Synthesis of nigranoic acid and manwuweizic acid derivatives as HDAC inhibitors and anti-inflammatory agents

• Published in: Bioorganic chemistry 2021-04, Vol.109, p.104728-104728, Article 104728
• Main Authors: Ni, Dong-Xuan, Wang, Qi, Li, Yi-Ming, Cui, Yi-Man, Shen, Tian-Ze, Li, Xiao-Li, Sun, Han-Dong, Zhang, Xing-Jie, Zhang, Ruihan, Xiao, Wei-Lie
• Format: Article
• Language: English
• Subjects: HDAC inhibition; Inflammasome; Natural products modification; Triterpenoid
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104728

[Display omitted] •Nature-inspired compounds were found to inhibit HDAC and block inflammasome activation.•The active scaffold was discovered by virtual screening.•Derivatives of nigranoic acid and manwuweizic acid derivatives were prepared. 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 IC50 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.