Chem167_L12_May14

Excess reagents can be used to drive the reacon

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Unformatted text preview: library Please read: High throughput screening (HTS) •  Came first, before combichem •  Easy to test many compounds, therefore mo/vated strategies to enumerate compounds to test •  Full circle: combichem so good that now we are back to making HTS even more HT, more efficient Combichem •  Combinatorial libraries can synthesize and test mixtures of compounds or synthesized and tested in parallel Solid phase techniques •  Reac/ons carried out on solid support, eg resin bead Ester forma/on Solid phase advantages •  A range of star/ng materials can be bound to separate beads and mixed à༎ all the star/ng materials can be subjected to the next rxn •  The beads / constructs can be washed to remove excess reagents or byproducts •  Large amounts of excess reagents can be used to drive the reac/on •  Intermediates in a rxn are bound to the bead and do not need to be purified •  Allows individualized product analysis per bead •  Can be automated Bead – Linker – synthesis Bead is not an impenetrable marble; it is a polymer that breathes and “swells”, allowing access to interior func/onal groups for chemistry The linker is the unit covalently aYached to the bead / polymer chain cons/tu/ng the solid support - contains a reac/ve func/onal group with which the star/ng material in the proposed synthesis can react - must be stable and yet, easy to cleave, to enable product release There are lots of different linker types Good for pep9de synthesis Wang resin N- protected amino acid linked to resin via ester link Remains stable over pep/de synth steps Cleaves with trifluroace/c acid (TFA) Ques9on: You want to synthesize all the possible dipep/des of 5 different amino acids How many reac/ons would you need to carry out to do this using tradi/onal chem? 25: GAFVS GG, GA, GF, GV, GS, AG, AA, AF, AV, AS,… Split and mix Designed to produce a mixture of products in each reac/on vessel Same 5 amino acid dipep/de experiment can yield 25 dipep/des in 5 mixtures These strategies are used to make VERY LARGE LIBRARIES OF COMPOUNDS (1k – 10k per library) Photolithography Miniaturiza/on & spa/al resolu/on Products made on plate of immobilized solid support Nitroveratryloxycarbonyl (NHX) protec/ng group (photolabile) Light removes the NVOC/NHX Treatment with protected aa Coupling reac/on only occurs where light has deprotected constructs Incuba/on of plate with fluorescent tagged receptor enables easy detec/on of ac/ve compounds Strategizing: Basic scaffolds More basic scaffolds Which is “tadpole’- like? Which...
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