Design, synthesis, and evaluation of the antiproliferative activity of hydantoin-derived antiandrogen-genistein conjugates

• Authors: Alex George, Georgia Institute of Technology; Idris Raji, Georgia Institute of Technology; Bekir Cinar, Clark Atlanta University; Omer Kucuk, Emory University; Adegboyega K. Oyelere, Georgia Institute of Technology
• Journal Title: Bioorganic and Medicinal Chemistry
• Volume: Volume 26, Number 8
• Publisher: Elsevier | 2018-05-01, Pages 1481-1487
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bmc.2018.01.009
• Subjects: Chemistry, Biochemistry; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Physical Sciences; Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic; Pharmacology & Pharmacy; Chemistry; Prostate cancer; Genistein; Androgen receptor; Antiandrogen; LNCaP; DU145; PROSTATE-CANCER CELLS; TUMOR-SUPPRESSOR GENES; KAPPA-B ACTIVATION; ANDROGEN RECEPTOR; CYCLE ARREST; MECHANISMS; CARCINOMA; APOPTOSIS; LNCAP; LINE

Abstract

Androgen receptor (AR) signaling is vital to the viability of all forms of prostate cancer (PCa). With the goal of investigating the effect of simultaneous inhibition and depletion of AR on viability of PCa cells, we designed, synthesized and characterized the bioactivities of bifunctional agents which incorporate the independent cancer killing properties of an antiandrogen and genistein, and the AR downregulation effect of genistein within a single molecular template. We observed that a representative conjugate, 9b, is much more cytotoxic to both LNCaP and DU145 cells relative to the antiandrogen and genistein building blocks as single agents or their combination. Moreover, conjugate 9b more effectively down regulates cellular AR protein levels relative to genistein and induces S phase cell cycle arrest. The promising bioactivities of these conjugates warrant further investigation.