三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

Xiaoming Xu; Siqi Guo; Jing Zhang; Yantao Chen; Yaqing Kang; Na Liu; Junfang Liu; Cheng Luo; Shijie Chen; Hua Chen

doi:10.6023/cjoc201911012

三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

Translated title of the contribution: Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities

Xiaoming Xu
, Siqi Guo
, Jing Zhang
, Yantao Chen
, Yaqing Kang
, Na Liu
, Junfang Liu
, Cheng Luo
, Shijie Chen^*
, Hua Chen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

A series of novel derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications on a lead disruptor of telomeric silencing 1-like (DOT1L) inhibitor 8. All the compounds have been evaluated for their DOT1L inhibitory activities at the concentration of 50 μmol/L. The results showed that the tested compounds showed certain DOT1L inhibitory activities. Among them, N, N-dimethyl-4-(6-methyl-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-3-yl)aniline (14b) and (R)-tert-butyl (1-((3-(4-(dimethylamino)phenyl)-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-6-yl)methyl)-piperidin-3-yl)carba- mate (16a) were the best ones with IC₅₀ values of 7.37 and 7.84 μmol/L, respectively, near that of the positive control 8. The structure-activity analysis showed that when the triazolo-thiadiazole moiety occupied the binding-site of S-adenosylmethionine (SAM) in DOT1L and R¹ group was 4-N, N-dimethyl, the hydrophobic substituents as the tailed R² groups would be accommodated into the DOT1L binding site, and the sizes of the substituents seemed no effects on their DOT1L inhibitory activities of the compounds.

Translated title of the contribution	Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities
Original language	Chinese (Traditional)
Pages (from-to)	1345-1354
Number of pages	10
Journal	Chinese Journal of Organic Chemistry
Volume	40
Issue number	5
DOIs	https://doi.org/10.6023/cjoc201911012
State	Published - 1 May 2020
Externally published	Yes

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@article{1e908957f09e4338931c2aa2435a3ef0,

title = "三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性",

abstract = "A series of novel derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications on a lead disruptor of telomeric silencing 1-like (DOT1L) inhibitor 8. All the compounds have been evaluated for their DOT1L inhibitory activities at the concentration of 50 μmol/L. The results showed that the tested compounds showed certain DOT1L inhibitory activities. Among them, N, N-dimethyl-4-(6-methyl-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-3-yl)aniline (14b) and (R)-tert-butyl (1-((3-(4-(dimethylamino)phenyl)-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-6-yl)methyl)-piperidin-3-yl)carba- mate (16a) were the best ones with IC50 values of 7.37 and 7.84 μmol/L, respectively, near that of the positive control 8. The structure-activity analysis showed that when the triazolo-thiadiazole moiety occupied the binding-site of S-adenosylmethionine (SAM) in DOT1L and R1 group was 4-N, N-dimethyl, the hydrophobic substituents as the tailed R2 groups would be accommodated into the DOT1L binding site, and the sizes of the substituents seemed no effects on their DOT1L inhibitory activities of the compounds.",

keywords = "DOT1L inhibitor, Hydrophobic substituent, Structural modification, Structure-activity analysis, Ttriazolo-thiadiazole",

author = "Xiaoming Xu and Siqi Guo and Jing Zhang and Yantao Chen and Yaqing Kang and Na Liu and Junfang Liu and Cheng Luo and Shijie Chen and Hua Chen",

note = "Publisher Copyright: {\textcopyright} 2020 Chinese Chemical Society \& SIOC, CAS.",

year = "2020",

month = may,

day = "1",

doi = "10.6023/cjoc201911012",

language = "繁体中文",

volume = "40",

pages = "1345--1354",

journal = "Chinese Journal of Organic Chemistry",

issn = "0253-2786",

publisher = "Science Press ",

number = "5",

}

TY - JOUR

T1 - 三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

AU - Xu, Xiaoming

AU - Guo, Siqi

AU - Zhang, Jing

AU - Chen, Yantao

AU - Kang, Yaqing

AU - Liu, Na

AU - Liu, Junfang

AU - Luo, Cheng

AU - Chen, Shijie

AU - Chen, Hua

PY - 2020/5/1

Y1 - 2020/5/1

N2 - A series of novel derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications on a lead disruptor of telomeric silencing 1-like (DOT1L) inhibitor 8. All the compounds have been evaluated for their DOT1L inhibitory activities at the concentration of 50 μmol/L. The results showed that the tested compounds showed certain DOT1L inhibitory activities. Among them, N, N-dimethyl-4-(6-methyl-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-3-yl)aniline (14b) and (R)-tert-butyl (1-((3-(4-(dimethylamino)phenyl)-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-6-yl)methyl)-piperidin-3-yl)carba- mate (16a) were the best ones with IC50 values of 7.37 and 7.84 μmol/L, respectively, near that of the positive control 8. The structure-activity analysis showed that when the triazolo-thiadiazole moiety occupied the binding-site of S-adenosylmethionine (SAM) in DOT1L and R1 group was 4-N, N-dimethyl, the hydrophobic substituents as the tailed R2 groups would be accommodated into the DOT1L binding site, and the sizes of the substituents seemed no effects on their DOT1L inhibitory activities of the compounds.

AB - A series of novel derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications on a lead disruptor of telomeric silencing 1-like (DOT1L) inhibitor 8. All the compounds have been evaluated for their DOT1L inhibitory activities at the concentration of 50 μmol/L. The results showed that the tested compounds showed certain DOT1L inhibitory activities. Among them, N, N-dimethyl-4-(6-methyl-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-3-yl)aniline (14b) and (R)-tert-butyl (1-((3-(4-(dimethylamino)phenyl)-[1, 2, 4]triazolo[3, 4-b] [1, 3, 4]thiadiazol-6-yl)methyl)-piperidin-3-yl)carba- mate (16a) were the best ones with IC50 values of 7.37 and 7.84 μmol/L, respectively, near that of the positive control 8. The structure-activity analysis showed that when the triazolo-thiadiazole moiety occupied the binding-site of S-adenosylmethionine (SAM) in DOT1L and R1 group was 4-N, N-dimethyl, the hydrophobic substituents as the tailed R2 groups would be accommodated into the DOT1L binding site, and the sizes of the substituents seemed no effects on their DOT1L inhibitory activities of the compounds.

KW - DOT1L inhibitor

KW - Hydrophobic substituent

KW - Structural modification

KW - Structure-activity analysis

KW - Ttriazolo-thiadiazole

UR - https://www.scopus.com/pages/publications/85086338405

U2 - 10.6023/cjoc201911012

DO - 10.6023/cjoc201911012

M3 - 文章

AN - SCOPUS:85086338405

SN - 0253-2786

VL - 40

SP - 1345

EP - 1354

JO - Chinese Journal of Organic Chemistry

JF - Chinese Journal of Organic Chemistry

IS - 5

ER -

三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

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