2. Academic Validation
  3. 1-Benzyloxy-5-phenyltetrazole derivatives highly active against androgen receptor-dependent prostate cancer cells

1-Benzyloxy-5-phenyltetrazole derivatives highly active against androgen receptor-dependent prostate cancer cells

  • Eur J Med Chem. 2023 Jan 15:246:114982. doi: 10.1016/j.ejmech.2022.114982.
Shiting Zhao 1,  Abdelsalam S Ali 2,  Xinyu Kong 3,  Yan Zhang 3,  Xiaomin Liu 4,  Melissa A Skidmore 2,  Craig M Forsyth 5,  G Paul Savage 2,  Donghai Wu 6,  Yong Xu 7,  Craig L Francis 8
Affiliations

Affiliations

  • 1 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangzhou Medical University, Guangzhou, 511436, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Drug Discovery Chemistry Team, CSIRO, Clayton, VIC, 3168, Australia.
  • 3 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 5 School of Chemistry, Monash University, Clayton, VIC, 3800, Australia.
  • 6 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangzhou Medical University, Guangzhou, 511436, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: wu_donghai@gibh.ac.cn.
  • 7 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangzhou Medical University, Guangzhou, 511436, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: xu_yong@gibh.ac.cn.
  • 8 Drug Discovery Chemistry Team, CSIRO, Clayton, VIC, 3168, Australia. Electronic address: craig.francis@csiro.au.
PMID: 36495632 DOI: 10.1016/j.ejmech.2022.114982
Abstract

A series of 1-benzyloxy-5-phenyltetrazole derivatives and similar compounds were synthesized and evaluated for their in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) prostate Cancer cells. The most active compounds had in vitro IC50 values against 22Rv1 cells of <50 nM and showed apparent selectivity for this cell type over PC3 cells; however, these active compounds had short half-lives when incubated with mouse liver microsomes and/or when plasma concentration was monitored during in vivo pharmacokinetic studies in mice or rats. Importantly, lead compound 1 exhibited promising inhibitory effects on cell proliferation, expression of AR and its splicing variant AR-v7 as well as AR regulated target genes in 22Rv1 cells, which are so called castration-resistant prostate Cancer (CRPC) cells, and a 22Rv1 CRPC xenograft tumour model in mice. Structural changes which omitted the N-O-benzyl moiety led to dramatic or total loss of activity and S-benzylation of a cysteine derivative, as a surrogate for in vivo S-nucleophiles, by representative highly active compounds, suggested a possible chemical reactivity basis for this "activity cliff" and poor pharmacokinetic profile. However, representative highly active compounds did not inhibit a cysteine protease, indicating that the mode of activity is unlikely to be protein modification by S-benzylation. Despite our efforts to elucidate the mode of action, the mechanism remains unclear.

Keywords

Androgen receptor; Mouse xenograft; Pharmacokinetic; Prostate cancer; SAR; Synthesis; Tetrazole.

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