67194-86-9Relevant articles and documents
Rational Re-engineering of a Transcriptional Silencing PreQ1 Riboswitch
Wu, Ming-Cheng,Lowe, Phillip T.,Robinson, Christopher J.,Vincent, Helen A.,Dixon, Neil,Leigh, James,Micklefield, Jason
supporting information, p. 9015 - 9021 (2015/08/03)
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).
Novel 5-substituted, 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity
Gangjee, Aleem,Zeng, Yibin,Ihnat, Michael,Warnke, Linda A.,Green, Dixy W.,Kisliuk, Roy L.,Lin, Fu-Tyan
, p. 5475 - 5491 (2007/10/03)
Recent evidence suggests that combination therapy of cancer with receptor tyrosine kinase (RTK) inhibitors, which are usually cytostatic, with conventional chemotherapeutic agents, which are usually cytotoxic, provide an improved treatment option. We have
The synthesis of new 2,4-diaminofuro[2,3-d]pyrimidines with 5-biphenyl, phenoxyphenyl and tricyclic substitutions as dihydrofolate reductase inhibitors
Gangjee,Dubash,Queener
, p. 935 - 942 (2007/10/03)
Nonclassical 2,4-diamino-5-substituted furo[2,3-d]pyrimidines 4a-i, 5a-b and 7a-f were synthesized as extended aromatic ring appended analogs of previously reported antifolates 1a-b. The extended aromatic system was designed to better interact with a phenylalanine residue (Phe69) of dihydrofolate reductase from the opportunistic pathogen Pneumocystis carinii to afford potent and selective inhibitors of Pneumocystis carinii dihydrofolate reductase. The target compounds were synthesized by nucleophilic displacement of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine 3 with the appropriate aromatic amine or thiol. The compounds were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii, and their selectivity was determined using rat liver dihydrofolate reductase as the mammalian reference. In the C8-N9 bridged series, compound 4e, with a 3-(2-methoxydibenzofuran)- side chain, exhibited greatest potency and was more than 3 times as selective for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase. Compounds 4b and 4c also exhibited selectivity. Compounds in the C8-S9 bridged series showed comparable potencies, and each showed higher selectivity for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase.
