The Resurgence of CombiChem Technologies
10 Nov 2014
The generation of large diverse libraries of new compounds from defined building blocks for screening, known as ‘combinatorial chemistry’, is a key part of the drug discovery process. Two recent studies in Nature Chemistry provide examples of 'modern combichem' and describe the products and techniques used to combine the features of natural product biosynthesis into the creation of compound libraries.
Both methods described in these papers rely on minimal purification of their compound mixtures, and do not separate the compounds produced before assaying them for activity. Both combinatorial systems have a mechanism to determine which compounds in the assay mixture are active, without the need for separation. This is very important for downstream processing and scale-up.
Synthetic fermentation
The paper, by Yi-Lin Huang and Jeffrey Bode, describes how amide-forming ligation chemistry, described as ‘synthetic fermentation’, can be adapted to combinatorial ends for drug discovery. It demonstrates the preparation of a 6,000-member library from 23 simple precursors using several medicinal chemistry techniques. The ease of running these catalytic reactions without enzymes, allows for defined mixtures of compounds to be produced well-by-well in a screening plate for use directly in downstream screening processes. With the use of these techniques and the many different starting materials available, a library as large as 30,000 compounds could be produced greatly increasing the number of possible products for screening.
Reaction pathways
The other paper, from George Karageorgis, Stuart Warriner and Adam Nelson, uses deliberate variations in reaction pathways, exploiting the multiple reactivity of a natural α-diazo amide group. Different reaction conditions, created by using different concentrations of the starting material, produced a range of structures, and as in the amide ligation work, defined mixtures are produced in each well of a screening plate. This is another example of classic medicinal chemistry driving on compound activity, but this process combines combinatorial reaction discovery with ligand discovery.
Medicinal chemistry
In both papers, the medicinal chemistry techniques are similar. Thin layer chromatography and flash layer chromatography were performed on SiliCycle SiliaFlash® F60 (40-63 µm, 60 Å). NMR Spectra of the compounds was measured using Bruker Biospin Avance or Bruker Biospin AV spectrophotometers. High-resolution mass spectra and MS/MS spectra were measured using the Bruker Daltonics maXis ESI-QTOF or Bruker SolariX ESI/MALDI-FTICR. Analytical LC/MS was performed on a Dionex UltiMate 3000 RSLC or Agilent 1200 series LC system.
A combination of these two aqueous, no-workup combinatorial chemistry methodologies, using discretely analyzed and ordered compounds that can be sent down different synthetic pathways by varying the reaction conditions, is the perfect set-up to complement automated drug discovery.
References
Nature Chemistry, doi:10.1038/nchem.2074
Nature Chemistry, doi:10.1038/nchem.2034
Nature Chemistry, doi:10.1038/nchem.2048
Related Products
Request Quote for All Products
Metal Scavengers and Organic Scavengers – SiliaMetS® & SiliaBond®
SiliCycle Inc.SiliCycle is a pioneer in metal and organic scavenging solutions. We have nearly two decades of know-how in silica-grafting and scavenging technologies, and the broadest portfolio of scavengers.The removal of post-reaction residues has become a major issue in the pharmaceutical industry, among others. Purification of APIs by traditional methods (chromatography, activated carbon, distillation, etc.) often leads to problems such as high costs, time loss, low efficiency and reduced final yields. To overcome these drawbacks, SiliCycle has developed two families of scavengers that have significantly improved how chemists purify APIs: SiliaMetS Metal Scavengers and SiliaBond Organic Scavengers. The backbone of all those products is SiliCycle SiliaFlash® F60 (40-63 µm, 60 Å) which provides superior performance for all types of applications, due to its narrow particle size distribution and exceptional purity. What's more, we can provide different particle sizes or pore diameters on a custom basis.SiliCycle’s quality is famous and recognized, proven by countless applications and patents in literature. With our strong, extensive and confidential team of experts, your projects are in the best possible hands. SiliaMetS, your Metal Scavenging Final Solution Highly selective and cost-effective alternative for metal removal Expert team to help you consider every parameter: metal catalyst, solvent, residual reagent, by-products, structure of the API, temperature… Kits available for initial screenings. No leaching (no contamination). High selectivity (total recovery of the API). Wide range of metal species scavenged. Fast kinetics even at r.t. for maximal time-savings. Excellent stability (thermally and mechanically). New technologies compatibility (flow chemistry, microwave). Available both in Bulk or Fixed Bed (SPE or Flash cartridges) Mode. SiliaBond, your Best Bet for Removing Unwanted Organic Impurities and PGIs: Designed to react and bind a very large array of excess reagents and by-products High selectivity (total recovery of the API) Kits available for initial screenings Great for purification of potentially genotoxic impurities (PGI) Eliminates tedious post-reaction purifications Available both in Bulk for direct trapping or in SPE cartridges for the so-called “catch-and release” method Electrophile and Nucleophile Scavengers available Large team of experts always available to help you develop the best experimental conditions
AVANCE 1000
Bruker BioSpin launches a breakthrough one Gigahertz Ultra-High Field AVANCE 1000 MHz NMR spectrometer. Incorporating a record-breaking 23.5 Tesla standard-bore (54 mm) superconducting NMR magnet, the AVANCE 1000 MHz NMR spectrometer, brings one Gigahertz technology to NMR research. AVANCE 1000 MHz NMR Spectrometer with the first 1 GHz CryoProbe installedThe high field strength and high field stability in combination with the first 5 mm triple-resonance CryoProbe enables unique 1 GHz NMR applications. Bruker is proud to be able to equip researchers with such an outstanding instrument that will helpto push the frontiers in biochemistry, structural biology and other molecular research. The first Avance 1000 system was delivered to the new ‘Centre de RMN à Très Hauts Champs’ in Lyon, France in July 2009. Bruker BioSpin has successfully completed installation in November 2009. The AVANCE 1000 now offers unparalleled research opportunities, both to CRMN and to other National and European scientists who will access the unique facility.
Agilent Analytical HPLC Systems
Agilent TechnologiesWhether you need assistance with your daily HPLC routines, confidence in your HPLC results, protection for your HPLC investments, or support for your sustainability goals, Agilent HPLC & UHPLC products can help achieve your lab's HPLC objectives both today and tomorrow.