5′-Chloro-2,2′-dihydroxychalcone and related flavanoids as treatments for prostate cancer

Yohei Saito, Atsushi Mizokami, Hiroyuki Tsurimoto, Kouji Izumi, Masuo Goto, Kyoko Nakagawa-Goto

Research output: Contribution to journalArticle

Abstract

Several flavonoids and their biosynthetic precursor chalcones were designed and synthesized to improve the biological effects of the lead compound 2′-hydroxyflavonone against androgen receptor (AR)-dependent transcriptional stimulation. Newly synthesized chalcones 19 and 26 suppressed AR-dependent transcription as well as DHT-dependent growth stimulation at a low micromolar level. These compounds were also effective against ligand-independent constitutively active mutant AR derived from castration-resistant PCa (CRPC). Compounds 19 and 26 showed broad spectrum antiproliferative activity at 5–10 μM against multiple tumor cell lines including androgen-independent and taxane-resistant prostate cancer as well as a multidrug-resistant subline. Mode of action studies suggested that 19 induced sub-G1 accumulation in PC-3 cells by disrupting the microtubule network without affecting cell cycle progression. Furthermore, the in vivo effectiveness of chalcone 19 was confirmed in a xenograft model antitumor assay. Thus, chalcone 19 has the potential to be a bifunctional lead for treatment of AR-dependent PCa at lower doses as well as AR-independent PCa, including CRPC, at higher doses.

LanguageEnglish (US)
Pages1143-1152
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume157
DOIs
StatePublished - Sep 5 2018

Fingerprint

Chalcone
Androgen Receptors
Chalcones
Cells
Lead compounds
Transcription
Flavonoids
Heterografts
Androgens
Tumors
Assays
2,2'-dihydroxychalcone
Ligands

Keywords

  • Androgen receptor reporter assay
  • Castration-resistant prostate cancer
  • Chalcone
  • LNCaP
  • PC-3

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

5′-Chloro-2,2′-dihydroxychalcone and related flavanoids as treatments for prostate cancer. / Saito, Yohei; Mizokami, Atsushi; Tsurimoto, Hiroyuki; Izumi, Kouji; Goto, Masuo; Nakagawa-Goto, Kyoko.

In: European Journal of Medicinal Chemistry, Vol. 157, 05.09.2018, p. 1143-1152.

Research output: Contribution to journalArticle

Saito, Yohei ; Mizokami, Atsushi ; Tsurimoto, Hiroyuki ; Izumi, Kouji ; Goto, Masuo ; Nakagawa-Goto, Kyoko. / 5′-Chloro-2,2′-dihydroxychalcone and related flavanoids as treatments for prostate cancer. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 157. pp. 1143-1152.
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