Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors
Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in th...
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MDPI AG
2022-05-01
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| Series: | Molecules |
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| author | Yangrong Xu Hangjun Tang Yijie Xu Jialin Guo Xu Zhao Qingguo Meng Junhai Xiao |
| author_facet | Yangrong Xu Hangjun Tang Yijie Xu Jialin Guo Xu Zhao Qingguo Meng Junhai Xiao |
| author_sort | Yangrong Xu |
| collection | DOAJ |
| description | Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using α-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and <b>7a</b> and its stereoisomer <b>13a</b> exhibited excellent activities against Hela cells with IC<sub>50</sub> = 0.31 µM and IC<sub>50</sub> = 5.19 µM, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of <b>7a</b>, a small-scale virtual screen using reverse docking for HDAC isoforms (1–10) was performed and the results showed that HDAC6 was the best receptor for <b>7a</b>, suggesting that HDAC6 may be a potential target for <b>7a</b>. The interaction pattern analysis showed that the α-amino amide moiety of <b>7a</b> coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex’s conformational stability. In this work, we identified <b>7a</b> as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors. |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:18:44Z |
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| spelling | doaj.art-f2c2ddc6a4c34e87b1607addebf4260b2023-11-23T12:24:49ZengMDPI AGMolecules1420-30492022-05-012710333510.3390/molecules27103335Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 InhibitorsYangrong Xu0Hangjun Tang1Yijie Xu2Jialin Guo3Xu Zhao4Qingguo Meng5Junhai Xiao6National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, ChinaNational Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaDepartment of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, ChinaNational Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaHydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using α-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and <b>7a</b> and its stereoisomer <b>13a</b> exhibited excellent activities against Hela cells with IC<sub>50</sub> = 0.31 µM and IC<sub>50</sub> = 5.19 µM, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of <b>7a</b>, a small-scale virtual screen using reverse docking for HDAC isoforms (1–10) was performed and the results showed that HDAC6 was the best receptor for <b>7a</b>, suggesting that HDAC6 may be a potential target for <b>7a</b>. The interaction pattern analysis showed that the α-amino amide moiety of <b>7a</b> coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex’s conformational stability. In this work, we identified <b>7a</b> as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors.https://www.mdpi.com/1420-3049/27/10/3335HDAC6 inhibitorsnon-hydroxamateα-amino amidesynthesisbioactivity evaluationcrystal structure |
| spellingShingle | Yangrong Xu Hangjun Tang Yijie Xu Jialin Guo Xu Zhao Qingguo Meng Junhai Xiao Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors Molecules HDAC6 inhibitors non-hydroxamate α-amino amide synthesis bioactivity evaluation crystal structure |
| title | Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors |
| title_full | Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors |
| title_fullStr | Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors |
| title_full_unstemmed | Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors |
| title_short | Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors |
| title_sort | design synthesis bioactivity evaluation crystal structures and in silico studies of new α amino amide derivatives as potential histone deacetylase 6 inhibitors |
| topic | HDAC6 inhibitors non-hydroxamate α-amino amide synthesis bioactivity evaluation crystal structure |
| url | https://www.mdpi.com/1420-3049/27/10/3335 |
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