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