combinatorial chemistry. synthesis of many structures (diversity) combinatorial technology,...
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Combinatorial Chemistry
• Synthesis of many structures (diversity)
•• combinatorial technology, combinatorial library molecular diversity
What is Combinatorial Chemistry?
A synthetic strategy which leads to a large set of compounds.
• Product of matrix chemistry (systematic synthesis)
• Automation of synthesis (speed)
Why do we need Combinatorial Chemistry ?Why do we need Combinatorial Chemistry ?
1. From New Drug discovery --- biodiversity drug design
2. From Genome Project --- post-Genome Era more new drug targets
GenomeProject
TargetIdentification
Lead Search Development
Issues : ! Human Diversity ----- Customized Drug ! Possible Targets ----- Too many
Solutions for Lead Compound Search :1. Existing Sample collection : a. Natural Sources scarce
b. Drug Design lead to homogeneous & specific sets of compounds.2. De Novo Design
Too many unexpected & complicated synthesis
3. Combinatorial Chemistry
Drug Development of 21st Century
Drug-like Compounds
How Many We Want from Combinatorial Chemistry
possible combination of drug like compounds : ~ 1063 -64
synthesizable number of compounds : ~ 10 24
Practical number of compounds in a library : 106 with design < 103 with virtual screening , virtual library
Solution (?) -- Combination of Design & Informatics
’70 : Natural Products ’80 : Rational Design
’90 : Combi. Chem.& HTS
’00 : Information Guided Design
Rational Design
Diverse Design
Serendipity
100
106
1013
( immune system)
Paradigm Shift of Drug Development
1. Nature does it all the time. -- can we mimic mother nature ?
2. Are there ways to automate the synthesis ?
-- Immune System –Molecular Diversity
-- Peptide synthesizer : 40 min./cycle-- DNA synthesizer : 1.5 min./cycle
3. Are there ways to generate many compounds at a time ?
Combinatorial Chemistry
Combinatorial Chemistry
-- Peptide synthesizer : 40 min./cycle-- DNA synthesizer : 1.5 min./cycle
Solid Phase Organic Synthesis
•• solid phase synthesis : needs optimization for every new reaction •• Time required to develop a combinatorial chemistry : 6 - 24 months :
•• Size of the combinatorial library Purpose of the library
: General Library Lead Search SAR Construction Target Area
1. Mixture Library
a. SELEX -- nucleotide library --- 4n
b. Positional scanning -- peptide library --- 20n
c. Phage Display -- peptide library --- 108
d. Split- mix method ( bead tech.) -- general
e. simple mixture
Combinatorial Chemistry : Strategy
SELEX(Systematic Evolution of Ligands by Exponential Enrichment)
2. Matrix Library
a. Pin Technology
b. Chip Technology
c. Parallel Array synthesis
Combinatorial Chemistry : Strategy
Multicomponent Reaction
1. Passerini reaction
R1 COOH + R2 CO + R4 N=CR3 R1 O
HNR4
O
O
R2 R3
R1 COOH + R2 CHO + R3 NH2 R1 N
HNR4
O
O
R2
+ R4 N=C
R3
2. Ugi reaction
R1 COOH + R2 CHO + R3 NH R1 NNR4
O
O
R2
+ R5 N=C
R5R4
R3
Multicomponent Reaction
3. Hantzsch reaction
+ NH3 +R1COOR2
O
R3X
O
NH
R3 R1
COOR2
+ NH3 R3 CHO+R1
COOR2O
NH
R3
R1 R1
COOR2R2OOC