9.05 (1H, s, OH), 8.78 (1H, s, 4’-NH), 8.39 (1H, s, H-2’), 8.12 (1H, s, H-5’), 7.71 (2H, d,
: δ 164.54 (C-1), 159.44 (C-4’), 154.74 (C-2’), 147.91 (C-2”), 143.31 (C-5), 135.74 (C-6’), 134.77 (C-7’),
131.80 (C-2), 127.85 (C-8’), 127.51 (C-3,
: δ 11.14 (1H, s, NH), 9.00
(1H, s, OH), 8.73 (1H, t,
: δ 162.94 (C-1), 159.52 (C-4’), 156.03 (C-2’), 152.00 (C-2”), 143.44 (C-
5), 131.76 (C-2), 127.44 (C-3, C-7), 127.39 (C-4, C-6), 124.70 (C-5’), 117.3
: δ 11.21 (1H, s,
NH), 10.04 (1H, s, OH), 8.65 (1H, s, H-2’), 8.03-7.78 (1H, m, 4’-NH), 7.92 (1H, d,
: δ 167.58 (C-7’), 164.45 (C-1), 159.42 (C-4’), 155.76 (C-2’), 150.92 (C-6’), 149.95 (C-2”), 144.08, 142.12 (C-5),
138.58, 132.12 (C-2), 130.09, 129.96, 127.88, 127.77 (C-3, C-7), 127.52 (C-4, C-6), 107.73 (C-1”),
: δ 11.11
(1H, s, NH), 9.00 (2H, s, OH, 4’-NH), 8.45 (1H, s, H-2’), 8.42 (1H, dd,
: δ 165.87 (C-7’), 164.51 (C-1), 159.66 (C-4’), 156.65 (C-2’), 151.70 (C-2”,
: δ 11.17 (1H, s, NH), 9.01
(1H, s, OH), 8.85 (1H, t,
: δ 164.58 (C-1), 160.61 (C-6’), 159.14 (C-4’,
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: δ 11.15
(1H, s, NH), 9.00 (1H, s, OH), 8.99-8.98 (1H, m, 4’-NH), 8.49 (1H, s, H-2’), 8.48 (1H, d,
: δ 164.53 (C-1), 162.79 (C-4’), 159.13 (C-2’), 155.89 (C-2”),
148.35 (C-5), 142.82 (C-2), 133.54 (C-6’), 131.89
: δ
: δ
9.02 (1H, s, OH), 8.54 (1H, s, H-2’), 8.01 (1H, s, H-8’), 8.00 (1H, d,
164.49 (C-1), 159.69 (C-4’), 156.54 (C-2’), 154.94 (C-7’), 144.30 (C-2”), 143.80 (C-5), 142.71 (C-2), 127.68 (C-3, C-7), 127.50 (C-
4, C-6), 125.54 (C-8’), 121.39 (C-5’), 116.84 (
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