166047-40-1

Upstream product

• 1004-38-2 2,4,6-triaminopyrimidine 
• 53106-70-0 2-chloro-2-formylacetonitrile 

Downstream Products

• 166047-51-4 (S)-2-{4-[(2,4-Diamino-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoylamino}-pentanedioic acid diethyl ester 
• 188910-74-9 (S)-2-{4-[(2,4-Diamino-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-methyl-amino]-benzoylamino}-pentanedioic acid diethyl ester 

Relevant academic research and scientific papers

Rational Re-engineering of a Transcriptional Silencing PreQ1 Riboswitch

Re-engineered riboswitches that no longer respond to cellular metabolites, but that instead can be controlled by synthetic molecules, are potentially useful gene regulatory tools for use in synthetic biology and biotechnology fields. Previously, extensive genetic selection and screening approaches were employed to re-engineer a natural adenine riboswitch to create orthogonal ON-switches, enabling translational control of target gene expression in response to synthetic ligands. Here, we describe how a rational targeted approach was used to re-engineer the PreQ1 riboswitch from Bacillus subtilis into an orthogonal OFF-switch. In this case, the evaluation of just six synthetic compounds with seven riboswitch mutants led to the identification of an orthogonal riboswitch-ligand pairing that effectively repressed the transcription of selected genes in B. subtilis. The streamlining of the re-engineering approach, and its extension to a second class of riboswitches, provides a methodological platform for the creation of new orthogonal regulatory components for biotechnological applications including gene functional analysis and antimicrobial target validation and screening. (Graph Presented).

Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

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.

Nitrile reductase from Geobacillus kaustophilus: A potential catalyst for a new nitrile biotransformation reaction

The cloning, expression and characterization of a nitrile reductase (NRed) from the thermophile Geobacillus kaustophilus is reported. The enzyme shows a 12-fold increase in activity in response to a temperature change from 25 °C to 65 °C. The substrate scope regarding its biocatalytic applicability was investigated by testing a range of common nitriles. The narrow substrate range observed for the wild-type enzyme prompted the rational design of GkNRed active site mutants based on a previously published homology model from Bacillus subtilis. The activities of the mutants and the wild-type enzyme were investigated in their structure-function relationship regarding the natural substrate 7-cyano-7-deazaguanine (preQ0) as well as a range of synthesized preQ0-like substrate structures. A distinct dependence of the wild-type enzyme activity on specific structural modifications of the natural substrate was observed. Two non-natural nitriles derived from preQ 0 could be reduced to their corresponding amino compounds. Copyright

Pyrrolo?2,3d!derivatives

Pyrrolo?2,3-d!pyrimidine derivatives, and pharmaceutical acceptable salts thereof, useful in therapeutically and/or prophylactically treating patients with an illness are disclosed.

Pyrimidine derivatives and methods of making and using these derivatives

This invention discloses compounds, and pharmaceutically acceptable salts thereof, useful in therapeutically and/or prophylactically treating patients with an illness. Such illnesses include cancer, and secondary infections caused by Pneumocystis carinii and Toxoplasmosis gondii in immunocompromised patients. The compounds themselves, methods of making these compounds, and methods of using these compounds are all disclosed.