452070-80-3Relevant academic research and scientific papers
Optimization of Drug Candidates That Inhibit the D-Loop Activity of RAD51
Budke, Brian,Tueckmantel, Werner,Miles, Kelsey,Kozikowski, Alan P.,Connell, Philip P.
, p. 1031 - 1040 (2019/04/30)
RAD51 is the central protein in homologous recombination (HR) repair, where it first binds ssDNA and then catalyzes strand invasion via a D-loop intermediate. Additionally, RAD51 plays a role in faithful DNA replication by protecting stalled replication forks; this requires RAD51 to bind DNA but may not require the strand invasion activity of RAD51. We previously described a small-molecule inhibitor of RAD51 named RI(dl)-2 (RAD51 inhibitor of D-loop formation #2, hereafter called 2 h), which inhibits D-loop activity while sparing ssDNA binding. However, 2 h is limited in its ability to inhibit HR in vivo, preventing only about 50 % of total HR events in cells. We sought to improve upon this by performing a structure–activity relationship (SAR) campaign for more potent analogues of 2 h. Most compounds were prepared from 1-(2-aminophenyl)pyrroles by forming the quinoxaline moiety either by condensation with aldehydes, then dehydrogenation of the resulting 4,5-dihydro intermediates, or by condensation with N,N′-carbonyldiimidazole, chlorination, and installation of the 4-substituent through Suzuki–Miyaura coupling. Many analogues exhibited enhanced activity against human RAD51, but in several of these compounds the increased inhibition was due to the introduction of dsDNA intercalation activity. We developed a sensitive assay to measure dsDNA intercalation, and identified two analogues of 2 h that promote complete HR inhibition in cells while exerting minimal intercalation activity.
Synthesis of polysubstituted phenanthridines via ligand-free copper-catalyzed annulation
Chen, Yan-Fu,Hsieh, Jen-Chieh
, p. 4642 - 4645 (2015/01/08)
A novel procedure for the cascade reaction of the addition of a Grignard reagent to a nitrile with a copper-catalyzed C-N bond coupling was developed, which afforded various polysubstituted phenanthridines in moderate to good yields with tolerance for a wide variety of substrates. Experimental data demonstrated that the reaction proceeded more likely through a Cu(I/III) catalytic cycle.
A one-pot access to 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes
Pawlas, Jan,Begtrup, Mikael
, p. 2687 - 2690 (2007/10/03)
A one-pot f-BuLi-induced synthesis of 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes is reported. Aryl-and hetaryl nitriles, cyanamides, and trimethylacetonitrile gave phenanthridine products. The method was extended to provide bisphenanthridine 10 by a one-pot bis-cyclization, using 1,3-dicyanobenzene and PhF in 1:5 ratio. Reaction of 1-fluoronaphthalene and 4-chlorofluorobenzene with benzonitrile afforded the regioisomerically pure products 11 and 12, respectively.
