Novel Orthogonal Synthesis of a Tagged Combinatorial Triazine Library via Grignard Reaction
TL;DR: In this article, a novel orthogonal synthesis via Grignard monoalkylation or monoarylation of cyanuric chloride in solution was employed to prepare aryl- or alkyl-substituted triazine building blocks.
Abstract: To expand the diversity of 1,3,5-triazine libraries to aryl and alkyl functionalities through the C–C bond, we employed a novel orthogonal synthesis via Grignard monoalkylation or monoarylation of cyanuric chloride in solution to prepare aryl- or alkyl-substituted triazine building blocks. These aryl- or alkyl-substituted triazine building blocks were captured by a resin-bound amine, followed by amination and acidic cleavage with high purity. Herein, we demonstrate a novel orthogonal synthesis of a tagged aryl- and alkyl-triazine library on solid support, utilizing building blocks prepared via Grignard reaction in solution. Through incorporation of a triethylene glycol linker at one of the alternate sites on the triazine scaffold we explored an intrinsic tagged library approach.
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TL;DR: This is the thirteenth installment of the comprehensive survey series in high throughput chemistry, where 370 libraries and 24 molecular probes extracted from 355 literature citations are presented.
Abstract: This is the thirteenth installment of the comprehensive survey series in high throughput chemistry.1 Biologically active libraries reported in 2009 are captured in Tables 1–5 under the headings of proteases, nonproteolytic enzymes, GPCRs, nonGPCRs, and oncolytics/antiinfectives. Table 6 lists molecular probes. Compound collections without disclosed biological activity are delineated in Tables 7–10 under the headings of scaffold derivatization/acyclic synthesis, monocyclic-, bicyclic/spirocyclic-, and polycyclic/macrocyclic synthesis. Polymer-supported reagents/scavengers/linkers are presented in Tables 11 (nonfluorous) and Table 12 (fluorous). There are 370 libraries and 24 molecular probes extracted from 355 literature citations.2–491 Approximately 90% of the citations originated from academic laboratories, with the majority of these from European and Asian laboratories. Solution-phase methodology accounted for ca. 85% of chemical library synthesis.
76 citations
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TL;DR: A novel triazine library is screened, based on the ability of compounds to increase neurite outgrowth from cerebellar neurons on inhibitory myelin substrates, to provide insight into the mechanisms through which glial-derived inhibitors of regeneration act, and could lead to the development of novel therapies for CNS injury.
Abstract: A major barrier to regeneration of CNS axons is the presence of growth-inhibitory proteins associated with myelin and the glial scar To identify chemical compounds with the ability to overcome the inhibition of regeneration, we screened a novel triazine library, based on the ability of compounds to increase neurite outgrowth from cerebellar neurons on inhibitory myelin substrates The screen produced four "hit compounds," which act with nanomolar potency on several different neuronal types and on several distinct substrates relevant to glial inhibition Moreover, the compounds selectively overcome inhibition rather than promote growth in general The compounds do not affect neuronal cAMP levels, PKC activity, or EGFR (epidermal growth factor receptor) activation Interestingly, one of the compounds alters microtubule dynamics and increases microtubule density in both fibroblasts and neurons This same compound promotes regeneration of dorsal column axons after acute lesions and potentiates regeneration of optic nerve axons after nerve crush in vivo These compounds should provide insight into the mechanisms through which glial-derived inhibitors of regeneration act, and could lead to the development of novel therapies for CNS injury
56 citations
Cites methods from "Novel Orthogonal Synthesis of a Tag..."
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TL;DR: This work optimized the combinatorial derivatization of the triazine core using Suzuki cross-coupling and adapted this approach to polymer-supported amino acids and prepared aryl triazines with different charge distribution.
Abstract: A synthetic methodology to prepare collections of trisubstituted aryl 1,3,5-triazines with broad structural diversity via Suzuki coupling has been developed. We first optimized the combinatorial derivatization of the triazine core using Suzuki cross-coupling. Second, in order to further expand the methodology for the preparation of negatively charged triazines, we adapted this approach to polymer-supported amino acids and prepared aryl triazines with different charge distribution. With a collection of 160 aryl triazine derivatives in good purities and without any purification step, we proved the viability of this orthogonal scheme for the preparation of triazine libraries using amine/amino acid-captured solid supports and Suzuki cross-coupling.
13 citations
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TL;DR: Through an unbiased phenotypic screening for improved biofuel generation in oleaginous yeast, it is found one diaryl triazine derivative (E4) which increased the biolipid production up to 86%.
