Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Zonghui Ma; Ling Jiang; Guoxin Li; Dailin Liang; Luanfeng Li; Li Liu; Cheng Jiang

doi:10.1016/j.bioorg.2020.103971

Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Zonghui Ma, Ling Jiang, Guoxin Li, Dailin Liang, Luanfeng Li, Li Liu, Cheng Jiang

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

5 Scopus citations

Abstract

LDH1A1, one of 19 NAD(P)⁺-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC₅₀ values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).

Original language	English (US)
Article number	103971
Journal	Bioorganic Chemistry
Volume	101
DOIs	https://doi.org/10.1016/j.bioorg.2020.103971
State	Published - Aug 2020
Externally published	Yes

Keywords

ALDH1A1
Enzyme inhibition
Glucose consumption improvement
Selective
Synthesis

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

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10.1016/j.bioorg.2020.103971

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title = "Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity",

abstract = "LDH1A1, one of 19 NAD(P)+-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).",

keywords = "ALDH1A1, Enzyme inhibition, Glucose consumption improvement, Selective, Synthesis",

author = "Zonghui Ma and Ling Jiang and Guoxin Li and Dailin Liang and Luanfeng Li and Li Liu and Cheng Jiang",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = aug,

doi = "10.1016/j.bioorg.2020.103971",

language = "English (US)",

volume = "101",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

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T1 - Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

AU - Ma, Zonghui

AU - Jiang, Ling

AU - Li, Guoxin

AU - Liang, Dailin

AU - Li, Luanfeng

AU - Liu, Li

AU - Jiang, Cheng

PY - 2020/8

Y1 - 2020/8

N2 - LDH1A1, one of 19 NAD(P)+-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).

AB - LDH1A1, one of 19 NAD(P)+-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).

KW - ALDH1A1

KW - Enzyme inhibition

KW - Glucose consumption improvement

KW - Selective

KW - Synthesis

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DO - 10.1016/j.bioorg.2020.103971

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SN - 0045-2068

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JO - Bioorganic Chemistry

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ER -

Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Abstract

Keywords

ASJC Scopus subject areas

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