Bioprecursor Prodrugs
Reduction example - Mitomycin C - Mutamycin® - Bristol
Adenocarcinoma of the stomach and
Myers
pancreas H2N
H2N
O
O
H2 N
OH
OMe
NH
N
H3 C
O
O
H
H2N
Reduction H2N
O
O
H
OMe
-OCH3
NH
N
H3 C
O
H2 N
NH
N
+
H3 C
OH
A hydroquinone electron donating
A quinone electron withdrawing
O
H
-H+
H+
OH
H2 N
H2 N
H3 C
N
NH
OH
Further alkylation
H2N
DNA
OH
DNA
O
-CO2
H3 C
OH
N
+
Electrophile
NH
-NH3
O
OH
H2 N
N
H3 C
OH
NH
Bioprecursor Prodrugs
Phosphorylation example –
H
N
O
HO
O
H
N
I
Viral Thymidine
O
Kinase
O
O
O P O
O
O
OH
Iodoxuridine - Herplex®
Allergan - lipid soluble!
Opthalmic product for
Herpes simplex keratitis
Higher affininty for viral
kinases than mammalian
kinases but some toxicity
O
I
Not lipid soluble
OH
ATP
H
N
O
O
O
O
-O P O P O P O
O
O
O
O
O
I
OH
TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporated
into DNA affording incorrect base pairing and template activity
Chemical Delivery Systems
• 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–
HO
HO
HO
CO2H
Decarboxylase
NH2
HO
NH2
Dopamine
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