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Rapid Discovery of Highly Potent and Selective Inhibitors of Histone-supportinginformation


Supporting Information for

Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries
Takayoshi Suzuki,*,?,? Yosuke Ota,§ Masaki Ri,# Masashige Bando,? Aogu Gotoh,?,§ Yukihiro Itoh,? Hiroki Tsumoto,§ Prima R. Tatum,§ Tamio Mizukami,║ Hidehiko Nakagawa,§ Shinsuke Iida,# Ryuzo Ueda,# Katsuhiko Shirahige,? and Naoki Miyata*,§
?

Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 403-8334, Japan,

?

PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan,
§

Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan,

#

Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan,

?

Institute of Molecular and Cellular Biosciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan



Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho,

Nagahama, Shiga, 526-0829, Japan
Contents

Results of LCMS analysis of representative compounds (Figure S1) The 120-member triazole library for HDAC inhibitors obtained by the combination of alkynes A1–A8 and azides B1–B15 (Figure S2) The 31-member C32-based library for HDAC8-selective inhibitors obtained by the combination of alkyne A3 and azides B16–B46 (Figure S3) Elemental Analysis Data
S1

S2

S4

S4 S5

a)

H HO N O S

A2 [M+H] +=168

b)

H HO N O S

N N N

C26 [M+H]+=351

c)

H HO N S O

N N N C27 [M+H]+=351

Figure S1. Results of LCMS analysis of representative compounds: a) alkyne A2 (4.64 min); b) C26 (16.1 min) (reaction mixture of A2 and B11); c) C27 (16.4 min) (reaction mixture of A2 and B12).
S2

d)

HO

H N O A3 [M+H] +=162

e)

HO

H N O N N N C31 [M+H]+=295

f)
H N O N N N C32 [M+H] +=309

HO

Figure S1 (continued). LCMS analysis of representative compounds: d) alkyne A3 (4.45 min); b) C31 (11.0 min) (reaction mixture of A3 and B1); c) C32 (12.5 min) (reaction mixture of A3 and B2).
S3

B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15

Hydroxyamic Acid Derivatives (C1-C60) o -Aminoanilide Derivatives (C61-C120) A1 A2 A3 A4 A5 A6 A7 A8 C1 C16 C31 C46 C61 C76 C91 C106 C2 C17 C32 C47 C62 C77 C92 C107 C3 C18 C33 C48 C63 C78 C93 C108 C4 C19 C34 C49 C64 C79 C94 C109 C5 C20 C35 C50 C65 C80 C95 C110 C6 C21 C36 C51 C66 C81 C96 C111 C7 C22 C37 C52 C67 C82 C97 C112 C8 C23 C38 C53 C68 C83 C98 C113 C9 C24 C39 C54 C69 C84 C99 C114 C10 C25 C40 C55 C70 C85 C100 C115 C11 C26 C41 C56 C71 C86 C101 C116 C12 C27 C42 C57 C72 C87 C102 C117 C13 C28 C43 C58 C73 C88 C103 C118 C14 C29 C44 C59 C74 C89 C104 C119 C15 C30 C45 C60 C75 C90 C105 C120

Figure S2. The 120-member triazole library for HDAC inhibitors obtained by the combination of alkynes A1–A8 and azides B1–B15.

Azide B16 B17 B18 B19 B20 B21 B22 B23

Triazole C121 C122 C123 C124 C125 C126 C127 C128

Azide B24 B25 B26 B27 B28 B29 B30 B31

Triazole C129 C130 C131 C132 C133 C134 C135 C136

Azide B32 B33 B34 B35 B36 B37 B38 B39

Triazole C137 C138 C139 C140 C141 C142 C143 C144

Azide B40 B41 B42 B43 B44 B45 B46

Triazole C145 C146 C147 C148 C149 C150 C151

Figure S3. The 31-member C32-based library for HDAC8-selective inhibitors obtained by the combination of alkyne A3 and azides B16–B46.

S4

Elemental Analysis Data

Compd A3 C9H7NO2

calcd C, 67.07; H, 4.38; N, 8.69

found C, 66.89; H, 4.47; N, 8.71

A4

C9H7NO2·1/10H2O

C, 66.33; H, 4.45; N, 8.60

C, 66.48; H, 4.72; N, 8.87

A5

C9H8N2O

C, 67.49; H, 5.03; N, 17.49

C, 67.80; H, 5.09; N, 17.11

A6

C7H5NO2S·1/4H2O

C, 63.27; H, 4.29; N, 11.35

C, 63.17; H, 4.30; N, 11.29

A7

C15H12N2O·1/3H2O

C, 74.36; H, 5.27; N, 11.56

C, 74.67; H, 5.21; N, 11.68

A8

C15H12N2O·1/5H2O

C, 75.11; H, 5.21; N, 11.68

C, 75.08; H, 5.09; N, 11.67

C31 C16H14N4O2·H2O

C, 61.53; H, 5.16; N, 17.94

C, 61.43; H, 5.25; N, 17.98

C32 C17H16N4O2·H2O

C, 62.57; H, 5.56; N, 17.17

C, 62.21; H, 5.52; N, 17.25

C142 C15H14N4O2S

C, 57.31; H, 4.49; N, 17.82

C, 57.23; H, 4.77; N, 17.60

C149 C16H14N4O2S

C, 58.88; H, 4.32; N, 17.17

C, 58.72; H, 4.34; N, 16.97

S5


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