NATURAL PRODUCTS (AC PART 3)

- Epipodophyllotoxins
- Camptothecins
- Vinca Alkaloids
- Taxanes

Examples of Natural Products

Epipodophyllotoxins

They are semisynthetic derivatives of podophyllotoxin.

Mayapple (Mandrake) Root

The natural source from which podophyllotoxin is isolated.

Inhibitor of microtubule function.

The original mechanism of action of podophyllotoxin before chemical modification.

Inhibition of topoisomerase enzymes.

The different mechanism of action that resulted from chemical modification of podophyllotoxin to create epipodophyllotoxins.

Removal of the 4’-methyl group of podophyllotoxin.

The specific chemical modification to podophyllotoxin that led to the change in its mechanism of action.

Addition of the glycosidic portion of the molecules.

Another significant alteration made to podophyllotoxin.

Oxidative-O-dealkylation

The specific metabolic reaction that occurs to one of the methoxy groups in epipodophyllotoxins.

Catechol analogs

The analogs formed after the CYP3A4-mediated oxidative-O-dealkylation of epipodophyllotoxins.

They are more potent than the parent molecules.

How the potency of the catechol analogs compares to the parent epipodophyllotoxin molecules.

Quinones

The compounds that may be formed from the further oxidation of catechol analogs?

Topoisomerase II

The enzyme that Etoposide acts upon.

It stabilizes the cleavable complex to single and double- strand breaks.

How Etoposide affects the topoisomerase II-DNA complex.

Apoptosis

The cellular process that is activated if enough DNA breaks are initiated by Etoposide.

- S Phase
- G2 Phase

Etoposide are considered cell cycle specific and act in what specific phase?

Topoisomerase I

The enzyme inhibited by camptothecins.

Treatment of various cancers

The general clinical use of camptothecins.

Camptothecin

The lead drug for the camptothecins class of agents.

Camptotheca acuminata

The natural source from which camptothecin was isolated.

Catharanthus roseus (Periwinkle)

The natural source from which vinca alkaloids are extracted.

Hypoglycemic properties

The original property for which vinca alkaloids were investigated.

Antineoplastic actions

The type of action later discovered for vinca alkaloids.

- Catharanthine Moiety
- Vindoline Moiety

Main moieties that compose the vinca alkaloids.

Indole subunit

The specific subunit contained within the catharanthine moiety of vinca alkaloids.

Dihydroindole subunit

The specific subunit contained within the vindoline moiety of vinca alkaloids.

Carbon–Carbon Bond

How the catharanthine and vindoline moieties are joined in vinca alkaloids.

Microtubules

- The main component of the mitotic spindle.
- Function as part of the cell’s cytoskeleton.
- Important in maintaining cellular shape.
- They are also involved in transport within the cell and cell signaling as well as playing a pivotal role in the movement of chromosomes during mitosis.

Tubulin

What vinca alkaloids bind to once inside the cell.

Disruption of the formation and function of the mitotic spindle.

The consequence of vinca alkaloids binding to tubulin.

M Phase

The cell cycle phase for which vinca alkaloids are considered specific.

Taxanes (Taxol or Paclitaxel)

Discovered in the 1960s as part of a large-scale screening program on plant extracts conducted by the National Cancer Institute.

Taxanes bind to tubulin at a site distinct from the vinca alkaloids.

How the binding site of taxanes on tubulin compares to that of the vinca alkaloids.

- Treadmilling
- Dynamic Instability

What specific process does taxanes inhibits?

M phase, when microtubule dynamics are undergoing the greatest change.

The cell cycle phase in which cells are most affected by taxanes and the reason why.