Synthesis and Evaluation of Tricyclic Derivatives Containing a Non-Aromatic Amide as Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors

Abstract

A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors were successfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5H)-one 23c displayed potent activity in a PARP-1 enzymatic assay and cell-based assay (IC 50 = 0.142 µM, ED 50 = 0.90 µM) with good water solubility. Further, molecular modeling studies confirmed the obtained biological results.

Synthesis and evaluation of thiopyrano[3,4-c]quinoline-9-carboxamide derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

“…4-(3,6-dihydro-2H-thiopyran-4-yl)morpholine 3 was obtained by refluxing 4-oxothiane 1 with morpholine 2 in the presence of catalytic p-TsOHÁH 2 O and subsequently treated without further purification. The ketamide 5, prepared by reaction of the enamine 3 with ethyl 4-isocyanobenzoate 4, was cyclized in 70% sulfuric acid to the thiopyranoquinoline-9-carboxylate 6 (Khuthier et al, 1987;Park et al, 2010;Stork et al, 1963). Hydrolysis of the carboxylate 6 with 1 N NaOH solution gave its corresponding carboxylic acid 7, which was optimized by conversion of acid group to amide.…”

“…We have recently reported tricyclic PARP-1 inhibitors, 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinoline-5(6H)-one derivatives (Park et al, 2010). These derivatives include a non-aromatic A-ring and fit well to the active site even though their conformations are not flat.…”

Recent Advances in One-Pot Modular Synthesis of 2-Quinolones

“…Brexipiprazole is a successor of the top-selling generic antipsychotic agent, Aripiprazole. Targets on this scaffold, β-adrenergic receptors [ 2 , 3 , 4 , 5 ], muscarinic acetylcholine receptors [ 6 , 7 , 8 ], vascular endothelial growth factor receptors [ 9 , 10 ], poly [ADP-ribose] polymerase-1 [ 11 , 12 , 13 , 14 , 15 ], tyrosine-protein kinases [ 16 ], and serine/threonine-protein kinases [ 17 , 18 , 19 ], have been extensively studied for decades. In addition to such target investigations, new lead compounds disclosed in recent reports [ 20 , 21 , 22 , 23 , 24 ] imply further potential pharmaceutical utility of the skeleton ( Figure 1 B).…”

“…Brexipiprazole is a successor of the top-selling generic antipsychotic agent, Aripiprazole. Targets on this scaffold, β-adrenergic receptors [2][3][4][5], muscarinic acetylcholine receptors [6][7][8], vascular endothelial growth factor receptors [9,10], poly [ADP-ribose] polymerase-1 [11][12][13][14][15], tyrosine-protein kinases [16], and serine/threonine-protein kinases [17][18][19], have been extensively studied for decades. In addition In addition, 2-quinolones are embedded as core structures in natural products [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43].…”