ABSTRACT
Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.
Subject(s)
Antineoplastic Agents , Drug Delivery Systems , Gene Expression Regulation, Leukemic/drug effects , Leukemia , Neoplasm Proteins , Transcription Factors , Transcription, Genetic/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HEK293 Cells , Humans , K562 Cells , Leukemia/drug therapy , Leukemia/genetics , Leukemia/metabolism , Leukemia/pathology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.
ABSTRACT
Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1), a neurotensin receptor-1 antagonist, with its machine-assisted flow chemistry alternative. By using these enabling tools, combined with solid-supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.
Subject(s)
Pyrazoles/chemical synthesis , Quinolines/chemical synthesis , Receptors, Neurotensin/antagonists & inhibitors , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacologyABSTRACT
The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R(1) = 2-methyl-5-nitrobenzyl, R(2) = H).
ABSTRACT
This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.
ABSTRACT
Here we describe general flow processes for the synthesis of alkyl and aryl azides, and the development of a new monolithic triphenylphosphine reagent, which provides a convenient format for the use of this versatile reagent in flow. The utility of these new tools was demonstrated by their application to a flow Staudinger aza-Wittig reaction sequence. Finally, a multistep aza-Wittig, reduction and purification flow process was designed, allowing access to amine products in an automated fashion.
Subject(s)
Amines/chemical synthesis , Azides/chemical synthesis , Imines/chemical synthesis , Organophosphorus Compounds/chemistry , Alkylation , Molecular StructureABSTRACT
Having demonstrated in the preceding publication the flow synthesis of aryl azides, we describe here a general protocol for the in-line purification of these versatile intermediates. As part of this investigation, we evaluated the use of ReactIR 45m as a tool for real-time detection of hazardous azide contaminants. This azide synthesis and purification process was then incorporated into a multistep flow sequence to generate a small collection of 5-amino-4-cyano-1,2,3-triazoles directly from aniline starting materials in a fully automated fashion.
ABSTRACT
In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.
Subject(s)
Casein Kinase I/antagonists & inhibitors , Combinatorial Chemistry Techniques/instrumentation , Protein Kinase Inhibitors/chemical synthesis , Pyridazines/chemical synthesis , Combinatorial Chemistry Techniques/methods , Equipment Design , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyridazines/chemistryABSTRACT
The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
Subject(s)
Azides/chemistry , Carbamates/chemical synthesis , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Urea/chemical synthesis , Carbamates/chemistry , Carboxylic Acids/chemistry , Equipment Design , Mass Spectrometry/instrumentation , Mass Spectrometry/methods , Molecular Structure , Sensitivity and Specificity , Stereoisomerism , Urea/analogs & derivatives , Urea/chemistryABSTRACT
The preparation and use of an azide-containing monolithic reactor is described for use in a flow chemistry device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.