Abstract: Herein we report the solid-phase synthesis of a combinatorial aryl, alkyl-triazine library and its application to biofuel production. The combination of Grignard reactions and solid supported Suzuki coupling reactions afforded unique 120 triazine compounds with high purities and minimum purification steps. Through an unbiased phenotypic screening for improved biofuel generation in oleaginous yeast, we found one diaryl triazine derivative (E4) which increased the biolipid production up to 86%.
13 citations
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University of Gothenburg1, Université Paris-Saclay2, Paris Descartes University3, National University of Singapore4, University of Bonn5, University of Paris6, University of Southampton7, University of Antwerp8, University Medical Center Groningen9, Rockefeller University10, Hokkaido University11, UCL Institute of Neurology12
TL;DR: Several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.
Abstract: Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.
12 citations
Cites methods from "Novel Orthogonal Synthesis of a Tag..."
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References
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TL;DR: A novel high-throughput screen capable of isolating inhibitors of Abeta aggregation from large libraries of inactive candidates and confirmed that the selected compound inhibits aggregation of synthetic Abeta42 peptide.
Abstract: Aggregation of the Alzheimer's peptide Abeta produces toxic multimeric species that play a key role in the development of Alzheimer's disease. Compounds that inhibit this aggregation may prove useful as therapeutic agents for the prevention or treatment of Alzheimer's disease. Although aggregation inhibitors may already exist in combinatorial libraries, finding these compounds in a cost-effective high-throughput manner poses an enormous challenge. To meet this challenge, we have developed a novel high-throughput screen capable of isolating inhibitors of Abeta aggregation from large libraries of inactive candidates. The screen uses a fusion of Abeta42 to GFP. In the absence of inhibition, the rapid misfolding and aggregation of Abeta42 causes the entire fusion protein to misfold, thereby preventing fluorescence. Compounds that inhibit Abeta42 aggregation enable GFP to fold into its native structure and be identified by the resulting fluorescent signal. By implementing the screen on a pilot library of triazine derivatives, we have identified several putative inhibitors. One of the selected compounds was studied in detail by a series of biochemical and biophysical methods. These studies confirmed that the selected compound inhibits aggregation of synthetic Abeta42 peptide. The fluorescence-based method described here is rapid and inexpensive and can be used to screen large libraries for inhibitors of Abeta42 aggregation and/or amyloidogenesis.
164 citations
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TL;DR: The first orthogonal combinatorial synthesis of a high-purity triazine library was demonstrated and novel triazine-based microtubule inhibitors were discovered by an efficient zebrafish embryo screening and in vitro microtubules polymerization assay.
Abstract: The first orthogonal combinatorial synthesis of a high-purity triazine library was demonstrated. Novel triazine-based microtubule inhibitors were discovered by an efficient zebrafish embryo screening and in vitro microtubule polymerization assay.
163 citations
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TL;DR: The X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
Abstract: A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
153 citations
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TL;DR: A synthesis program directed toward improving the stability of imidoyl thiourea based non-nucleoside reverse transcriptase inhibitors led to the discovery of diaryltriazines (DATAs), a new class of potent NNRTIs.
Abstract: A synthesis program directed toward improving the stability of imidoyl thiourea based non-nucleoside reverse transcriptase inhibitors (NNRTIs) led to the discovery of diaryltriazines (DATAs), a new class of potent NNRTIs. The synthesis and anti-HIV structure–activity relationship (SAR) studies of a series of DATA derivatives are described.
127 citations
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TL;DR: The use of the melamine motif, a substrate of the P2 transporter, as a potential tool to selectively deliver polyamine analogues to the parasites is described and a number of compounds were shown to competitively inhibit uptake of adenosine, indicating that they are recognized by the transporter.
Abstract: The P2 transporter is a nucleoside transporter which is unique to the protozoan parasite Trypanosoma brucei, the causative organism of Human African Trypanosomasis. The transporter has been shown to bind some structural motifs not recognized by other transporters. In this paper we describe the use of the melamine motif, a substrate of the P2 transporter, as a potential tool to selectively deliver polyamine analogues to the parasites. The synthesis of a number of polyamine analogues attached to a variety of melamine analogues is described. Many of the compounds were shown to competitively inhibit uptake of adenosine, indicating that they are recognized by the transporter. Some of the compounds showed good in vitro activity against the parasites.
121 citations