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Combinatorial Chemistry

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Dr. Hans Briem Einf hrung in die Arzneimittelforschung - Vorlesung WS 2000/2001 ... septum. polypropylene reactor vessels. polymer beads. filter. valve ... – PowerPoint PPT presentation

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Title: Combinatorial Chemistry


1
  • Combinatorial Chemistry

2
  • The Split-Pool Synthesis Strategy

3
  • One bead - one substance concept
  • Each bead contains only one sort of product
    (50-200 pmol concentration)
  • Product can be screened either on bead or after
    cleavage from bead
  • Single beads can be spotted in microtiter plates
    or immobilized and screened individually

4
  • How can we find the active component(s) of the
    library?
  • Deconvolution (iterative or parallel)
  • Microsequencing
  • Tag-based encoding methods

5
Iterative Deconvolution
6
Parallel Deconvolution (Positional Scanning)
7
Microsequencing of peptides by Edman degradation
8
Tag-based encoding methods
Encoding principle
  • each individual bead contains an encoding tag
  • each tag uniquely encodes the building blocks
    on the bead

Encoding tags in use
  • DNA (analysis by PCR)
  • Peptides (analysis by Edman degradation)
  • Haloaromatic groups (suitable for "binary code")
  • Secondary amides (suitable for "binary code")
  • Radiofrequency transponders

9
Chemical encoding tags for solid-phase synthesis
10
Example of chemical "binary code" (taken from
Ohlmeyer et al. PNAS 90, 1993, 10922-10926)
Binary translation table Ser (S) 001 Ile
(I) 010 Lys (K) 011 Leu (L) 100 Gln (Q)
101 Glu (E) 110 Asp (D) 111
Sequence E Q K L I
S Binary Code 110 101 011 100 010 001
Tags T18 ... T1
"1" in binary code means "tag is present" "0" in
binary code means "tag is absent"
Peptide Sequence E Q K L I S Tag
Sequence T18 T17 T15 T13 T11 T10 T9 T5 T1
11
Tag analysis by electron capture GC (taken from
Ohlmeyer et al. PNAS 90, 1993, 10922-10926)
12
Encoding by Radiofrequency chips
  • Synthesis by Spit-and-Pool principle
  • Polymer beads are located in a microreactor
    vessel
  • Each microreactor vessel contains one
    semi-conductor chip
  • Unique radiofrequency signals can be recorded
    and detected

13
IRORI Kan - , Chiron Pin Technology
14
Biopolymers used in Combinatorial Chemistry
vinyl. Sulfonyl- peptides
Peptides
vinyl. Peptides
Peptoids
Oligo-carbamates
Oligosulfones
Oligo- ureas
Oligosulfoxides
15
Phage-display libraries
  • Bacteriophages can produce desired peptides
  • DNA which encodes peptides is inserted in phage
    genome

DNA
16
  • Non-polymeric combinatorial libraries
  • Since biopolymers are often not "drug-like",
    efforts have been made to synthesize single,
    "drug-like" molecules combinatorially
  • Solid-phase or solution phase synthesis is
    possible for a wide variety of organic reactions
  • Automation support synthesis

17
  • Some examples...

18
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20
  • Automation

21
Solid phase-combinatorial chemistry to prepare
single compounds
22
Schematic representation of a reaction block for
solid-phase synthesis
23
Solution-phase combinatorial chemistry
24
Automation I
Synthesis robot for solid-phase chemistry A
Reactor block B/C Reagent supplies D Robot
arm with pipetting needles
25
Automation II
Reactor block for solid or solution phase
synthesis A Reaction vessels B Teflon
device C Pipetting needles
26
Automation III
"Igel" multipipetting synthesizer for solution
phase chemistry
27
  • Combinatorial Chemistry is more than just large
    numbers!
  • systematic variation of substituents on a
    common template
  • is a key feature of combinatorial chemistry

28
  • The systematic variation of substituents
  • is ideally suited to explore SAR patterns of
    hits found
  • in combichem libraries

Variations in R1
Variations in R2
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