α-Trifluoromethyl Chalcones as Potent Anticancer Agents for Androgen Receptor-Independent Prostate Cancer

Abstract

α-Trifluoromethyl chalcones were prepared and evaluated for their antiproliferative activities against androgen-independent prostate cancer cell lines as well as five additional types of human tumor cell lines. The most potent chalcone 5 showed superior antitumor activity in vivo with both oral and intraperitoneal administration at 3 mg/kg. Cell-based mechanism of action studies demonstrated that 5 induced cell accumulation at sub-G1 and G2/M phases without interfering with microtubule polymerization. Furthermore, several cancer cell growth-related proteins were identified by using chalcone 5 as a bait for the affinity purification of binding proteins.

Novel α-Trifluoromethyl Chalcone Exerts Antitumor Effects Against Prostate Cancer Cells

“…It influences the acid dissociation constant, intrinsic potency, molecular structure, binding affinity to target molecules, membrane permeability, metabolic pathways, and pharmacokinetic properties of bioactive molecules (29). We previously focused on this property and determined whether the insertion of fluorine or fluorinated functional groups into synthetic chalcones could enhance their activity and successfully synthesized YS71 (17). YS71 suppressed cell proliferation of PC-3, DU145, and their paclitaxel-and cabazitaxel-resistant lines; moreover, it exhibited antitumor activity against PC-3 xenografts in severe combined immunodeficiency mice.…”

“…The structural formula of YS71 is presented in Figure 1. YS71 was prepared according as previously described (17). Briefly, Claisen-Schmidt condensation of acetophenone with 3,4-difluorobenzaldehyde produced 3,4-difluoro chalcone.…”

“…They have attracted considerable attention owing to their wide range of biological activities, including anti-inflammatory, antioxidant, and even antitumor activities, like flavonoids, as well as their clinical potential (15,16). We previously reported the synthesis of a novel α-trifluoromethyl chalcone obtained via Claisen-Schmidt condensation of an allyl methyl ketone with an aromatic aldehyde, and demonstrated its enhanced antitumor effect; it was designated YS71 (17). In the present study, we compared the efficacy of YS71 in androgendependent, androgen-independent, and taxane-resistant PCa cells with that of the derivative of 2'-HF, 16MS7F1924.…”