TY - JOUR
T1 - Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors
AU - Nepali, Kunal
AU - Chang, Ting Yu
AU - Lai, Mei Jung
AU - Hsu, Kai Cheng
AU - Yen, Yun
AU - Lin, Tony Eight
AU - Lee, Sung Bau
AU - Liou, Jing Ping
N1 - Funding Information:
We thank Dr. Sun Young Rha (Songdang Institute for Cancer Research) for providing YCC cell lines and Nian-Zhe Lee (Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, TMU) for assistance. We also appreciate the technical supports provide by the TMU Core Facility. This research was supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 107-2113-M-038 -001; MOST 108-2113-M-038-005, MOST108-2320-B-038-10-MY2).
Funding Information:
We thank Dr. Sun Young Rha (Songdang Institute for Cancer Research) for providing YCC cell lines and Nian-Zhe Lee (Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, TMU) for assistance. We also appreciate the technical supports provide by the TMU Core Facility. This research was supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 107-2113-M-038 -001 ; MOST 108-2113-M-038-005 , MOST108-2320-B-038-10-MY2 ).
Publisher Copyright:
© 2020
PY - 2020/6/15
Y1 - 2020/6/15
N2 - This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.
AB - This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.
KW - Drug resistance
KW - Histone deacetylase inhibitors
KW - Isosters
KW - Purines
UR - http://www.scopus.com/inward/record.url?scp=85083296780&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083296780&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2020.112291
DO - 10.1016/j.ejmech.2020.112291
M3 - Article
AN - SCOPUS:85083296780
SN - 0223-5234
VL - 196
JO - CHIM.THER.
JF - CHIM.THER.
M1 - 112291
ER -
