Structurally novel HDAC inhibitors based on the trans-β-arylacryl tetrahydroisoquinoline scaffold: the design, synthesis, and anti-cancer activity
10.16438/j.0513-4870.2022-1083
- VernacularTitle:基于反式-β-芳基烯丙酰四氢异喹啉母核的HDAC抑制剂:设计、合成及其抗肿瘤活性研究
- Author:
Xin GAO
1
;
Wei-wei HAN
1
;
Shi-yi TIAN
1
;
Fang FANG
1
,
2
,
3
,
4
;
Xiao-dong MA
1
,
2
,
3
,
4
;
Hua-yi CHAI
1
;
Jing-jing HAN
1
Author Information
1. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
2. Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China
3. Anhui Province Key Laboratory of Research &
4. Development of Chinese Medicine, Hefei 230012, China
- Publication Type:Research Article
- Keywords:
HDAC inhibitor;
tetrahydroisoquinoline;
italic>trans-β-arylacryl;
anti-cancer
- From:
Acta Pharmaceutica Sinica
2023;58(2):413-422
- CountryChina
- Language:Chinese
-
Abstract:
In this study, a series of 18 histone deacetylases inhibitors (HDACis), derived from our in-house anti-cancer trans-β-arylacryl 1,2,3,4-tetrahydroisoquinoline-based scaffold, were designed, synthesized, and antitumor evaluated. HDAC1 inhibitory activity assay showed that compounds 13d-13f and 13m-13o demonstrated attractive enzymatic activity with IC50 at single-digit nanomolar or subnanomolar level.In addition, 13o exerted superior anti-proliferative activity (A549, IC50 = 0.89 μmol·L-1; HCT116, IC50 = 0.49 μmol·L-1) to that of vorinostat (SAHA).Besides,13e, with the most potent HDAC1 enzymatic activity (IC50 = 3.8 nmol·L-1), also displayed attractive cellular activity (A549, IC50 = 1.74 μmol·L-1; HCT116, IC50 = 2.43 μmol·L-1). The Western blot analysis illustrated that 13e treatment increased the acetylation of H3 and α-tubulin in a dose-dependent manner in A549 cells. In summary, 13e and 13o deserve further functional investigation.
