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
2
;
Xiao-dong MA
2
;
Hua-yi CHAI
1
;
Jing-jing HAN
1
Author Information
1. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
2. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Research & 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.
