PMC

Structures of Stat3 inhibitors 1–8.

Low-energy GOLD^[] docking conformation of S3I-201 (8); hydrophobic residues are indicated in light grey, hydrophilic residues are dark grey.

Low-energy GOLD^[] docking conformations of A) compound 9 and B) compound 14; hydrophobic residues are indicated in light grey, hydrophilic residues are dark grey.

a) TFA/toluene (1:1), RT, 4 h, 95 %; b) NH₄Cl, DIPEA, HBTU, DMF, RT, 16 h, 99 %; c) H₂, 10 % Pd/C, MeOH/THF (1:1), RT, 1–16 h, 85–100 %.

a) R³ = Boc: Boc₂O, cat. DMAP, CH₂Cl₂, RT, 1 h, 95 %; R³ = aryl: R³F or R³Cl, DIPEA, DMSO, 120 °C, 16 h, 76–96 %; b) H₂, 10 % Pd/C, MeOH/THF (1:1), RT, 1–16 h, 85–100 %.

a) R⁴B(OH)₂, Pd(PPh₃)₄, K₂CO₃, DMF, 100 °C, 24 h, 16–73 %; b) LiOH·H₂O, THF/H₂O (3:1), RT, 24 h, 76–99 %; c) TFA/toluene (1:2), RT, 16 h, 85 %; d) H₂, 10 % Pd/C, MeOH/THF (1:1), RT, 1–16 h, 85–100 %.

a) (CF₃CO)₂O, DIPEA, CH₂Cl₂, 0 °C →RT, 3 h, 93 %; b) (COCl)₂, AlCl₃, CH₂Cl₂, 0 °C, 1 h; c) H₂, 10 % Pd/C, DIPEA, EtOAc, RT, 2 h, 63 % (two steps).

a) TsN(Boc)CH₂CO₂H (46), PPh₃Cl₂, CHCl₃, 60 °C, 12 h, 48 %; b) AcOCH₂COCl, DIPEA, CH₂Cl₂, RT, 4 h, 64 %; c) (Boc)₂O, cat. DMAP, THF, 12 h, 81 %; d) H₂, 10 % Pd/C, MeOH/THF (1:1), RT, 1–16 h, 85–94 %; e) LiOH·H₂O, THF/MeOH/H₂O (3:1:1); 89 % f) p-TsCl, DIPEA, CH₂Cl₂, RT, 3 h, 85 %.

a) LiOH·H₂O, THF/H₂O (3:1), RT, 10 min, 98 %; b) R³ = Boc: Boc₂O, cat. DMAP, CH₂Cl₂, RT, 1 h, 95 %; R³ = aryl: R³F or R³Cl, DIPEA, DMSO, 120 °C, 16 h, 80–99 %; R³ = p-CNC₆H₄SO₂: p-CNC₆H₄SO₂Cl, DIPEA, RT, 16 h, 99 %; R³ = p-CNC₆H₄CO₂: p-CNC₆H₄CO₂H, HBTU, DIPEA, DMF, RT, 16 h, 89 %; c) H₂, 10 % Pd/C, MeOH/THF (1:1), RT, 1–16 h, 85–100 %.

Western blot analysis showing A) inhibition of Stat3 phosphorylation (pYStat3) and B) repression of Stat3-regulated gene products, Bcl-xL and Survivin, in human breast (MDA-MB-468) and multiple myeloma (JJN-3) cells as a function of treatment with 27 h (100 µm, 24 h). Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as a lane loading control.

a) 1. BnBr, KOtBu, DMF, 0 °C →RT, 5 h; 2. BnBr, KOtBu, DMF, 0 °C →RT, 16 h, 54 %; b) 1. RCHO, AcOH, 4 Å MS, MeOH, 45 °C, 3 h; 2. NaCNBH₃, RT, 12 h,75–96 %; c) p-TsCl, DIPEA, CH₃CN, 0 °C →RT, 1 h, 93 %; d) MeI, Cs₂CO₃, DMF, RT, 16 h, 85 %; e) LiOH·H₂O, THF/MeOH/H₂O (3:1:1), RT, 1 h, 95 %; f) PPh₃Cl₂, CHCl₃, 60 °C, 12 h, 89–95 %; g) H₂, 10 % Pd/C, MeOH/THF (1:1), RT, 1–16 h, 85–100 %; or for 26 a and 26 b: h) LiOH·H₂O, THF/H₂O (3:1), RT, 24 h, 76–86 %; i) TFA/toluene (1:2), RT, 16 h, 85–93 %