Anticancer Agents/Drug Metabolism

What are some agents that inhibit DNA biosynthesis

Inhibitors for enzymes that catalyse the formation of thymine

• 5-fluorouracil

• cycloserine

• methotrexate

How does 5-fluorouracil work?

Prodrug - in vivo, it is activated by conversion to 2-deoxyfluorouridolate, then phosphorylated

Then binds to the enzyme active site irreversibly inhibiting it

How does methotrexate work?

• It is a competitive inhibitor of dihydrofolate reductase, it inhibits the reduction of dihydrofolate to tetrahydrofolate

• Tetrahydrofolate is a THF cofactor, which is essential for thymidylate, purine, and some amino acid synthesis

• Therefore, methotrexate inhibits DNA, RNA, and protein synthesis

Not useful as an antibacterial agent as it has low specificity for bacterial DHFR

Describe the structure of a microtubule

Formed of tubulin heterodimers (alpha and beta subunit)

What are vinca alkaloids

Assembly inhibitors of microtubules

They bind to free tubulin dimers and form non biologically active aggregates

e.g. vinblastine + vincristine

What do spindle poisons do

Prevent the assembly or disassembly of microtubules

How do microtubule disassembly inhibitors work

Bind to the tubulin and prevent its disassembly back into free subunits

e.g. paclitaxol - for solid tumors

What are some requirements for a drug to be orally available

1. Must be able to be formulated as a tablet/syrup

2. Must be able to survive stomach acid (pH 2.0)

3. Must have an overall neutral ionisation state to be able to cross the cell membrane

4. Must have the correct hydrophilic/hydrophobic balance (LogP)

What are Lipinski’s rules

For a compound to be orally available and show good absorption/permeation of biological tissue, it must:

1. Have a molecular weight of less than or equal to 500

2. Have a clogP of no more than 5 (mlogP less than or equal to 4.15, XlogP less than or equal to 5.7)

3. Have no more than 5 hydrogen bond donors (-OH, -NH)

4. Have no more than 10 hydrogen bond acceptors (O, N)

5. Have no more than 5 fused rings

What are exceptions to Lipinski’s rules

In general if one rule is broken the compound could still be orally active but if two are then it wont be.

If the compounds have active biological transport systems the rules are not applicable

What are phase I reactions

In the liver, the body tries to start metabolising compounds by making them more soluble so they can be excreted

In phase I, the body tries to introduce or unmask polar groups.

These reactions are catalysed by flavin mono-oxygenase enzymes, esterases, proteases or epoxidases.

What are phase II reactions

Increasing the solubility of compounds formed in phase I reactions through conjugation reactions. All increase the polarity of the molecules for excretion.

e.g. addition of a sulfate by a sulfatase enzyme, addition of a glutathione tripeptide, addition of a sugar to an OH to form a glycoside.