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.
- 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: [email protected].
- 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: [email protected].
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.