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.2017 Apr 13;60(7):3082-3093.
doi: 10.1021/acs.jmedchem.7b00105. Epub 2017 Mar 20.

1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment

Affiliations

1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment

Claudia Ferroni et al. J Med Chem..

Abstract

Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Androgen receptor targeting therapeutics for the treatment of PC.
Figure 2.
Figure 2.
Classes of synthesized triazole derivatives.
Figure 3.
Figure 3.
Evaluation of PSA mRNA levels after exposure of LNCaP cell lines to triazoles. Twenty-four hours after seeding, cells were treated for 24 h with 10μM compounds. Cells were then collected, processed for mRNA extraction, and analyzed using RT-qPCR. Blue bars: no-spacer triazoles (type I). Green bars: one-spacer triazoles (type II). Red bars: two-spacer triazoles (type III).
Figure 4.
Figure 4.
Influence of 1,4-triazole ring substituents on the PSA level reduction.
Figure 5.
Figure 5.
Cytotoxic activity of novel triazole derivatives against human PC LNCaP (A) and LNCaP-AR (B) cells. Twenty-four hours after seeding, cells were exposed to the compounds for 144 h to the compounds and cytotoxicity was measured using a sulforhodamine B (SRB) assay. (R)-Bicalutamide and enzalutamide were used as references. The mean of three independent experiments is reported.
Figure 6.
Figure 6.
Cytotoxic activity of14d against human CW22Rv1 cells. Twenty-four hours after seeding, cells were exposed for 144 h to the compounds. The cytotoxic potency was measured using a sulforhodamine B (SRB) assay. (R)-Bicalutamide and enzalutamide were used as references. The mean of three independent experiments is reported.
Figure 7.
Figure 7.
Antitumor activity of oral14d and enzalutamide against human prostate CW22Rv1 carcinoma tumor xenograft. CW22Rv1 cells (5 × 106/mouse) were injected into the right flank of the mice on day 0. Treatment started when tumors were not palpable (day 1). Drugs and vehicle (for control group) were administrated orally at the dose of 50 mg/kg according the qdx5/wx3w schedule. Tumor size was measured by caliper, and tumor volume was calculated using TV =a ×b2/2, wherea andb are the long and short diameters of the tumor, respectively. Points indicate mean from five mice per group, and bars indicate SD.
Figure 8.
Figure 8.
Putative binding mode of AR modulators: predicted binding mode of (R)-bicalutamide (A), enzalutamide (B), and compound14d (C). Hydrogen bonds are represented as red dotted lines. Binding pose of (R)-bicalutamide was obtained through rigid docking starting from AR crystallographic structures (PDB code 2AXA), whereas poses of enzalutamide and14d were obtained from IFD simulations.
Scheme 1.
Scheme 1.. Synthesis of No-Spacer Triazoles 3a–ca
aReagents: (a) Ph3P, CBr4, DCM, from 0 °C to rt, 15 min, 72–99%; (b)n-BuLi, DIPA, THF, 0 °C, 1 h; –78 °C, 3 h; from −78 °C to rt, 12 h, 9–51%; (c)t-BuONO, TMSN3, CH3CN, from 0 °C to rt, 2 h; CuSO4, Na L-ascorbate, rt, 12 h, 24–32%.
Scheme 2.
Scheme 2.. Synthesis of One-Spacer Triazoles 5a–ma
aReagents: (a) K2CO3, propargyl bromide, acetone, reflux, 24 h, 79–100%; (b)t-BuONO, TMSN3, CH3CN, from 0 °C to rt, 2 h; CuSO4, Na L-ascorbate, rt, 12 h, 16–87%; (c) CuI, phenanthroline, KOH, DMSO/H2O, 100 °C, 24 h, 43%.
Scheme 3.
Scheme 3.. Synthesis of One-Spacer Triazoles 8a–da
aReagents: (a)t-BuONO, TMSN3, CH3CN, from 0 °C to rt, 2 h; CuSO4, Na L-ascorbate, rt, 12 h, 69–89%; (b) Ph3P, DIAD, THF, 0 °C, 30 min; rt, 12 h, 24–77%.
Scheme 4.
Scheme 4.. Introduction of 5-Substituent on 1,4-Substitued 1,2,3-Triazolesa
aReagents: (a)n-BuLi, acetaldehyde, THF, −78 °C to rt, 1 h, 44%; (b)t-BuONO, TMSN3, CH3CN, from 0 °C to rt, 2 h; CuI, DIPEA, NBS, THF, rt, 12 h, 35%.
Scheme 5.
Scheme 5.. Synthesis of Two-Spacer Triazoles 14a–da
aReagents: (a) DCM, 0 °C, 2 h, 100%; (b) CuSO4, NaHCO3, MeOH, rt, 30 min; TBTA, Na L-ascorbate, 80 °C, 10 min, microwave, 76–92%; (c) LiOH, THF/MeOH, rt, 12 h, 88–100%; (d) PCl3, CH3CN, 100 °C, 5 min, microwave, 56–72%.
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