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

Bioorg Med Chem. 2018 May 1;26(8):1481-1487. doi: 10.1016/j.bmc.2018.01.009.

Alex George ¹, Idris Raji ¹, Bekir Cinar ², Omer Kucuk ³, Adegboyega K Oyelere ⁴

Affiliations

1 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
2 Department of Biological Sciences, The Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA.
3 Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. Electronic address: omer.kucuk@emory.edu.
4 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA. Electronic address: aoyelere@gatech.edu.

PMID: 29456113 DOI: 10.1016/j.bmc.2018.01.009

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.

Keywords

Androgen receptor; Antiandrogen; DU145; Genistein; LNCaP; Prostate cancer.

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