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SCR7 pyrazine has been used as a non-homologous end joining (NHEJ) modulator to study its effect on CRISPR/Cas9-mediated editing.

SCR7 pyrazine is an inhibitor of DNA ligase IV.

scr7 pyrazine is an inhibitor of dna ligase iv [1].dna ligase iv is involved in sealing of double-strand breaks (dsbs) during nonhomologous end-joining (nhej). dsbs have been considered as one of the most lethal types of dna damage within cells. unrepaired dsbs may lead to chromosomal rearrangements such as translocations and deletions, resulting in oncogenic transformations or cell death. in higher eukaryotes, nhej is one of the primary mechanisms of dsb repair and is active throughout the cell cycle. nhej plays a major role in providing resistance to cancer cells to these radio- and chemotherapy agents [1].scr7 blocked ligase iv-mediated joining by interfering with its dna binding in cell-free repair system. scr7 inhibited nhej in a ligase iv-dependent manner within cells, and activated the intrinsic apoptotic pathway. scr7 dose-dependent decreased cell proliferation in mcf7, a549, and hela cells with an ic50 of 40, 34, and 44 μm, respectively. in t47d, a2780, and ht1080 cells, the ic50 values were 8.5, 120, and 10 μm, respectively [1].scr7 treatment (10 mg/kg, six doses) significantly reduced breast adenocarcinoma-induced tumor and impeded tumor progression in mouse models in mouse models. coadministered of scr7 with dsb-inducing therapeutic modalities significantly enhanced their sensitivity.

SCR7 pyrazine is reported to be an inhibitor of non-homologous end joining (NHEJ) and has been shown to enhance the efficiency of CRISPR-Cas9 genome editing. The effect of SCR7 pyrazine on the efficiency and targeting precision of CRISPR applications has been shown to be cell type specific and context dependent. SCR7 pyrazine is a product of spontaneous cyclization of SCR7, first reported by Srivastava, M., et al.

Method A: Benzaldehyde (466 mg, 4.4 mmol) was dissolved in DMF (1.5 mL) and acetic acid (0.5 mL) and the resulting solution was slowly added to solid 4,5-diamino-6-hydroxy-2-mercaptopyrimidine (316 mg, 2.0 mmol). The reaction mixture was heated under reflux conditions for 3 h and subsequently cooled to room temperature and 10 mL of ice water was slowly added. The precipitated yellow solid was collected by vacuum filtration and dried naturally. The dried solid was dissolved in 60 mL of chloroform and the chloroform solution was filtered to remove insoluble matter. The entire chloroform solution was upsampled onto a silica gel column pre-filled with dichloromethane, and the first yellow band was collected by column chromatography using dichloromethane:ethyl acetate (2:1, v/v) as eluent. The eluate was concentrated under reduced pressure to afford the target product 257 mg (0.77 mmol, 39% yield). The product was characterized as follows: 1H NMR (DMSO-d6) δ 13.42 (br.s, 1H), 12.82 (br.s, 1H), 7.43-7.34 (m, 10H); 13C NMR (DMSO-d6) δ 175.7, 158.5, 155.9, 149.1, 147.0, 137.7, 137.1, 129.8 (CH), 139.8 (CH), 137.1 (CH), 137.7, 137.1 (CH). 129.8 (CH), 129.7 (CH), 129.5 (CH), 128.8 (CH), 128.3 (CH), 128.2 (CH), 127.2; HRMS (ESI) m/z calcd for C18H13N4OS [M+H]+ 333.0810, found 333.0802; IR ( Nujol) νmax 3407 (br), 1698, 1633, 1552, 1126, 722, 695, 665 cm-1; mp 200-203 °C (dec.); UV/Vis λmax 380 nm (ε = 12,000 M-1 cm-1).

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[1] srivastava m, nambiar m, sharma s, et al. an inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression[j]. cell, 2012, 151(7): 1474-1487.