Design and Synthesis of a Heterocyclic Compound Collection for Probing the Spatial Charactistics of ATP Binding SitesPresented at the CSIR Conference Centre

CSIR Biosciences

C.P. Kenyon, P.M. Matlaba, C.J. Parkinson, A.L. Rousseau

and C.W. van der Westhuyzen

February 28, 2006

Slide 2 © CSIR 2006 www.csir.co.za

• The kinases

• The nature of the ATP site

• A basis for selectivity

• Types of potential guest molecules

• Methodology for preparation

Slide 3 © CSIR 2006 www.csir.co.za

The Kinases• Proteins which transfer phosphoryl residues

• Utilise ATP as phosphate source

• All have an ATP site

• Why are kinases attractive targets?

Slide 4 © CSIR 2006 www.csir.co.za

Basic Structural Characteristics of the ATP Site

Typical ATP binding site

SugarBindingRegion

N

N N

N

N

O

OH OH

OPO

PO

PO-

O O -O

-O O- O

Mg2+

Mg2+

-O O

H2N O

H H

OHN

N H

Slide 5 © CSIR 2006 www.csir.co.za

Pharmaceutical example: Interactions of SB203580 in the p38 MAP Kinase

Slide 6 © CSIR 2006 www.csir.co.za

Rational Basis of Design

Slide 7 © CSIR 2006 www.csir.co.za

Scaffold Selection

N

N

N

N

N

N

N

N

NN

N

X

Pyrimidines Purines Imidazopyridines

Slide 8 © CSIR 2006 www.csir.co.za

Spatial Comparison of Scaffolds

Slide 9 © CSIR 2006 www.csir.co.za

Pyrimidines and Purines

N

N

N

N

N

N

N

N

N

Slide 10 © CSIR 2006 www.csir.co.za

Synthesis of Pyrimidines and Purines

N

N

Cl

Cl

N

N

NHR'

Cl

N

N

NHR'

Cl

NO

N

N

NHR1

NH2

NHR2

N

N N

N

NHR1

R2

N

N N

N

NHR2

R1

+

Slide 11 © CSIR 2006 www.csir.co.za

N

N

Cl

Cl

N

N

Cl

NH

N

N

Cl

NH

Ph

N

N

Cl

NH

OH

N

N

Cl

NH

CO2Me

Ph

N

N

N

NH

NO

N

N

N

NH

NO

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

Ph

N

N

N

N

N

Ph

N

N

N

NH

Ph

NO

N

N

N

NH

Ph

NO

N

N

N

NH

OH

NON

N

N

NH

OH

NO

Slide 12 © CSIR 2006 www.csir.co.za

Imidazopyridines

N

N

X

Slide 13 © CSIR 2006 www.csir.co.za

The Classical Approach

N

NH2

O

Cl

+

N

N

Cl

N

N

Slide 14 © CSIR 2006 www.csir.co.za

Diversity Orientated Approach

N

NH2

N

N RRCHO

R'

N

N

NR

NHR'

Slide 15 © CSIR 2006 www.csir.co.za

A l d e h y d e I s o c y a n i d e

N

N

N

NO

N

CHO

N

NP h

NH

7 2 %

N

NP h

NH

6 0 %

N

NP h

NH

N

O 1 4 %

N

NP h

NH

7 8 %

N

CHO

N

N

NH

N

5 4 %

N

N

NH

N

5 7 %

N

N

NH

N

O

N

2 0 %

N

N

NH

N

5 9 %

OCHO

N

N

NH

O

2 5 %

N

N

NH

O

6 0 %

N

O

N

N

HN

O

2 6 %

N

N

NH

O

7 3 %

CHO

H 3 CO

N

N

HN

OC H 3

4 8 %

N

N

HN

OC H 3

2 2 %

N

O

N

N

HN

OC H 3

2 0 %

N

N

HN

OC H 3

4 2 %

Slide 16 © CSIR 2006 www.csir.co.za

N

N

NH

N

O

NN

N

NH

O

Slide 17 © CSIR 2006 www.csir.co.za

The Way Ahead

Explore the untapped dimensionKinase and ATP –ase studies

Thanks To………

CSIR Thematic Programmes

Department of Science and Technology