1. Synthesis of nigranoic acid and manwuweizic acid derivatives as HDAC inhibitors and anti-inflammatory agents.
- Author
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Ni DX, Wang Q, Li YM, Cui YM, Shen TZ, Li XL, Sun HD, Zhang XJ, Zhang R, and Xiao WL
- Subjects
- Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents chemistry, Cell Line, Cell Survival drug effects, Dose-Response Relationship, Drug, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Inflammasomes antagonists & inhibitors, Inflammasomes metabolism, Isoenzymes antagonists & inhibitors, Isoenzymes metabolism, Mice, Molecular Structure, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Structure-Activity Relationship, Triterpenes chemical synthesis, Triterpenes chemistry, Anti-Inflammatory Agents pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Triterpenes pharmacology
- Abstract
As a successful anti-tumor drug target, the family of histone deacetylases (HDACs) is also a critical player in immune response, making the research of anti-inflammatory HDAC inhibitors an attractive new focus. In this report, triterpenoids nigranoic acid (NA) and manwuweizic acid (MA) were identified as HDAC inhibitors through docking-based virtual screening and enzymatic activity assay. A series of derivatives of NA and MA were synthesized and assessed for their biological effects. As a result, hydroxamic acid derivatives of NA and MA showed moderately increased activity for HDAC1/2/4/6 inhibition (the lowest IC
50 against HDAC1 is 1.14 μM), with no activity against HDAC8. In J774A.1 macrophage, compound 1-3, 13 and 17-19 demonstrated inhibitory activity against lactate dehydrogenase (LDH) and IL-1β production, without affecting cell viability. Compound 19 increased the histone acetylation level in J774A.1 cells, as well as inhibited IL-1β maturation and caspase-1 cleavage. These results indicated that compound 19 blocks the activation of NLRP3 inflammasome, probably related to HDAC inhibition. This work provided a natural scaffold for developing low-cytotoxic and anti-inflammatory HDAC inhibitors, as well as a class of tool molecules for studying the relationship between HDACs and NLRP3 activation., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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