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

• Type of Material: Article
• 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
• Language: English
• Date: 2018-05-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2019 Elsevier B.V. or its licensors or contributors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmc.2018.01.009
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry
• ISSN: 0968-0896
• Volume: 26
• Issue: 8
• Start Page: 1481
• End Page: 1487
• Grant/Funding Information: Alex George is a grateful recipient of the Georgia Tech’s President’s Undergraduate Research Award; This project was financially supported in part by NIH grant R21CA185690 (A.K.O.); and NIH/NIMHD/RCMI Grant 5G12MD007590 (B.C.).
• Keywords: LNCAP; Physical Sciences; PROSTATE-CANCER CELLS; Chemistry, Organic; APOPTOSIS; Genistein; CYCLE ARREST; Antiandrogen; TUMOR-SUPPRESSOR GENES; KAPPA-B ACTIVATION; Chemistry; LINE; Life Sciences & Biomedicine; ANDROGEN RECEPTOR; DU145; Androgen receptor; CARCINOMA; Science & Technology; Pharmacology & Pharmacy; MECHANISMS; Prostate cancer; LNCaP; Chemistry, Medicinal; Biochemistry & Molecular Biology
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry

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.