2. Academic Validation
  3. Effects of substituent pattern on the intracellular target of antiproliferative benzo[b]thiophenyl chromone derivatives

Effects of substituent pattern on the intracellular target of antiproliferative benzo[b]thiophenyl chromone derivatives

  • Eur J Med Chem. 2021 Oct 15:222:113578. doi: 10.1016/j.ejmech.2021.113578.
Yohei Saito 1,  Yukako Taniguchi 1,  Sachika Hirazawa 1,  Yuta Miura 1,  Hiroyuki Tsurimoto 1,  Tomoki Nakayoshi 2,  Akifumi Oda 2,  Ernest Hamel 3,  Katsumi Yamashita 1,  Masuo Goto 4,  Kyoko Nakagawa-Goto 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
  • 2 Graduate School of Pharmacy, Meijo University, Tempaku-ku, Nagoya, 468-8503, Japan.
  • 3 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, 21702, United States.
  • 4 Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, United States. Electronic address: goto@med.unc.edu.
  • 5 School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan; Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, United States. Electronic address: kngoto@p.kanazawa-u.ac.jp.
PMID: 34171512 DOI: 10.1016/j.ejmech.2021.113578
Abstract

A new biological scaffold was produced by replacing the 6π-electron phenyl ring-B of a natural flavone skeleton with a 10π-electron benzothiophene (BT). Since aromatic rings are important for ligand protein interactions, this expansion of the π-electron system of ring-B might change the bioactivity profile. One of the resulting novel natural product-inspired compounds, 2-(benzo[b]thiophen-3-yl)-5-hydroxy-7-isopropoxy-6-methoxyflavone (6), effectively arrested the cell cycle at the G2/M phase and displayed significant antiproliferative effects with IC50 values of 0.05-0.08 μM against multiple human tumor cell lines, including a multidrug resistant line. A structure-activity relationship study revealed that a 10π-electron system with high aromaticity, juxtaposed 4-oxo and 5-hydroxy groups, and 7-alkoxy groups were important for potent antimitotic activity. Interestingly, two BT-flavonols (3-hydroxyflavone), 16 and 20, with 3-hydroxy and 5-alkoxy groups, induced distinct biological profiles affecting the cell cycle at the G1/S phase by inhibition of DNA replication through an interaction with Topoisomerase I.

Keywords

Antiproliferative activity; Benzothiophene; Flavone; Flavonol; Topoisomerase I; Tubulin.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z