Discovery of new tranylcypromine derivatives as highly potent LSD1 inhibitors

Design, Synthesis, and Evaluation of the Selective and Orally Active LSD1 Inhibitor with the Potential of Treating Heart Failure

“…Therefore, we first prepared compounds with monosubstitution at all three positions of the phenyl group on the triazole ring to examine the impact of substitution positions at the phenyl ring on biological activity against LSD1. As shown in Table , compounds bearing a 4-substituted phenyl group consistently exhibited higher activity compared to other isomers ( 5c vs 5a or 5b , 5f vs 5d or 5e , 5i vs 5g or 5h ), aligning with our previous findings . Indeed, introducing a substituent at the 4-position of the aromatic ring had less steric hindrance and promoted compound stability in the binding site through short-range interactions with accessible residues (Figures S3–S5).…”

“…Compounds 4a – 4g were synthesized according to the procedures shown in Scheme , utilizing commercially available benzyl bromide, 2-phenethyl bromide, cyclohexyl bromide, 1-methylpiperidin-4-amine, pyrimidin-5-ylboronic acid, 3-aminopyridine, and 1-methyl-1 H -pyrazol-3-amine as starting materials. tert -Butyloxycarbonyl-protected propargylamine 16 was prepared following our previously reported procedures . Alkyl azides 15a – 15c were obtained through a substitution reaction of alkyl bromide 14a – 14c with sodium azide.…”

“…In a previous report, we demonstrated that replacing the 1,3,4-oxadiazole ring in ORY-2001 with its bioisostere, the triazole ring, allowed the identification of a series of TCP-based derivatives . These derivatives exhibited potent activity against LSD1 and its homologous protein, MAO A, with high selectivity toward MAO B .…”

“…In a previous report, we demonstrated that replacing the 1,3,4oxadiazole ring in ORY-2001 with its bioisostere, the triazole ring, allowed the identification of a series of TCP-based derivatives. 25 These derivatives exhibited potent activity against LSD1 and its homologous protein, MAO A, with high selectivity toward MAO B. 26 Among these, compound 2, featuring a 2-(3,4-difluorophenyl)cyclopropylamine linked to a 1-phenyl-1H-1,2,3-triazole group, exhibited higher inhibitory activity against LSD1 and greater potential for modification compared to most of the previously reported compounds, making it a suitable lead compound (Figure 2).…”

A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62

“…Intermediates 4a – q were prepared according to the procedure reported by literatures. ,− Briefly, aniline or substituted aniline (1 mmol) was dissolved in 6 M hydrochloride solution (1 mL) and stirred for 30 min in an ice bath. A solution of sodium nitrite (0.10 g, 1.5 mmol) in water (3.5 mL) was added dropwise and then stirred for 10 min in an ice bath.…”