14892-97-8Relevant academic research and scientific papers
Synthesis and structure determination of SCR7, a DNA ligase inhibitor
Greco, George E.,Conrad, Zane A.,Johnston, Alycia M.,Li, Qingyao,Tomkinson, Alan E.
, p. 3204 - 3207 (2016)
In contrast to a published report, reaction of 4,5-diamino-6-hydroxy-2-mercaptopyrimidine with 2?equiv of aromatic aldehydes produces a mixture of 6,7-diaryl-2-thioxopteridine-4-one and 6,7-diaryl-2-thioxo-7,8-dihydropteridine-4-one rather than a diimine. These compounds represent the correct structure for SCR7, a substance reported to be an inhibitor of nonhomologous end-joining, a DNA repair pathway. The dihydropteridine can be isolated as a minor product, and it can be oxidized to the pteridine.
Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner
Vartak, Supriya V.,Swarup, Hassan A.,Gopalakrishnan, Vidya,Gopinatha, Vindya K.,Ropars, Virginie,Nambiar, Mridula,John, Franklin,Kothanahally, Sharath Kumar S.,Kumari, Rupa,Kumari, Nitu,Ray, Ujjayinee,Radha, Gudapureddy,Dinesh, Depina,Pandey, Monica,Ananda, Hanumappa,Karki, Subhas S.,Srivastava, Mrinal,Charbonnier, Jean Baptiste,Choudhary, Bibha,Mantelingu, Kempegowda,Raghavan, Sathees C.
, p. 3959 - 3976 (2018)
Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18H14N4OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18H12N4OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.
NOVEL NUCLEIC ACID MODIFIERS
-
Sheet 7, (2019/07/20)
The present inventions generally relate to site-specific delivery of nucleic acid modifiers and includes novel DNA-binding proteins and effectors that can be rapidly programmed to make site-specific DNA modifications. The present inventions also provide a synthetic all-in-one genome editor (SAGE) systems comprising designer DNA sequence readers and a set of small molecules that induce double-strand breaks, enhance cellular permeability, inhibit NHEJ and activate HDR, as well as methods of using and delivering such systems.
Discovery of HIV-1 integrase inhibitors: Pharmacophore mapping, virtual screening, molecular docking, synthesis, and biological evaluation
Bhatt, Hardik,Patel, Paresh,Pannecouque, Christophe
, p. 154 - 166 (2014/02/14)
HIV-1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV-1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Q fit value were used to design 30 molecules bearing pteridine ring and were docked on co-crystal structure of HIV-1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave-assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti-HIV activity against the replication of HIV-1 (IIIB) in MT-4 cells. The used approach of molecular docking and anti-HIV activity data of designed molecules will provide significant insights to discover novel HIV-1 Integrase Inhibitors. Computer-aided drug design approaches like pharmacophore mapping, virtual screening, and molecular docking were used to design novel compounds bearing pteridine ring system. Designed compounds were synthesized by conventional and microwave-irradiated methods showing advantage of MWI method. All synthesized compounds were evaluated as HTV-1 integrase inhibitors and further explored to discover novel HIV-I integrase inhibitors.
