Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors

Yohan Seo, Jinhwang Kim, Jiwon Chang, Seong Soon Kim, Wan Namkung, Ikyon Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Anoctamin 1 (ANO1), a calcium-activated chloride channel, is highly expressed and amplified in a number of carcinomas including breast, pancreatic and prostate cancers. Downregulation of ANO1 expression and function significantly inhibits cell proliferation, migration, and invasion of various cancer cell lines. Development of potent and selective ANO1 inhibitors is currently desirable, which may provide a new strategy for cancer treatment. Our previous study revealed a new class of ANO1 inhibitor, (E)-2-(4-chloro-2-methylphenoxy)-N'-(2-methoxybenzylidene)acetohydrazide (Ani9) and structural optimization via chemical modification of Ani9 basic skeleton was undertaken for the development of more potent and specific inhibitors of ANO1. Structure-activity relationship studies with newly synthesized derivatives revealed a number of potent ANO1 inhibitors, among which 5f is the most potent inhibitor with an IC50 value of 22 nM. The selectivity analyses showed that 5f has excellent selectivity to ANO1 (>1000-fold over ANO2). In cellular assays, 5f significantly inhibited cell proliferation of PC3, MCF7, and BxPC3 cells expressing high levels of ANO1. In addition, 5f strongly reduced the protein levels of ANO1 in PC3 cells. This study will be useful in the development of ANO1 inhibitors for treatment of cancer and other ANO1-related diseases.

Original languageEnglish
Pages (from-to)245-255
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume160
DOIs
Publication statusPublished - 2018 Dec 5

Fingerprint

Cell proliferation
Cells
Derivatives
Chloride Channels
Oncology
Structural optimization
Chemical modification
Cell Proliferation
Assays
Neoplasms
MCF-7 Cells
Structure-Activity Relationship
Pancreatic Neoplasms
Skeleton
Inhibitory Concentration 50
Cell Movement
Prostatic Neoplasms
Down-Regulation
Breast Neoplasms
Carcinoma

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors",
abstract = "Anoctamin 1 (ANO1), a calcium-activated chloride channel, is highly expressed and amplified in a number of carcinomas including breast, pancreatic and prostate cancers. Downregulation of ANO1 expression and function significantly inhibits cell proliferation, migration, and invasion of various cancer cell lines. Development of potent and selective ANO1 inhibitors is currently desirable, which may provide a new strategy for cancer treatment. Our previous study revealed a new class of ANO1 inhibitor, (E)-2-(4-chloro-2-methylphenoxy)-N'-(2-methoxybenzylidene)acetohydrazide (Ani9) and structural optimization via chemical modification of Ani9 basic skeleton was undertaken for the development of more potent and specific inhibitors of ANO1. Structure-activity relationship studies with newly synthesized derivatives revealed a number of potent ANO1 inhibitors, among which 5f is the most potent inhibitor with an IC50 value of 22 nM. The selectivity analyses showed that 5f has excellent selectivity to ANO1 (>1000-fold over ANO2). In cellular assays, 5f significantly inhibited cell proliferation of PC3, MCF7, and BxPC3 cells expressing high levels of ANO1. In addition, 5f strongly reduced the protein levels of ANO1 in PC3 cells. This study will be useful in the development of ANO1 inhibitors for treatment of cancer and other ANO1-related diseases.",
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Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors. / Seo, Yohan; Kim, Jinhwang; Chang, Jiwon; Kim, Seong Soon; Namkung, Wan; Kim, Ikyon.

In: European Journal of Medicinal Chemistry, Vol. 160, 05.12.2018, p. 245-255.

Research output: Contribution to journalArticle

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AU - Chang, Jiwon

AU - Kim, Seong Soon

AU - Namkung, Wan

AU - Kim, Ikyon

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