SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES
Compounds that inhibit the catalytic function of lysine-specific demethylase 1 (LSD1) are interesting as therapeutic agents. Recently, we identified three lysine-phenylcyclopropylamine conjugates, NCD18, NCD25, and NCD41, which are potent LSD1 inactivators. However, in our previous study, because we...
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Elsevier
2014-02-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037014600052 |
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| author | Yukihiro Itoh Daisuke Ogasawara Yosuke Ota Tamio Mizukami Takayoshi Suzuki |
| author_facet | Yukihiro Itoh Daisuke Ogasawara Yosuke Ota Tamio Mizukami Takayoshi Suzuki |
| author_sort | Yukihiro Itoh |
| collection | DOAJ |
| description | Compounds that inhibit the catalytic function of lysine-specific demethylase 1 (LSD1) are interesting as therapeutic agents. Recently, we identified three lysine-phenylcyclopropylamine conjugates, NCD18, NCD25, and NCD41, which are potent LSD1 inactivators. However, in our previous study, because we tested those compounds as mixtures of (1S,2R)- and (1R,2S)-disubstituted cyclopropane rings, the relationship between the stereochemistry of the cyclopropane ring and their biological activity remained unknown. In this work, we synthesized optically active compounds of NCD18, NCD25, and NCD41 and evaluated their LSD1 inhibitory activities. In enzyme assays, the LSD1 inhibitory activities of (1R,2S)-NCD18 and (1R,2S)-NCD25 were approximately eleven and four times more potent than those of the corresponding (1S,2R)-isomers, respectively. On the other hand, (1S,2R)-NCD41 was four times more potent than (1R,2S)-NCD41. Binding simulation with LSD1 indicated that the aromatic rings of the compounds and the amino group of the cyclopropylamine were important for the interaction with LSD1, and that the stereochemistry of the 1,2-disubstituted cyclopropane ring affected the position of the aromatic rings and the hydrogen bond formation of the amino group in the LSD1 catalytic site. These findings are expected to contribute to the further development of LSD1 inactivators. |
| first_indexed | 2024-04-13T20:16:47Z |
| format | Article |
| id | doaj.art-c0ac128d1d6f4d0e8b8810054bdd5f51 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-13T20:16:47Z |
| publishDate | 2014-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-c0ac128d1d6f4d0e8b8810054bdd5f512022-12-22T02:31:42ZengElsevierComputational and Structural Biotechnology Journal2001-03702014-02-019141910.5936/csbj.201402002SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATESYukihiro Itoh0Daisuke Ogasawara1Yosuke Ota2Tamio Mizukami3Takayoshi Suzuki4Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334, JapanGraduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334, JapanGraduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334, JapanGraduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829, JapanGraduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334, JapanCompounds that inhibit the catalytic function of lysine-specific demethylase 1 (LSD1) are interesting as therapeutic agents. Recently, we identified three lysine-phenylcyclopropylamine conjugates, NCD18, NCD25, and NCD41, which are potent LSD1 inactivators. However, in our previous study, because we tested those compounds as mixtures of (1S,2R)- and (1R,2S)-disubstituted cyclopropane rings, the relationship between the stereochemistry of the cyclopropane ring and their biological activity remained unknown. In this work, we synthesized optically active compounds of NCD18, NCD25, and NCD41 and evaluated their LSD1 inhibitory activities. In enzyme assays, the LSD1 inhibitory activities of (1R,2S)-NCD18 and (1R,2S)-NCD25 were approximately eleven and four times more potent than those of the corresponding (1S,2R)-isomers, respectively. On the other hand, (1S,2R)-NCD41 was four times more potent than (1R,2S)-NCD41. Binding simulation with LSD1 indicated that the aromatic rings of the compounds and the amino group of the cyclopropylamine were important for the interaction with LSD1, and that the stereochemistry of the 1,2-disubstituted cyclopropane ring affected the position of the aromatic rings and the hydrogen bond formation of the amino group in the LSD1 catalytic site. These findings are expected to contribute to the further development of LSD1 inactivators.http://www.sciencedirect.com/science/article/pii/S2001037014600052epigeneticshistone demethylaselysine-specific demethylaseprotein-targeted drug deliveryligand-protein interactiondrug discovery |
| spellingShingle | Yukihiro Itoh Daisuke Ogasawara Yosuke Ota Tamio Mizukami Takayoshi Suzuki SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES Computational and Structural Biotechnology Journal epigenetics histone demethylase lysine-specific demethylase protein-targeted drug delivery ligand-protein interaction drug discovery |
| title | SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES |
| title_full | SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES |
| title_fullStr | SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES |
| title_full_unstemmed | SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES |
| title_short | SYNTHESIS, LSD1 INHIBITORY ACTIVITY, AND LSD1 BINDING MODEL OF OPTICALLY PURE LYSINE-PCPA CONJUGATES |
| title_sort | synthesis lsd1 inhibitory activity and lsd1 binding model of optically pure lysine pcpa conjugates |
| topic | epigenetics histone demethylase lysine-specific demethylase protein-targeted drug delivery ligand-protein interaction drug discovery |
| url | http://www.sciencedirect.com/science/article/pii/S2001037014600052 |
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