Optimization of Drug Candidates that Inhibit the D-loop Activity of RAD51.
Optimization of Drug Candidates that Inhibit the D-loop Activity of RAD51.
ChemMedChem. 2019 Apr 07;:
Authors: Budke B, Tueckmantel W, Miles K, Kozikowski AP, Connell PP
Abstract
RAD51 is the central protein in homologous recombination repair (HR), 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 2h), which inhibits D-loop activity while sparing ssDNA binding. However, 2h 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 analogs of 2h. 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 analogs exhibited enhanced activity against human RAD51, but in several of these compounds the increased inhibition was due to the introduction of dsD...
Source: ChemMedChem - Category: Chemistry Authors: Budke B, Tueckmantel W, Miles K, Kozikowski AP, Connell PP Tags: ChemMedChem Source Type: research
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