Introduction of Mercaptoethyl at Sorafenib Pyridine-2-Amide Motif as a Potentially Effective Chain to Further get Sorafenib-PEG-DGL

Abstract

The crystal structure of the sorafenib and B-RAF complex indicates that the binding cavity occupied by the pyridine-2-carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti-cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine-2-amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC₅₀ 58.79 and 63.67 M, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib-PEG-DGL, which could be developed as a delivery vehicle to improve the concentration of anti-tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.

Keywords: antiproliferation; molecular modeling; nanoparticles (NPs); sorafenib analogs.

Figure 1

The structure of sorafenib (top) and the binding mode (bottom, left) and binding cavity (bottom, right) of sorafenib and B-RAF kinase.

Figure 2

Design of sorafenib derivatives and nanoparticles (NPs).

Scheme 1

Synthetic routes of 2a–b, 4 and the key intermediate 7. Reagents and conditions: (a) TBSCl, imidazole, dichloromethane (DCM), rt, 1 h, 98%; (b) triphenylmethanol, trifluoroacetic acid (TFA), rt, 2 h, 90%; (c) 4-amino phenol, (CH₃)₃COK, K₂CO₃, 80 °C, 3 h, 90% and (d) KOH (2.5 mol/L), reflux, 2 h, 90%.

Scheme 2

Synthetic routes of target compounds 10a–c and 15a–b. Reagents and conditions: (e) 2a–b or 4, HOBt, EDC^.HCl, DIEA, DCM, rt, 10 h, 86–88%; (f) 4-chloro-3-trifluoromethylphenyl isocyanate, DCM, rt, 2 h, 85–93%; (g) I: TBAF, THF, rt, 1 h, 95%; II: TIS, TFA, DCM, rt, 84%. (h) MeOH, SOCl₂, reflux, 8 h, 86%; (i) NH₂NH₂^.H₂O, EtOH, rt, 15 h, 95%; (j) Hydroxyacetone or 4-hydroxy-2-butanone, HAc, EtOH, reflux, 8 h, 75% and (k) NaBH₃CN, HAc, MeOH, rt, 8 h, 87%.

Figure 3

Predicted binding mode of sorafenib and compound 10b (affinity: −11.2 kcal/mol) in B-RAF kinase. Sorafenib is in green and compound 10b in red.