Reduction example - Mitomycin C - Mutamycin® - Bristol Myers Adenocarcinoma of the stomach and pancreas

N

O

O

NH2

CH3

O

NH2O

NH

OMeH

A quinone - electron withdrawing

-H+

-CO2

-NH3

Electrophile

DNA

NH2

CH3NHN

OH

OH

N

NH2

CH3

O

NH2O

NH

H

+

NH2

CH3

O

NH2O

NHN

OH

OH

H+

-OCH3

N

OH

OH

NH2

CH3

O

NH2O

NH

OMeH

A hydroquinone - electron donating

Reduction

DNA

NH2

CH3NHN

OH

OH+

Further alkylation

Bioprecursor Prodrugs

Phosphorylation example–

O

NH

O

O

I

OH

OPO

O

O

Viral Thymidine

KinaseO

NH

O

O

I

OH

OH

Iodoxuridine - Herplex®

Allergan - lipid soluble!Opthalmic product forHerpes simplex keratitisHigher affininty for viralkinases than mammaliankinases but some toxicity

O

NH

O

O

I

OH

OPO

O

O

POP-O

O

O

O

O

TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporated into DNA affording incorrect base pairing and template activity

ATP

Not lipid soluble

Bioprecursor Prodrugs

• We have already seen 2 examples of this:– Sulfasalazine – an azo compound– Methenamine – An urinary antibacterial agent

• Requirements– Prodrug reach the site of action in high concentrations– Knowledge of high metabolism at site– Other factors

• Extent of organ or site perfusion• Information on the rate of prodrug conversion to the active form at

both target and non-target sites• Rate of input/output of prodrug from the target site

• Limit side effects and increase effectiveness

Chemical Delivery Systems

Types of carriers that have been used– Proteins

– Polysaccharides– Liposomes– Emulsions

– Cellular carriers (erythrocytes and leukocytes)– Magnetic control targeting

– Implanted mechanical pumps

What is the Basic Goal?– Protect a non-specific biological environment from a drug– Protect a drug from a non-specific biological environment

– Especially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents

Chemical Delivery Systems

• The ideal situation:– Prodrug readily transported to the site of action– Prodrug is rapidly absorbed at the site– Selective and rapid conversion to the active drug – Kidney and Liver are easy targets due to high perfusion and

high metabolic rates• Other tissue sites can be problematic for the same reasons

– Drug migrate slowly (site of action to a site of excretion)– Ideal situation is VERY complex to achieve

• Example: Methenamine– the lower the pH, the faster the rate of formaldehyde formed– blood pH 7.4 therefore, little formaldehyde formed

Chemical Delivery Systems

Example: Cancer Chemotherapy– Tumor cells have a much higher growth fraction

– This translates into higher enzymatic activity that can be exploited

– Target a prodrug to these sites and exploit higher enzyme activity

Example: L-Dopa or Levodopa – Anti-Parkinsonism agent – Larodopa® – Roche and Dopar® - Procter & Gamble

– Brain has a specific transport system for L-amino acids

– Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects

OH

OH

NH2

CO2H OH

OH

NH2

Decarboxylase

Dopamine

Chemical Delivery Systems