Fig 1.
(A) Mechanism of catalysis for LSD1; (B) Structures of representative LSD1 inhibitors; (C) Mechanism of cyclopropylamine containing LSD1 inhibitors.
Fig 2.
Reagents and conditions: (i) triethyl phosphonoacetate/t-BuOK, THF; (ii) Me3S(O)I, t-BuOK, DMSO; (iii) K2CO3, MeOH, reflux; (iv) diphenylphosphoryl azide, Et3N, t-BuOH, toluene, reflux; (v) NaH, 1-chloroacetyl-4-methylpiperazine, DMF; (vi) HCl/MeOH; (vii) aldehyde, NaBH3(CN), AcOH; (viii) Ac2O for compound 22 or PhNCO for 23; (ix) Aryl-CHO; (x) CHBr3, KOH; (xi) MeMgBr, Ti(O-i-Pr)4; (xii) Mg, then Boc-N = N-Boc; (xiii) NaH, then 1-chloroacetyl-4-(Boc)piperazine for 32 or 1-chloroformyl-4-(Boc)piperazine for 33; (xiv) (Boc)2O, Et3N; (xv) PhBr, CuI, Pd(dppf)Cl2, (i-Pr)2NEt.
Table 1.
Structures and LSD1 inhibitory activities of compounds 1–35.
Table 2.
Inhibitory activity (IC50, μM) against MAO-A and -B and selectivity index for LSD1.
Fig 3.
Docking results of compound 10 (as tube models with C atoms in green).
(A) Five docking structure of 10 with the lowest energies in the active site of LSD1 (shown as a semi-transparent electrostatic surface); (B) The lowest-energy docking structure in the active site of LSD1, showing selected interacting amino acid residues (with C atoms in purple) and FAD (with C atoms in brown); (C) Five docking structure of 10 with the lowest energies in the active site of MAO-A (shown as a semi-transparent electrostatic surface); (D) The lowest-energy docking structure in the active site of MAO-A, showing selected interacting amino acid residues (with C atoms in purple) and FAD (with C atoms in brown).