1. Patrick: An Introduction to Medicinal Chemistry 5e ANTICANCER AGENTS
Chapter 21
ANTICANCER AGENTS
MATRIX METALLOPROTEINASE INHIBITORS
modfied

2. 1. Matrix metalloproteinases
Notes
Zinc-dependent enzymes
Play an important role in metastasis
Destructive enzymes
Play a role in the breakdown, normal turnover and remodelling of the extracellular matrix
Play a role in releasing VEGF from storage depots in extracellular matrix
Four types - collagenases, gelatinases, stromelysins and membrane type

3. 1. Matrix metalloproteinases
Reaction catalysed by collagenases
Wiggly lines removed
Notes
Proteins are substrates for these enzymes
Enzyme hydrolyses the peptide bond between glycine and isoleucine

4. 1. Matrix metalloproteinases
Binding interactions
Wiggly lines removed
Notes
Zinc ion interacts with the susceptible carbonyl oxygen
Activates the peptide bond for hydrolysis
NH of the susceptible peptide forms a hydrogen bond to alanine
Bridging water molecule present between zinc cofactor and glutamate residue
Bridging water acts as a nucleophile for hydrolysis
Bridging water is activated by glutamate and zinc

5. 2. Matrix metalloproteinase inhibiters
Notes
Potential agents for inhibiting angiogenesis and metastasis
First-generation inhibitors are based on the structure of the substrate
Susceptible peptide bond is replaced with a stable transition-state isostere
Hydrophobic substituents are present to fit the enzyme subsites
Substituents mimicking P1’ or P2’ (right-hand side inhibitors) are better than substituents mimicking P1 or P2 (left-hand-side inhibitors)
Functional group(s) are included to form H-bonds with the enzyme backbone
A group is included to form a strong interaction with the zinc ion cofactor
Zinc ligands commonly used - thiol, carboxylate or hydroxamic acid
First-generation

6. 2. Matrix metalloproteinase inhibiters
Marimastat
Transition-state
isostere
t-Butyl group
Hydroxamic acid
Notes
Orally active synthetic compound
Undergoing phase III clinical trials for breast and prostrate cancer
Hydroxamic acid acts as the zinc ligand
Hydroxymethylene group acts as the transition-state isostere
Isostere replaces the NH of the previously susceptible peptide bond
Hydroxyl group of the isostere is good for aqueous solubility

7. 2. Matrix metalloproteinase inhibiters
Marimastat
Transition-state
isostere
t-Butyl group
Hydroxamic acid
Notes
t-Butyl group acts as a steric shield to protect N-terminal amide from hydrolysis
t-Butyl group desolvates peptide bonds
No desolvation penalty for binding

8. 2. Matrix metalloproteinase inhibiters
Marimastat - binding interactions
P1’
P2’
P3’
HBD
Notes
Three hydrophobic substituents fit enzyme sub pockets
Substituents bind using van der Waals interactions
Hydroxamic acid acts as a bidentate ligand for zinc
Hydroxamic acid NH acts as a hydrogen bond donor
The alcohol group is good for activity and solubility
The alcohol group is directed away from the protein surface and forms a hydrogen bond to water

9. 2. Matrix metalloproteinase inhibiters
BMS
Thiol
Hydantoin ring
Right-hand
Sub pockets
Notes
Thiol group acts as a zinc ligand
Substituents (P1-P3’) fit four enzyme sub pockets
Right-hand half is identical to marimastat

10. 2. Matrix metalloproteinase inhibiters
Design aims for second-generation inhibitors
Reduce or eliminate peptide character
Increase selectivity
Decrease side effects
Increase aqueous solubility
Increase resistance to peptidases in gastrointestinal tract

11. 2. Matrix metalloproteinase inhibiters
Second-generation inhibitors
CGS 27023A
Steric shield
Notes
Hydroxamic acid acts as a zinc ligand
Two substituents fit enzyme sub pockets
Decreased peptide character
Lack of selectivity
Isopropyl group acts as a steric shield
Thought to protect hydroxamic acid from metabolism

12. 2. Matrix metalloproteinase inhibiters
Second-generation inhibitors
Pyridine
CGS 27023A
Prinomastat
Rigidification
Prinomastat
Steric shield
Notes on prinomastat
Isopropyl substituent is incorporated into a ring - rigidification
Less conformations are available
Results in increased activity
Pyridine ring allows extra binding interactions - extension strategy

13. 2. Matrix metalloproteinase inhibiters
Second-generation inhibitors
Zinc ligand
BAY
Notes
The carboxylate group acts as the ligand for the zinc ion
Entered clinical trials