- Nucleotides and nucleosides and methods for their use in DNA sequencing
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The present invention relates generally to labeled and unlabled cleavable terminating groups and methods for DNA sequencing and other types of DNA analysis. More particularly, the invention relates in part to nucleotides and nucleosides with chemically cleavable, photocleavable, enzymatically cleavable, or non-photocleavable groups and methods for their use in DNA sequencing and its application in biomedical research.
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- Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1
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The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.
- Khalaf, Abedawn I.,Huggan, Judith K.,Suckling, Colin J.,Gibson, Colin L.,Stewart, Kirsten,Giordani, Federica,Barrett, Michael P.,Wong, Pui Ee,Barrack, Keri L.,Hunter, William N.
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p. 6479 - 6494
(2014/10/16)
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- EC144 is a potent inhibitor of the heat shock protein 90
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Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl) methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC50 = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC 50 = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd× 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.
- Shi, Jiandong,Van De Water, Ryan,Hong, Kevin,Lamer, Ryan B.,Weichert, Kenneth W.,Sandoval, Cristina M.,Kasibhatla, Srinivas R.,Boehm, Marcus F.,Chao, Jianhua,Lundgren, Karen,Timple, Noelito,Lough, Rachel,Ibanez, Gerardo,Boykin, Christina,Burrows, Francis J.,Kehry, Marilyn R.,Yun, Theodore J.,Harning, Erin K.,Ambrose, Christine,Thompson, Jeffrey,Bixler, Sarah A.,Dunah, Anthone,Snodgrass-Belt, Pamela,Arndt, Joseph,Enyedy, Istvan J.,Li, Ping,Hong, Victor S.,McKenzie, Andres,Biamonte, Marco A.
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p. 7786 - 7795
(2012/11/07)
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- 7-Functionalized 7-deazapurine ribonucleosides related to 2-aminoadenosine, guanosine, and xanthosine: Glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose
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The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-deazapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of the 7-halogenated 6-chloro-2-pival
- Seela, Frank,Peng, Xiaohua
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