Budke, Brian; Tueckmantel, Werner; Miles, Kelsey; Kozikowski, Alan P.; Connell, Philip P. published an article in 2019, the title of the article was Optimization of drug candidates that inhibit the D-loop activity of RAD51.Safety of tert-Butyl trichloroacetimidate And the article contains the following content:
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. Addnl., 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-mol. inhibitor of RAD51 named RI(dl)-2 (RAD51 inhibitor of D-loop formation #2, hereafter called 2h(I)), which inhibits D-loop activity while sparing ssDNA binding. However, I 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 I. 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 dsDNA intercalation activity. We developed a sensitive assay to measure dsDNA intercalation, and identified two analogs of I that promote complete HR inhibition in cells while exerting minimal intercalation activity. The experimental process involved the reaction of tert-Butyl trichloroacetimidate(cas: 98946-18-0).Safety of tert-Butyl trichloroacetimidate
The Article related to rad51 d loop homologous recombination quinoxaline, dna repair, biological activity, cancer, inhibitors, structure-activity relationships, Pharmacology: Structure-Activity and other aspects.Safety of tert-Butyl trichloroacetimidate
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