New Diarylamine KV10.1 Inhibitors and Their Anticancer Potential

Figures

• 

  Figure 1. Structures of known ligands binding to the voltage-sensor domain of KV10.1.

• 

  Figure 2. Design of the hit compound ZVS-08 (1) analogues (Strategies I–V).

• 

  Scheme 1. Reagents, solvents, and conditions: (a) hydroquinone, K2CO3, CuO, pyridine, 110 °C, 72 h; (b) (±)-epichlorohydrin, MeCN, K2CO3, 80 °C, 16 h; (c) morpholine, acetonitrile, r.t., 72 h; (d) Me2NH × (e) HCl, K2CO3, MeCN, 70 °C, 24 h.

• 

  Scheme 2. Reagents, solvents, and conditions: (a) Oxalyl chloride, 2 drops of DMF, dichloromethane, 40 °C, 24 h; (b) 4-aminophenol, triethylamine (TEA), MeCN, reflux, 24 h; (c) (±)-epichlorohydrin, MeCN, K2CO3, 80 °C, 16 h; (d) morpholine, MeCN, r.t., 72 h; Me2NH × HCl, MeCN, K2CO3, 70 °C, 24 h.

• 

  Scheme 3. Reagents, solvents, and conditions: (a) 4-aminophenol, K2CO3, CuO, Cu, 2-ethoxyethanol, 130 °C, 16 h; (b) thionyl chloride, anhydrous MeOH, 70 °C, overnight; (c) (±)-epichlorohydrin, MeCN, K2CO3, 80 °C, 16 h; (d) Me2NH × HCl, acetonitrile, K2CO3, 70 °C, 24 h; (e) morpholine, dichloromethane, r.t., 72 h; (f) NaOH, EtOH, water, r.t., 72 h.

• 

  Scheme 4. Reagents, solvents, and conditions: (a) H2SO4, HNO3, 80 °C, 1 week; (b) 4-aminophenol, NaHCO3, MeCN, 90 °C, 24 h; (c) 4-aminophenol, NaHCO3, MeCN, 90 °C, 24 h; (d) 4-(2-chloroethyl)morpholine, KOH, EtOH, 100 °C, overnight; (e) (±)-epichlorohydrin, MeCN, K2CO3, 80 °C, 16 h; (f) 4-benzyloxy aniline, NaHCO3, toluene, 100 °C, 24 h; (g) Me2NH × HCl, MeCN, 70 °C, 24 h; (h) MeNH2, K2CO3, MeCN, 70 °C, 24 h; (i) morpholine, dichloromethane, r.t., 72 h; (j) appropriate amine, K2CO3, MeCN, 70 °C, 24 h.

• 

  Scheme 5. Reagents, solvents, and conditions: (a) 4-aminophenol or 4-amino-2,6-dibromophenol or 4-amino-2,6-dichlorophenol, NaHCO3, MeCN, 90 °C, 24 h; (b) 2-chloro-N,N-diethylethan-1-amine × HCl, KOH or K2CO3, EtOH or MeCN, 100 °C or 90 °C, overnight; (c) 1-(2-chloroethyl)pyrrolidine × HCl, K2CO3, MeCN, 90 °C, 24 h; (d) 1-(2-chloroethyl)piperidine × HCl, K2CO3, MeCN, 90 °C, 24 h; (e) 1-(2-chloroethyl)azepane hydrochloride × HCl, K2CO3, MeCN, 90 °C, 24 h; (f) 2-chloro-N,N-dimethylethan-1-amine × HCl, MeCN, KOH or K2CO3, 100 °C or 90 °C, 16 h.

• 

  Figure 3. (A) Dose–response curves of compound 17a for KV10.1 (blue) and hERG (red) inhibition. The IC50 values from the fit were 568 nM (95% CI 427 to 783 nM N = 4–7) for KV10.1 and 232 nM (CI: 186 to 296 nM N= 5–6) for hERG. (B) Dose–response curves of compound 18a for KV10.1 (blue) and hERG (red) inhibition. The IC50 values from the fit were 892 nM (95% CI 640 nM to 1.40 µM, N = 5–6) for KV10.1 and 177 nM (CI: 163 to 191 nM, N = 2–3) for hERG. (C) Dose–response curves of compound 18b for KV10.1 (blue) and hERG (red) inhibition. The IC50 values from the fit were 237 nM (95% CI 177 to 331 nM, N = 2–6) for KV10.1 and 4.9 nM (CI: 2.34 to 9.44 nM, N = 2–6) for hERG.

• 

  Figure 4. Effects of compounds 17a and 18b on the growth of Panc-1 and MCF-7 cells. (A) Compound 17a inhibited the growth of Panc-1 (red) and MCF-7 cells (blue) by approximately 50% at concentrations higher than 25 µM. The inhibition of growth was stronger on Panc-1 cells. (B) Compound 18b showed a similar behaviour on both cell lines. Compound 18b inhibited the growth of Panc-1 cells more potently than MCF-7.