2. Academic Validation
  3. 5'-Chloro-2,2'-dihydroxychalcone and related flavanoids as treatments for prostate cancer

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

  • Eur J Med Chem. 2018 Sep 5:157:1143-1152. doi: 10.1016/j.ejmech.2018.08.069.
Yohei Saito 1,  Atsushi Mizokami 2,  Hiroyuki Tsurimoto 1,  Kouji Izumi 3,  Masuo Goto 4,  Kyoko Nakagawa-Goto 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Science, Kanazawa University, Kanazawa, 920-1192, Japan.
  • 2 Department of Integrative Cancer Therapy and Urology, School of Medical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan. Electronic address: mizokami@staff.kanazawa-u.ac.jp.
  • 3 Department of Integrative Cancer Therapy and Urology, School of Medical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
  • 4 Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States.
  • 5 School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Science, Kanazawa University, Kanazawa, 920-1192, Japan; Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States. Electronic address: kngoto@p.kanazawa-u.ac.jp.
PMID: 30189396 DOI: 10.1016/j.ejmech.2018.08.069
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.

Keywords

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

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